Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate.

Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting approximately 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.

Early experience with bridging stent graft deployment without sheath support in branched and fenestrated endovascular aortic repair.

OBJECTIVE: To assess the early experience with modified version of simplified bare-wire target vessel (SMART) technique, implying delivery of bridging stent grafts without historically established sheath support, and to compare its outcome to standard endovascular aortic repair procedures with fenestrated/branched devices. METHODS: A retrospective analysis of 102 consecutive patients treated with fenestrated/branched devices from January 2020 to December 2022 was undertaken. The study population was divided into three groups-a sheath group (SG), SMART group, and nonsheath group (NSG). Primary end points were radiation exposure (dose-area product), fluoroscopy time, dose of contrast agent, operation time, and incidence of intraoperative target vessel (TV) complications and additional procedures. Freedom from secondary TV related reinterventions at the three follow-up phases were defined as secondary end points. RESULTS: A total of 183 TVs (38.8% visceral arteries [VA]; 56.3% renal arteries [RA]) in the SG, 36 TVs (44.4% VA, 55.6% RA) in the SMART group, and 168 TVs (47.6% VA; 50% RA) in the NSG were accessed. The mean number of fenestrations and bridging stent grafts was equally distributed in all three groups. The SMART group only included cases treated with fenestrated devices. The dose-area product was significantly lower in the SMART (median, 203 Gy × cm2; interquartile range [IQR], 179-365 Gy × cm2) and NSG (median, 340 Gy × cm2; IQR, 220-651 Gy × cm2) groups vs the SG (median, 464 Gy × cm2; IQR, 267-871 Gy × cm2; P = .007). Operation time was also significantly lower in the NSG (median, 265 minutes; IQR, 221-337 minutes) and SMART (median, 292 minutes; IQR, 234-351 minutes) groups vs the SG (median, 326 minutes; IQR, 277-375 minutes; P = .004), respectively. Intraoperative TV-related complications were most frequently observed in the SG (9/183 TVs; P = .008). CONCLUSIONS: This study reports the outcomes of three currently available TV stenting approaches. Previously reported SMART technique, and its modified version (NSG) proved to be a safe alternative to historically established TV stenting technique with sheath support (SG).

Monoplane versus biplane fluoroscopy in patients undergoing fenestrated/branched endovascular aortic repair.

OBJECTIVE: Endovascular aortic repair (EVAR) with fenestrated (F-EVAR) or branched (B-EVAR) endografts represents an indispensable tool of modern patient care in vascular surgery. The purpose of this retrospective study was to evaluate the center's initial experience of F/B-EVAR procedures performed under biplane angiography guidance compared with a historical control group. METHODS: From January 2020 to March 2022, 80 consecutive patients underwent F/B-EVAR under general anesthesia at a single institution. As from January 2021, the deployment of complex stent grafts was performed using an alternative intraoperative imaging modality-a biplane fluoroscopy and angiography. The cohort was divided into monoplane (MPA) and biplane (BPA) groups according to the imaging modality applied. The end points were operation time, fluoroscopy time, radiation exposure, dose of contrast agent, and technical success. RESULTS: The MPA group included 59 patients (78% male; median age; 74 years; interquartile range [IQR], 66-78 years) and the BPA group 21 patients (85.7% males; median age, 75 years; IQR, 69-79 years). Operation time (median, 320 minutes; IQR, 266-376 minutes) versus (median, 275 minutes; IQR, 216-333 minutes) was significantly lower in the BPA group (P = .006). The median fluoroscopy time (median, 82 minutes; IQR, 57-110 minutes vs median, 68 minutes; IQR, 54-92 minutes), contrast agent volume applied (median, 220 mL; IQR, 179-250 mL vs median, 200 mL; IQR, 170-250 mL), and radiation dose (dose-area product, median, 413 Gy × cm2; IQR, 249-736 Gy × cm2; vs median, 542 Gy × cm2; IQR, 196-789 Gy × cm2) were similar in both groups. Technical success of 96.6% (57/59 cases) versus 100% (21/21 cases) could be achieved in MPA and BPA group, respectively. CONCLUSIONS: F/B-EVAR procedures performed under BPA guidance were associated with a significant decrease in operation time.

Endovascular Repair of Penetrating Thoracic Aortic Ulcers Using Tubular Stent Grafts Versus Stent Grafts With a Proximal Scallop.

PURPOSE: In penetrating aortic ulcers (PAUs), limited data support tubular thoracic endovascular aortic repair (TEVAR) as a viable treatment option. For treatment of more proximal PAUs, hybrid approaches and-more recently-scalloped TEVAR (scTEVAR) have been advocated. Outcomes of scTEVAR specifically for PAUs have not yet been reported. This study reports long-term outcomes for tubular and scTEVAR in PAUs and compares the safety profile in both cohorts regarding the significantly more proximal landing zone (LZ) for scTEVAR. MATERIALS AND METHODS: This single-center retrospective cohort study includes all nonacute patients treated for complicated PAU with scTEVAR and tubular TEVAR. Patient and PAU characteristics as well as procedural success, complication and reintervention rates, and all-cause and aortic mortality were analyzed. RESULTS: Of 212 TEVAR procedures reviewed, 21 patients with tubular TEVAR and 19 patients with scTEVAR were included. Patient and PAU characteristics were similar, and LZ was significantly more proximal in the scTEVAR cohort (p=0.0001), with similar number and types of supra-aortic revascularization procedures. Clinical success was reached in all 40 patients (100%), and reintervention rate was 2/21 (9.5%) and 1/19 (5.3%), respectively. Over the mean follow-up of 63 (TEVAR) and 53 (scTEVAR) months, clinical success was stable in all patients with one (abdominal) aortic-related mortality in the scTEVAR cohort. CONCLUSION: Treatment of complicated PAUs with TEVAR as well as scTEVAR provides excellent and similar clinical success, stability of clinical success, and aortic survival with acceptable complication and reintervention rates. Scalloped TEVAR safely lengthens the proximal sealing zone to address more proximal pathologies. CLINICAL IMPACT: Treatment of asymptomatic complicated penetrating aortic ulcers (PAUs) with thoracic endovascular aortic repair (TEVAR) provides excellent clinical success and acceptable complication and reintervention rates. More patients become amenable to endovascular treatment by including scalloped TEVAR (scTEVAR) as a means to safely lengthen the proximal sealing zone to address more proximal pathologies.

Synergistic cytotoxicity of the CDK4 inhibitor Fascaplysin in combination with EGFR inhibitor Afatinib against Non-small Cell Lung Cancer.

In the absence of suitable molecular markers, non-small cell lung cancer (NSCLC) patients have to be treated with chemotherapy with poor results at advanced stages. Therefore, the activity of the anticancer marine drug fascaplysin was tested against primary NSCLC cell lines established from pleural effusions. Cytotoxicity of the drug or combinations were determined using MTT assays and changes in intracellular phosphorylation by Western blot arrays. Fascaplysin revealed high cytotoxicity against NSCLC cells and exhibit an activity pattern different of the standard drug cisplatin. Furthermore, fascaplysin synergizes with the EGFR tyrosine kinase inhibitor (TKI) afatinib to yield a twofold increased antitumor effect. Interaction with the Chk1/2 inhibitor AZD7762 confirm the differential effects of fascplysin and cisplatin. Protein phosphorylation assays showed hypophosphorylation of Akt1/2/3 and ERK1/2 as well as hyperphosphorylation of stress response mediators of H1299 NSCLC cells. In conclusion, fascaplysin shows high cytotoxicity against pleural primary NSCLC lines that could be further boosted when combined with the EGFR TKI afatinib.

Applicability of endovascular branched and fenestrated aortic arch repair devices to treat residual type A dissection after ascending replacement.

OBJECTIVE: Endovascular repair of post-type A aortic dissection (PTAD) after open ascending replacement has recently been shown as safe and feasible, but with limited anatomic applicability because only one stent graft was evaluated. We assessed anatomic and clinical applicability of six commercially available branched/fenestrated stent grafts for endovascular repair of PTAD. METHODS: On postoperative CT scans of 101 patients, we measured the aortic diameter at the sinutubular junction, supra-aortic vessels, and descending aorta, as well as the distances between these landmarks along the outer curvature of the arch and the diameters of the supra-aortic vessel. Anatomic applicability was evaluated according to the instructions for use, clinical applicability with regard to supra-aortic and iliac arteries. Assessed devices were the Cook aortic double branch, Terumo double branch, Najuta fenestrated, Endospan Nexus, Medtronic Mona LSA, and Gore TAG thoracic branch. RESULTS: Single devices were anatomically and clinically applicable between 19 of 101 (Mona LSA) and 83 of 101 (Najuta) cases. Reasons for rejection varied considerably across devices. With all devices available, anatomic applicability was 97 of 101 and clinical applicability 95 of 101. Combinations of a fenestrated and a branched device showed the most favorable clinical applicability for a pair of two devices, ranging from 86 of 101 to 94 of 101. CONCLUSIONS: Anatomic and clinical applicability of endovascular devices for the repair of PTAD is high for fenestrated and branched devices, and very high for the combination of fenestrated and branched devices. Manufacturers should amend specific device requirements for PTAD. Surgeons should emphasize the need for a sufficiently long and straight graft as a potential landing zone.

Growth prediction model for abdominal aortic aneurysms.

BACKGROUND: The most relevant determinant in scheduling monitoring intervals for abdominal aortic aneurysms (AAAs) is maximum diameter. The aim of the study was to develop a statistical model that takes into account specific characteristics of AAA growth distributions such as between-patient variability as well as within-patient variability across time, and allows probabilistic statements to be made regarding expected AAA growth. METHODS: CT angiography (CTA) data from patients monitored at 6-month intervals with maximum AAA diameters at baseline between 30 and 66 mm were used to develop the model. By extending the model of geometric Brownian motion with a log-normal random effect, a stochastic growth model was developed. An additional set of ultrasound-based growth data was used for external validation. RESULTS: The study data included 363 CTAs from 87 patients, and the external validation set comprised 390 patients. Internal and external cross-validation showed that the stochastic growth model allowed accurate description of the distribution of aneurysm growth. Median relative growth within 1 year was 4.1 (5-95 per cent quantile 0.5-13.3) per cent. Model calculations further resulted in relative 1-year growth of 7.0 (1.0-16.4) per cent for patients with previously observed rapid 1-year growth of 10 per cent, and 2.6 (0.3-8.3) per cent for those with previously observed slow growth of 1 per cent. The probability of exceeding a threshold of 55 mm was calculated to be 1.78 per cent at most when adhering to the current RESCAN guidelines for rescreening intervals. An online calculator based on the fitted model was made available. CONCLUSION: The stochastic growth model was found to provide a reliable tool for predicting AAA growth.

Novel prefabricated bovine pericardial grafts as alternate conduit for septic aortoiliac reconstruction.

OBJECTIVE: Infection of prosthetic aortic grafts represents a serious complication with high morbidity and mortality. Replacement with autologous material is recommended; however, in its absence, biological material should be favored. In the present retrospective cohort study, we evaluated the short- and midterm results with the use of commercially available prefabricated bovine pericardium grafts (BPGs) used for the management of aortic graft infection or aortic reconstructive surgery in the presence of systemic infection. METHODS: We performed a retrospective analysis of patients in whom BPGs had been used for aortic reconstruction at two vascular centers. Prefabricated vascular pericardium grafts were preferred over other biological reconstruction techniques for selected cases. Comorbidities, procedure-related details, perioperative morbidity, clinical outcomes, and mortality were analyzed. RESULTS: From 2014 to 2019, 21 patients had received BPGs at two Austrian vascular centers. Their median age was 63 years (interquartile range [IQR], 55-71 years), the patients were predominantly male (76%), and the median body mass index was 25.3 kg/m2 (IQR, 21.7-27.3 kg/m2). The major comorbidities included arterial hypertension, peripheral artery disease, smoking, and chronic pulmonary disease. The indications for surgery were vascular graft or endograft infection in 62% and aortic reconstruction in the presence of systemic infection in 38%. Three patients (14%) had aortoenteric fistulas. Surgery was technically successful in all cases. The median follow-up was 21.6 months (IQR, 6.0-34.6 months). The 30-day mortality was 9.5%. The 1- and 2-year overall survival was 84% and 75%, respectively. Of the 21 patients, 89% had remained free of recurrent infection. One of the two reinfections had resolved after treatment of the underlying focus. At 2 years, the primary and assisted primary patency rates were 86% and 94%, respectively. No limbs were lost during follow-up. CONCLUSIONS: Prefabricated BPGs represent a promising alternative for the management of aortic graft infections and aortoiliac reconstruction in the presence of systemic infection.

Thoracic endovascular repair for acute complicated type B aortic dissections.

OBJECTIVE: This study retrospectively assessed in-hospital mortality and long-term results of emergency thoracic endovascular aortic repair (TEVAR) for patients with life-threatening acute complicated type B aortic dissection (acTBD). METHODS: Between March 2001 and December 2016, there were 55 patients (40 male; median age, 52 ± 13 years) with an acTBD who were treated with TEVAR for malperfusion (58%), aortic rupture (18%), or persistent untreatable pain with true lumen reduction or rapid aortic diameter enlargement (24%) as a sign of disease progression. The patients were categorized according to clinical appearance into two groups: group A, malperfusion, pending rupture, or rupture; and group B, persistent ongoing pain, rapid enlargement of aortic diameter, or significant changes in the true to false lumen ratio. Four patients (7%) had undergone previous aortic surgery. RESULTS: Technical success (coverage of the primary intimal tear) was achieved in 50 patients (91%). The overall in-hospital mortality rate was 9% (n = 5), and there was a statistically significant difference in early mortality between group A and group B (7% vs 2%; P < .02). Causes of in-hospital death were all aorta related, including a rupture during the procedure and on the first postinterventional day in two patients and redissection (ascending aorta, n = 2; descending aorta, n = 1) with a consequent aortic rupture after TEVAR in the remaining three. Permanent neurologic dysfunction occurred in five patients (stroke, n = 2; paraplegia, n = 3). Overall, 19 patients (34%) developed early endoleaks (type IA, n = 5; type IB, n = 11; type II, n = 2; type IB plus type II, n = 1). Therefore, 5 patients needed early (within 30 days) endovascular intervention because of a type IA (n = 2), type IB (n = 3), or type II endoleak (n = 1) and the rapid progression of aortic diameter, persistent signs of ischemia (n = 2), or rupture (n = 1), whereas the remaining 14 patients were treated conservatively and followed up by computed tomography angiography. Seven patients with early endoleaks needed an endovascular intervention (n = 3) or conventional surgery (n = 4) because of aortic progression in the follow-up period (mean interval after procedure, 92 ± 56 months). The actual survival rates were 87%, 85%, and 75% at 1 year, 2 years, and 5 years, respectively, and freedom from aorta-related death was 87%, 87%, and 77% at 1 year, 2 years, and 5 years, respectively. Freedom from reintervention for any cause using a Kaplan-Meier analysis was 70%, 68%, 68%, and 63% at 6 months, 1 year, 2 years, and 5 years, respectively. CONCLUSIONS: TEVAR of acTBD has been proven to be an excellent treatment modality in this cohort of high-risk patients, with promising midterm and long-term results.

Worldwide results from the RESTORE II on elective endografting of thoracic aneurysms and dissections.

OBJECTIVE: To assess safety, performance, and efficacy of the RELAY thoracic stent graft (Bolton Medical, Barcelona, Spain) in the treatment of patients who require elective thoracic endovascular aortic repair including aneurysms and dissections. METHODS: The RELAY Endovascular Registry for Thoracic Disease II (RESTORE II) is a multicenter, prospective, international cohort study involving 21 centers in 12 countries worldwide. All consecutively included patients underwent elective thoracic endovascular aortic repair with a RELAY or RELAY NBS stent graft (including off the shelf and custom-made devices) to repair thoracic aortic aneurysms or dissections. Demographic, clinical, and aortic parameters were Web-based registers. Safety and efficacy data were collected for a follow-up period of 24 months. RESTORE was a precedent registry involving European sites that used RELAY first-generation devices. RESULTS: A total of 173 patients were enrolled in the registry from October 2010 to September 2014 (aneurysm [n = 99]/dissection [n = 74]). Overall technical success of the intervention reached 97.1% irrespective of the etiology and geographic origin of patients. Baseline clinical heterogeneity was observed between devices concerning the etiology of the disease and certain comorbidities and/or risk factor distribution (diabetes, hypertension, myocardial infarction, angina pectoris). An average of 1.36 stent graft components were used per patient, with mean intended treatment length of 197.0 ± 87.7/188.7 ± 103.1 mm and mean access site diameter of 10.3 ± 8.2/9.7 ± 1.7 mm in aneurysms/dissections, respectively. The rate of all-cause 30-day mortality was lower than in the RESTORE registry (4.0% vs 7.2%). Perioperative neurologic complications were infrequent: paraplegia/paraparesis (2.9%) and stroke (0.6%) (vs 2.0% and 1.6% in the RESTORE registry). Freedom from all-cause mortality at 2 years was 93.6%. At the final completion angiography, device-associated complications were detected in 4.6% of the patients (vs 5.3% in the RESTORE) and endoleak rate was 6.4% (type I 5.8% and type II 1.7%). CONCLUSIONS: The worldwide results of the RESTORE II registry show the safety and effectiveness of RELAY and RELAY NBS stent grafts for elective endovascular thoracic aortic repair. Compared with the RESTORE registry, the device presents a lower rate of perioperative complications.

Successful Treatment of a Ruptured Extracranial Vertebral Artery Aneurysm with Onyx Instillation.

The rupture of an extracranial vertebral artery aneurysm has only been rarely described in the literature and treatment options are therefore not standardized. Here we report the successful endovascular repair of a spontaneously ruptured extracranial left vertebral artery aneurysm using Onyx instillation. A 48-year-old woman was transferred to our clinic after having been intubated due to a massive hematoma of the left neck. A contrast-enhanced computed tomography (CT) showed a rupture of the left extracranial vertebral artery. Several issues complicated the therapeutic decision making in this rare case: first, the patient showed multiple aneurysms in CT angiography; therefore a connective tissue disease could not be excluded. Furthermore, as anamnestic work-up revealed that several episodes of postoperative bleeding and open surgery at this anatomic location are rarely performed, risks for postoperative complications were high. Therefore, the patient was hemodynamically stabilized and the ruptured aneurysm was treated in an endovascular approach with Onyx instillation and coil embolization. Complete exclusion of the aneurysm was achieved without periprocedural or neurological complications. Successful repair was confirmed by CT angiography on the first postoperative day as well as 12 months after the intervention. In conclusion, this case shows that endovascular Onyx embolization of ruptured vertebral aneurysms is a save and feasible method.

Extracorporeal membrane oxygenation in adult patients with hematologic malignancies and severe acute respiratory failure.

INTRODUCTION: Acute respiratory failure (ARF) is the main reason for intensive care unit (ICU) admissions in patients with hematologic malignancies (HMs). We report the first series of adult patients with ARF and HMs treated with extracorporeal membrane oxygenation (ECMO). METHODS: This is a retrospective cohort study of 14 patients with HMs (aggressive non-Hodgkin lymphoma (NHL) n = 5; highly aggressive NHL, that is acute lymphoblastic leukemia or Burkitt lymphoma, n = 5; Hodgkin lymphoma, n = 2; acute myeloid leukemia, n = 1; multiple myeloma, n = 1) receiving ECMO support because of ARF (all data as medians and interquartile ranges; age, 32 years (22 to 51 years); simplified acute physiology score II (SAPS II): 51 (42 to 65)). Etiology of ARF was pneumonia (n = 10), thoracic manifestation of NHL (n = 2), sepsis of nonpulmonary origin (n = 1), and transfusion-related acute lung injury (n = 1). Diagnosis of HM was established during ECMO in four patients, and five first received (immuno-) chemotherapy on ECMO. RESULTS: Before ECMO, the PaO2/FiO2 ratio was 60 (53 to 65), (3.3 to 3.7). Three patients received venoarterial ECMO because of acute circulatory failure in addition to ARF; all other patients received venovenous ECMO. All patients needed vasopressors, and five needed hemofiltration. Thrombocytopenia occurred in all patients (lowest platelet count was 20 (11 to 21) G/L). Five major bleeding events were noted. ECMO duration was 8.5 (4 to 16) days. ICU and hospital survival was 50%. All survivors were alive at follow-up (36 (10 to 58) months); five patients were in complete remission, one in partial remission, and one had relapsed. CONCLUSIONS: ECMO therapy is feasible in selected patients with HMs and ARF and can be associated with long-term disease-free survival.

Preliminary results of the austrian national registry with the novel iCover bridging stentgraft in fenestrated endovascular aortic repair.

OBJECTIVE: Bridging stentgrafts (BSGs) are one of the primary limiting factors regarding long-term results after fenestrated endovascular aortic repair (fEVAR). This study aims to report for the first time the outcome of a novel BSG called iCover from a national, multicentric retrospective database. METHODS: A cohort of 58 patients received 212 BSGs for the renovisceral arteries in fEVAR. Patients were followed-up clinically and with computed-tomography angiography. Study end points were mortality, occurrence of complications, technical success of the BSG implantation, defined as successful deployment with vessel patency and absence of type 1c, 3b, and 3c endoleak, and stability over the follow-up. RESULTS: Three BSG unrelated mortalities (5.1 %), four BSG unrelated major complications (6.8 %) and five minor complications (8.6 %) occurred. The technical success of iCover was 207/212 (97.6 %), target vessel patency was 100 % over a follow-up of 4.0 months, and no late BSG related endoleak was detected. In two cases, the BSG was dislodged from the balloon and could be parked in a safe position without further sequelae (0.9 %). CONCLUSION: The iCover represents a feasible BSG for fEVAR with an excellent safety profile and technical success rate in the early phase. Prudent post-dilatation and monitoring of the proximal and distal stent ends can potentially further improve outcome. Longer follow-up series are necessary.

Endovascular repair in type A aortic dissection: Anatomical candidacy for currently manufactured stent grafts and conceptual valve-carrying devices for an Endo-Bentall procedure.

OBJECTIVES: Endovascular treatment has been suggested as an alternative for open surgery for type A aortic dissection, but current devices have severe anatomical limitations. This study assesses the computed tomography-based anatomical suitability of currently manufactured stent grafts as well as 2 embodiments of valve-carrying devices. METHODS: In a retrospective single-centre cohort of 200 consecutive ascending/arch operations between 2009 and 2018, a total of 112 patients with type A aortic dissections were identified and evaluated for endovascular candidacy based on the locations of the entries, the landing zone diameters/lengths and the supra-aortic vessel origins according to the anatomical instructions for use criteria of 6 commercially available (tubular, branched or fenestrated) stent grafts. Two suggested valve-carrying devices with inner branches or fenestrations for the coronary arteries and branches for the supra-aortic vessels were also evaluated. RESULTS: The anatomical feasibility for commercial stent grafts ranged from 4% to 21%. The main limitations were proximal landing zone diameter (considering oversizing <15%), length due to dilatation and an entry too close to the sinotubular junction. For the valve-carrying conduits, anatomical feasibility was between 31% and 80%, with the main limiting factors being the diameter of the aortic annulus and its distance to the coronary arteries. CONCLUSIONS: The anatomical applicability of currently manufactured stent grafts for the treatment of type A aortic dissection is limited mainly by the absence of a suitable proximal landing zone in the ascending aorta and might substantially be improved by anchoring in the aortic annulus using a valve-carrying device that uses either fenestrations or branches for the coronary arteries.

Type II endoleaks after endovascular repair of abdominal aortic aneurysms: fate of the aneurysm sac and neck changes during long-term follow-up.

PURPOSE: To evaluate the frequency of type II endoleaks after endovascular aneurysm repair (EVAR) and to compare sac diameter and neck changes in patients with type II endoleak to endoleak-free patients with at least 3-year imaging follow-up. METHODS: Among 407 consecutive EVAR patients, 109 patients (101 men; mean age 72.1 years, range 55-86) had at least 3-year computed tomography (CT) data and no type I or III endoleak. In this cohort, 49 patients presented with a type II endoleak at some time and 60 patients had no endoleak. Patients with type II endoleaks were further divided into subgroups based on the vessel origin and the perfusion status (persistent or transient). The course of the perfusion status of type II endoleaks and changes in the aneurysm sac diameters, neck diameters, and renal to stent-graft distances (RSD) were evaluated in the defined groups. Reintervention and death rates were also reported. RESULTS: The mean follow-up was 68.1 ± 23.8 months. Compared to the no endoleak group, overall sac diameter increased significantly in the type II endoleak group (p = 0.007), but vessel origin did not have any influence. With regard to the perfusion status of type II endoleaks, aneurysm sac changes were significantly higher (p = 0.002) in the persistent endoleak group. During the study period, the increase in the proximal neck diameter was significantly higher in the no endoleak group compared to the type II endoleak group (p = 0.025). No significant difference was found in RSD changes between the defined groups. Reinterventions were performed in 20 (18.3%) patients (13 for type II endoleak); 2 (1.8%) patients without type II endoleak died of ruptured aneurysm. CONCLUSION: Persistent type II endoleaks led to significant aneurysm sac enlargement, but without increased mortality or rupture rates.

Mechanisms of symptomatic spinal cord ischemia after TEVAR: insights from the European Registry of Endovascular Aortic Repair Complications (EuREC).

PURPOSE: To test the hypothesis that simultaneous closure of at least 2 independent vascular territories supplying the spinal cord and/or prolonged hypotension may be associated with symptomatic spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR). METHODS: A pattern matching algorithm was used to develop a risk model for symptomatic SCI using a prospective 63-patient single-center cohort to test the positive predictive value (PPV) of prolonged intraoperative hypotension and/or simultaneous closure of at least 2 of 4 the vascular territories supplying the spinal cord (left subclavian, intercostal, lumbar, and hypogastric arteries). This risk model was then applied to data extracted from the multicenter European Registry on Endovascular Aortic Repair Complications (EuREC). Between 2002 and 2010, the 19 centers participating in EuREC reported 38 (1.7%) cases of symptomatic spinal cord ischemia among the 2235 patients in the database. RESULTS: In the single-center cohort, direct correlations were seen between the occurrence of symptomatic SCI and both prolonged intraoperative hypotension (PPV 1.00, 95% CI 0.22 to 1.00, p=0.04) and simultaneous closure of at least 2 independent spinal cord vascular territories (PPV 0.67, 95% CI 0.24 to 0.91, p=0.005). Previous closure of a single vascular territory was not associated with an increased risk of symptomatic spinal cord ischemia (PPV 0.07, 95% CI 0.01 to 0.16, p=0.56). The combination of prolonged hypotension and simultaneous closure of at least 2 territories exhibited the strongest association (PPV 0.75, 95% CI 0.38 to 0.75, p<0.0001). Applying the model to the entire EuREC cohort found an almost perfect agreement between the predicted and observed risk factors (kappa 0.77, 95% CI 0.65 to 0.90). CONCLUSION: Extensive coverage of intercostal arteries alone by a thoracic stent-graft is not associated with symptomatic SCI; however, simultaneous closure of at least 2 vascular territories supplying the spinal cord is highly relevant, especially in combination with prolonged intraoperative hypotension. As such, these results further emphasize the need to preserve the left subclavian artery during TEVAR.

Fotemustine chemoembolization of hepatic metastases from uveal melanoma: a retrospective single-center analysis.

OBJECTIVE: The purpose of the current study was to retrospectively evaluate response and survival in patients with hepatic metastasis from uveal melanoma treated by palliative transarterial chemoembolization (TACE) with fotemustine. MATERIALS AND METHODS: During the study period, 21 patients with hepatic metastases from uveal melanoma were treated by TACE. A series of TACE interventions (mean number per patient, 3.29 interventions; range, 1-6 interventions) was performed on each patient with an emulsion of fotemustine dissolved in 10 mL of saline mixed with 10 mL of an oily contrast agent. Tumor response based on the Response Evaluation Criteria in Solid Tumors was evaluated using contrast-enhanced CT scans obtained 6-10 weeks after embolization. RESULTS: CT showed partial regression after TACE in three patients (14%). Six patients (29%) presented with stable disease but no significant change in tumor size after TACE, and 12 patients (57%) presented with progressive disease after TACE treatment. The overall response rate was 43%. The mean survival after diagnosis of hepatic metastasis was 28.7 months. CONCLUSION: TACE of hepatic metastasis from uveal melanoma with fotemustine is well tolerated, and the survival rates in this study (mean, 28.7 months) are among the longest reported.

[Endovascular aortic repair of endoleaks : Diagnosis, treatment, and outcomes]. / Endovaskuläre Aortenreparatur bei Endoleaks : Diagnose, Behandlung und Ergebnisse.

All patients who underwent endovascular aortic repair (EVAR) need a thorough follow-up, at least yearly. Contrast-enhanced ultrasound and computed tomography angiography (CTA) are the most important modalities for detection of endoleaks, whereby CTA allows better differentiation of endoleak type. High pressure endoleaks (type I and III) are an absolute indication for treatment if they do not resolve spontaneously in the short term. Type II endoleaks are mostly benign and may be routinely controlled if there is no progression of the aneurysm. Type II endoleaks associated with aneurysm progression may be treated with embolization; however, whether they must be treated is a matter of discussion. Nonetheless, a type II endoleak must be treated when progression shortens the aneurysm neck and the threat of a type I endoleak is at hand. Type I endoleaks are the main limitation of stent grafts. An adequate proximal landing zone is the best prevention for type I endoleaks, even if fenestrated stent grafts have to be used. Various fixation devices for short necks are currently under investigation.

[Fenestrated and branched endovascular aortic prostheses : An update]. / Fenestrierte und verzweigte endovaskuläre Aortenprothesen : Ein Update.

BACKGROUND: Today, complex abdominal aortic pathologies involving the visceral arteries and without an adequate proximal neck can be treated using fenestrated/branched endovascular aortic repair (FEVAR/BEVAR) with similar safety and success rates as infrarenal aortic pathologies treated with tubular EVAR. METHODICAL INNOVATIONS AND CHALLENGES: Fenestrations (if the vessel originates from a nondilated aorta) or branches (if the vessel originates from a dilated aorta) may be used for the visceral arteries. Both types of openings are sealed via bridging stent grafts that connect to the target vessel. Multiple manufacturers offer fenestrated or branched endoprostheses, with only a few being CE certified and the majority in Europe being patient-specific custom-made devices. Therefore, they require a certain delivery time which precludes acute patients from such treatment. However, two stent grafts with four branches for thoracoabdominal aneurysms are available off the shelf and are anatomically suitable for the majority of patients, thus, allowing for acute treatment. All FEVAR and BEVAR main bodies require bridging stent grafts, all of which are used off-label. RECOMMENDATIONS: As bridging stent grafts are one of the main reasons for reinterventions, one should be aware of fractures and kinking of the bridging stent grafts during follow-up and should refrain from using single-layered bridging stent grafts in BEVAR.

Cytotoxicity of combinations of the pan-KRAS SOS1 inhibitor BAY-293 against pancreatic cancer cell lines.

KRAS is mutated in approximately 25% of cancer patients and first KRAS G12C-specific inhibitors showed promising responses. Pancreatic cancer has the highest frequency of KRAS mutations but the prevailing KRAS G12D mutation is difficult to target. Inhibition of the GTP exchange factor (GEF) SOS1-KRAS interaction impairs oncogenic signaling independently of the specific KRAS mutations. In general, cell lines exhibiting KRAS mutations show specific alterations in respect to glucose utilization, signal transduction and stress survival. The aim of this investigation was to check the putative synergy of the SOS1 inhibitor BAY-293 with modulators targeting specific vulnerabilities of KRAS-mutated cell lines in vitro. The cytotoxicity of BAY-293 combinations was tested against MIA PaCa-2 (G12C), AsPC1 (G12D) and BxPC3 (KRAS wildtype) cell lines using MTT tests and calculation of the combination indices (CI) according to the Chou-Talalay method. The results show that BAY-293 synergizes with modulators of glucose utilization, inhibitors of the downstream MAPK pathway and several chemotherapeutics in dependence of the specific KRAS status of the cell lines. In particular, divergent responses for BAY-293 combinations between pancreatic and NSCLC cell lines were observed for linsitinib, superior inhibitory effects of trametinib and PD98059 in NSCLC, and lack of activity with doxorubicin in case of the pancreatic cell lines. Phosphoproteome analysis revealed inhibition of distinct signaling pathways by BAY-293 for MIA PaCa-2 on the one hand and for Aspc1 and BH1362 on the other hand. In conclusion, BAY-293 exhibits synergy with drugs in dependence of the tumor type and specific KRAS mutation.