Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization.

Chimeric antigen receptor (CAR) T cell therapies have achieved promising outcomes in several cancers, however more challenging oncology indications may necessitate advanced antigen receptor designs and functions. Here we describe a bipartite receptor system comprised of separate antigen targeting and signal transduction polypeptides, each containing an extracellular dimerization domain. We demonstrate that T cell activation remains antigen dependent but can only be achieved in the presence of a dimerizing drug, rapamycin. Studies performed in vitro and in xenograft mouse models illustrate equivalent to superior anti-tumor potency compared to currently used CAR designs, and at rapamycin concentrations well below immunosuppressive levels. We further show that the extracellular positioning of the dimerization domains enables the administration of recombinant re-targeting modules, potentially extending antigen targeting. Overall, this novel regulatable CAR design has exquisite drug sensitivity, provides robust anti-tumor responses, and is uniquely flexible for multiplex antigen targeting or retargeting, which may further assist the development of safe, potent and durable T cell therapeutics.

Confirmed value of shear wave elastography for ultrasound characterization of breast masses using a conservative approach in Chinese women: a large-size prospective multicenter trial.

PURPOSE: This study aimed to investigate the value of shear wave elastography (SWE) for characterization of breast masses in a Chinese population. PATIENTS AND METHODS: Two thousand two hundred seventy-three women consented to be prospectively enrolled for the characterization of breast masses with ultrasound and SWE. Breast masses were known from symptoms, palpability, and/or previous imaging screening with mammography and/or ultrasound. Correlation of SWE qualitative and quantitative features with malignancy risk and impact on diagnostic performance of combining SWE features were assessed, and the Breast Imaging Reporting and Data System (BI-RADS) scoring was calculated using histopathology as reference. RESULTS: Data of 2,262 masses (median size: 13 mm; range: 1.3-50) from 2,262 patients (median age: 43 years; range: 18-91) were investigated, of which 752 (33.3%) were malignant. Sensitivity and specificity of BI-RADS diagnosis were 97.5% (733/752) and 54.8% (827/1,510), respectively. By logistic regression, the combination of maximum elasticity (E max) measurements with BI-RADS assessments increased the area under the receiver operating characteristic curve from 0.908 (95% CI: 0.896-0.920) to 0.954 (95% CI: 0.944-0.962). Using E max of 30 kPa or lower to selectively downgrade BI-RADS 4a masses to follow-up, and E max of 160 kPa or higher to selectively upgrade BI-RADS 3 lesions to biopsy, specificity significantly increased from 54.8% (827/1,510) to 66.1% (998/1,510) (P<0.001) while sensitivity decreased nonsignificantly from 97.5% (733/752) to 96.9% (729/752) (P=0.2891). Positive predictive value for biopsy recommendation increased from 51.7% (733/1,417) to 58.7% (729/1,241) (P<0.001). CONCLUSION: Adding SWE maximum stiffness to BI-RADS 3 and BI-RADS 4a breast masses in a Chinese population increased significantly the specificity of breast ultrasonography, without significant change in sensitivity.

Assessment of biopsy-proven liver fibrosis by two-dimensional shear wave elastography: An individual patient data-based meta-analysis.

Two-dimensional shear wave elastography (2D-SWE) has proven to be efficient for the evaluation of liver fibrosis in small to moderate-sized clinical trials. We aimed at running a larger-scale meta-analysis of individual data. Centers which have worked with Aixplorer ultrasound equipment were contacted to share their data. Retrospective statistical analysis used direct and paired receiver operating characteristic and area under the receiver operating characteristic curve (AUROC) analyses, accounting for random effects. Data on both 2D-SWE and liver biopsy were available for 1,134 patients from 13 sites, as well as on successful transient elastography in 665 patients. Most patients had chronic hepatitis C (n = 379), hepatitis B (n = 400), or nonalcoholic fatty liver disease (n = 156). AUROCs of 2D-SWE in patients with hepatitis C, hepatitis B, and nonalcoholic fatty liver disease were 86.3%, 90.6%, and 85.5% for diagnosing significant fibrosis and 92.9%, 95.5%, and 91.7% for diagnosing cirrhosis, respectively. The AUROC of 2D-SWE was 0.022-0.084 (95% confidence interval) larger than the AUROC of transient elastography for diagnosing significant fibrosis (P = 0.001) and 0.003-0.034 for diagnosing cirrhosis (P = 0.022) in all patients. This difference was strongest in hepatitis B patients. CONCLUSION: 2D-SWE has good to excellent performance for the noninvasive staging of liver fibrosis in patients with hepatitis B; further prospective studies are needed for head-to-head comparison between 2D-SWE and other imaging modalities to establish disease-specific appropriate cutoff points for assessment of fibrosis stage. (Hepatology 2018;67:260-272).

Quantitative Maximum Shear-Wave Stiffness of Breast Masses as a Predictor of Histopathologic Severity.

OBJECTIVE: The objective of our study was to compare quantitative maximum breast mass stiffness on shear-wave elastography (SWE) with histopathologic outcome. SUBJECTS AND METHODS: From September 2008 through September 2010, at 16 centers in the United States and Europe, 1647 women with a sonographically visible breast mass consented to undergo quantitative SWE in this prospective protocol; 1562 masses in 1562 women had an acceptable reference standard. The quantitative maximum stiffness (termed "Emax") on three acquisitions was recorded for each mass with the range set from 0 (very soft) to 180 kPa (very stiff). The median Emax and interquartile ranges (IQRs) were determined as a function of histopathologic diagnosis and were compared using the Mann-Whitney U test. We considered the impact of mass size on maximum stiffness by performing the same comparisons for masses 9 mm or smaller and those larger than 9 mm in diameter. RESULTS: The median patient age was 50 years (mean, 51.8 years; SD, 14.5 years; range, 21-94 years), and the median lesion diameter was 12 mm (mean, 14 mm; SD, 7.9 mm; range, 1-53 mm). The median Emax of the 1562 masses (32.1% malignant) was 71 kPa (mean, 90 kPa; SD, 65 kPa; IQR, 31-170 kPa). Of 502 malignancies, 23 (4.6%) ductal carcinoma in situ (DCIS) masses had a median Emax of 126 kPa (IQR, 71-180 kPa) and were less stiff than 468 invasive carcinomas (median Emax, 180 kPa [IQR, 138-180 kPa]; p = 0.002). Benign lesions were much softer than malignancies (median Emax, 43 kPa [IQR, 24-83 kPa] vs 180 kPa [IQR, 129-180 kPa]; p < 0.0001). Usual benign lesions were soft, including 62 cases of fibrocystic change (median Emax, 32 kPa; IQR, 24-94 kPa), 51 cases of fibrosis (median Emax, 36 kPa; IQR, 22-102 kPa), and 301 fibroadenomas (median Emax, 45 kPa; IQR, 30-79 kPa). Eight lipomas (median Emax, 14 kPa; IQR, 8-15 kPa), 154 cysts (median Emax, 29 kPa; IQR, 10-58 kPa), and seven lymph nodes (median Emax, 17 kPa; IQR, 9-40 kPa) were softer than usual benign lesions (p < 0.0001 for lipomas and cysts; p = 0.007 for lymph nodes). Risk lesions were slightly stiffer than usual benign lesions (p = 0.002) but tended to be softer than DCIS (p = 0.14). Fat necrosis and abscesses were relatively stiff. Conclusions were similar for both small and large masses. CONCLUSION: Despite overlap in Emax values, maximum stiffness measured by SWE is a highly effective predictor of the histopathologic severity of sonographically depicted breast masses.

Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels.

The ATP-sensitive potassium (K(ATP)) channel consisting of the inward rectifier Kir6.2 and SUR1 (sulfonylurea receptor 1) couples cell metabolism to membrane excitability and regulates insulin secretion. Inhibition by intracellular ATP is a hallmark feature of the channel. ATP sensitivity is conferred by Kir6.2 but enhanced by SUR1. The mechanism by which SUR1 increases channel ATP sensitivity is not understood. In this study, we report molecular interactions between SUR1 and Kir6.2 that markedly alter channel ATP sensitivity. Channels bearing an E203K mutation in SUR1 and a Q52E in Kir6.2 exhibit ATP sensitivity ∼100-fold higher than wild-type channels. Cross-linking of E203C in SUR1 and Q52C in Kir6.2 locks the channel in a closed state and is reversible by reducing agents, demonstrating close proximity of the two residues. Our results reveal that ATP sensitivity in K(ATP) channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.

Elastography in the assessment of sentinel lymph nodes prior to dissection.

OBJECTIVE: Breast cancer starts as a local tumor but can become metastatic and spread via the lymph nodes. When the pre-operative assessment of the axillary lymph nodes is negative patients generally undergo sentinel node biopsy (SNB), followed by a secondary surgical axillary lymph node dissection (ALND) if the SNB is positive. The extemporaneous anatomo-pathological analysis of the sentinel lymph node enables metastases to be detected and an ALND at the same time of the SNB. The goal of this study was to evaluate the added value of ShearWave Elastography (SWE), compared with the conventional pre-operative assessment, in the screening of sentinel lymph nodes with a high metastatic risk, which could then benefit from an extemporaneous anatomo-pathological analysis. PATIENTS AND METHODS: Women undergoing breast surgery with SNB were prospectively enrolled. Before surgery, they underwent ultrasound and elastography imaging of axillary lymph nodes using the SuperSonic Imagine device and its ShearWave™ elastography mode (SWE™). The results obtained were compared to the immunohistochemical results for the removed lymph nodes. RESULTS: 65 patients were enrolled. From the 103 lymph nodes examined by elastography and the 185 lymph nodes removed we were able to pair 81; 70 were healthy and 11 were malignant. The stiffness measurements (mean and maximal values) were significantly different between the healthy and metastatic lymph nodes, (p<0.05). The areas under the ROC curves were 0.76 (95% confidence interval (CI): 0.58-0.94) and 0.75 (95%CI: 0.55-0.95) for the mean and the maximal stiffness, respectively. CONCLUSION: These encouraging results show a correlation between the metastatic risk of lymph nodes and their increased mean stiffness. Elasticity variables and potential thresholds that seem to predict the metastatic status of axillary lymph nodes were identified. If confirmed by further larger studies, these results could be useful in clinical practice for the identification of lymph nodes at high metastatic risk that could benefit from a intra-operative analysis to reduce the number of secondary surgical procedures.

Shear wave elastography for breast masses is highly reproducible.

OBJECTIVES: To evaluate intra- and interobserver reproducibility of shear wave elastography (SWE) for breast masses. METHODS: For intraobserver reproducibility, each observer obtained three consecutive SWE images of 758 masses that were visible on ultrasound. 144 (19%) were malignant. Weighted kappa was used to assess the agreement of qualitative elastographic features; the reliability of quantitative measurements was assessed by intraclass correlation coefficients (ICC). For the interobserver reproducibility, a blinded observer reviewed images and agreement on features was determined. RESULTS: Mean age was 50 years; mean mass size was 13 mm. Qualitatively, SWE images were at least reasonably similar for 666/758 (87.9%). Intraclass correlation for SWE diameter, area and perimeter was almost perfect (ICC ≥ 0.94). Intraobserver reliability for maximum and mean elasticity was almost perfect (ICC = 0.84 and 0.87) and was substantial for the ratio of mass-to-fat elasticity (ICC = 0.77). Interobserver agreement was moderate for SWE homogeneity (κ = 0.57), substantial for qualitative colour assessment of maximum elasticity (κ = 0.66), fair for SWE shape (κ = 0.40), fair for B-mode mass margins (κ = 0.38), and moderate for B-mode mass shape (κ = 0.58), orientation (κ = 0.53) and BI-RADS assessment (κ = 0.59). CONCLUSIONS: SWE is highly reproducible for assessing elastographic features of breast masses within and across observers. SWE interpretation is at least as consistent as that of BI-RADS ultrasound B-mode features. KEY POINTS: • Shear wave ultrasound elastography can measure the stiffness of breast tissue • It provides a qualitatively and quantitatively interpretable colour-coded map of tissue stiffness • Intraobserver reproducibility of SWE is almost perfect while intraobserver reproducibility of SWE proved to be moderate to substantial • The most reproducible SWE features between observers were SWE image homogeneity and maximum elasticity.

Shear-wave elastography improves the specificity of breast US: the BE1 multinational study of 939 masses.

PURPOSE: To determine whether adding shear-wave (SW) elastographic features could improve accuracy of ultrasonographic (US) assessment of breast masses. MATERIALS AND METHODS: From September 2008 to September 2010, 958 women consented to repeat standard breast US supplemented by quantitative SW elastographic examination in this prospective multicenter institutional review board-approved, HIPAA-compliant protocol. B-mode Breast Imaging Reporting and Data System (BI-RADS) features and assessments were recorded. SW elastographic evaluation (mean, maximum, and minimum elasticity of stiffest portion of mass and surrounding tissue; lesion-to-fat elasticity ratio; ratio of SW elastographic-to-B-mode lesion diameter or area; SW elastographic lesion shape and homogeneity) was performed. Qualitative color SW elastographic stiffness was assessed independently. Nine hundred thirty-nine masses were analyzable; 102 BI-RADS category 2 masses were assumed to be benign; reference standard was available for 837 category 3 or higher lesions. Considering BI-RADS category 4a or higher as test positive for malignancy, effect of SW elastographic features on area under the receiver operating characteristic curve (AUC), sensitivity, and specificity after reclassifying category 3 and 4a masses was determined. RESULTS: Median participant age was 50 years; 289 of 939 (30.8%) masses were malignant (median mass size, 12 mm). B-mode BI-RADS AUC was 0.950; eight of 303 (2.6%) BI-RADS category 3 masses, 18 of 193 (9.3%) category 4a lesions, 41 of 97 (42%) category 4b lesions, 42 of 57 (74%) category 4c lesions, and 180 of 187 (96.3%) category 5 lesions were malignant. By using visual color stiffness to selectively upgrade category 3 and lack of stiffness to downgrade category 4a masses, specificity improved from 61.1% (397 of 650) to 78.5% (510 of 650) (P<.001); AUC increased to 0.962 (P=.005). Oval shape on SW elastographic images and quantitative maximum elasticity of 80 kPa (5.2 m/sec) or less improved specificity (69.4% [451 of 650] and 77.4% [503 of 650], P<.001 for both), without significant improvement in sensitivity or AUC. CONCLUSION: Adding SW elastographic features to BI-RADS feature analysis improved specificity of breast US mass assessment without loss of sensitivity.

Relative expression of a dominant mutated ABCC8 allele determines the clinical manifestation of congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is most commonly caused by mutations in the ß-cell ATP-sensitive K(+) (K(ATP)) channel genes. Severe CHI was diagnosed in a 1-day-old girl; the mother's cousin and sister had a similar phenotype. ABCC8 gene sequencing (leukocyte DNA) revealed a heterozygous, exon 37, six-base pair in-frame insertion mutation in the affected patient and aunt but also in her unaffected mother and grandfather. In expression studies using transfected COSm6 cells, mutant sulfonylurea receptor 1 (SUR1) protein was expressed on the cell surface but failed to respond to MgADP even in the heterozygous state. mRNA expression in lymphocytes determined by sequencing cDNA clones and quantifying 6FAM-labeled PCR products found that although the healthy mother predominantly expressed the normal transcript, her affected daughter, carrying the same mutant allele, primarily transcribed the mutant. The methylation pattern of the imprinting control region of chromosome 11p15.5 and ABCC8 promoter was similar for all family members. In conclusion, differences in transcript expression may determine the clinical phenotype of CHI in this maternally inherited dominant mutation. The use of peripheral lymphocytes as a peripheral window to the ß-cell transcription profile can serve in resolving ß-cell phenotypes. The severe, dominant-negative nature of the 1508insAS mutation suggests that it affects the functional stoichiometry of SUR1-regulated gating of K(ATP) channels.

A role of the sulfonylurea receptor 1 in endocytic trafficking of ATP-sensitive potassium channels.

The ATP-sensitive potassium (K(ATP) ) channel consisting of sulfonylurea receptor 1 (SUR1) and inward-rectifier potassium channel 6.2 (Kir6.2) has a well-established role in insulin secretion. Mutations in either subunit can lead to disease due to aberrant channel gating, altered channel density at the cell surface or a combination of both. Endocytic trafficking of channels at the plasma membrane is one way to influence surface channel numbers. It has been previously reported that channel endocytosis is dependent on a tyrosine-based motif in Kir6.2, while SUR1 alone is unable to internalize. In this study, we followed endocytic trafficking of surface channels in real time by live-cell imaging of channel subunits tagged with an extracellular minimal α-bungarotoxin-binding peptide labeled with a fluorescent dye. We show that SUR1 undergoes endocytosis independent of Kir6.2. Moreover, mutations in the putative endocytosis motif of Kir6.2, Y330C, Y330A and F333I are unable to prevent channel endocytosis. These findings challenge the notion that Kir6.2 bears the sole endocytic signal for K(ATP) channels and support a role of SUR1 in this trafficking process.

Characterization and functional restoration of a potassium channel Kir6.2 pore mutation identified in congenital hyperinsulinism.

The inwardly rectifying potassium channel Kir6.2 assembles with sulfonylurea receptor 1 to form the ATP-sensitive potassium (K(ATP)) channels that regulate insulin secretion in pancreatic beta-cells. Mutations in K(ATP) channels underlie insulin secretion disease. Here, we report the characterization of a heterozygous missense Kir6.2 mutation, G156R, identified in congenital hyperinsulinism. Homomeric mutant channels reconstituted in COS cells show similar surface expression as wild-type channels but fail to conduct potassium currents. The mutated glycine is in the pore-lining transmembrane helix of Kir6.2; an equivalent glycine in other potassium channels has been proposed to serve as a hinge to allow helix bending during gating. We found that mutation of an adjacent asparagine, Asn-160, to aspartate, which converts the channel from a weak to a strong inward rectifier, on the G156R background restored ion conduction in the mutant channel. Unlike N160D channels, however, G156R/N160D channels are not blocked by intracellular polyamines at positive membrane potential and exhibit wild-type-like nucleotide sensitivities, suggesting the aspartate introduced at position 160 interacts with arginine at 156 to restore ion conduction and gating. Using tandem Kir6.2 tetramers containing G156R and/or N160D in designated positions, we show that one mutant subunit in the tetramer is insufficient to abolish conductance and that G156R and N160D can interact in the same or adjacent subunits to restore conduction. We conclude that the glycine at 156 is not essential for K(ATP) channel gating and that the Kir6.2 gating defect caused by the G156R mutation could be rescued by manipulating chemical interactions between pore residues.

Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds.

The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.

Sulfonylurea receptor 1 mutations that cause opposite insulin secretion defects with chemical chaperone exposure.

The beta-cell ATP-sensitive potassium (K(ATP)) channel composed of sulfonylurea receptor SUR1 and potassium channel Kir6.2 serves a key role in insulin secretion regulation by linking glucose metabolism to cell excitability. Mutations in SUR1 or Kir6.2 that decrease channel function are typically associated with congenital hyperinsulinism, whereas those that increase channel function are associated with neonatal diabetes. Here we report that two hyperinsulinism-associated SUR1 missense mutations, R74W and E128K, surprisingly reduce channel inhibition by intracellular ATP, a gating defect expected to yield the opposite disease phenotype neonatal diabetes. Under normal conditions, both mutant channels showed poor surface expression due to retention in the endoplasmic reticulum, accounting for the loss of channel function phenotype in the congenital hyperinsulinism patients. This trafficking defect, however, could be corrected by treating cells with the oral hypoglycemic drugs sulfonylureas, which we have shown previously to act as small molecule chemical chaperones for K(ATP) channels. The R74W and E128K mutants thus rescued to the cell surface paradoxically exhibited ATP sensitivity 6- and 12-fold lower than wild-type channels, respectively. Further analyses revealed a nucleotide-independent decrease in mutant channel intrinsic open probability, suggesting the mutations may reduce ATP sensitivity by causing functional uncoupling between SUR1 and Kir6.2. In insulin-secreting cells, rescue of both mutant channels to the cell surface led to hyperpolarized membrane potentials and reduced insulin secretion upon glucose stimulation. Our results show that sulfonylureas, as chemical chaperones, can dictate manifestation of the two opposite insulin secretion defects by altering the expression levels of the disease mutants.

The French National Authority for Health reports on thoracic stent grafts.

OBJECTIVE: This study was conducted to determine the efficacy and safety of stent grafts in the treatment of thoracic aortic aneurysms and dissections. METHOD: Our health technology assessment method combined a critical review of the literature with experts' opinions. Several databases, useful Web sites, and the gray literature were searched from January 1995 to December 2004. Some manually retrieved major articles published in 2005 were also included. The draft report was submitted to and discussed by a working group of 12 members nominated by relevant medical societies. The amended report was submitted to a multidisciplinary group of 12 peer reviewers for comment. RESULTS: Endovascular stent grafting (ESG) repair for lesions of the thoracic aorta, including aneurysms, dissections, and aortic isthmus ruptures, is probably beneficial in terms of operative mortality and severe morbidity, with an incidence of paraplegia of 2.1% (range 0%-7%) for ESG vs 5% (range, 3%-15%) for surgery, provided that there is a rigorous medium-term assessment and that anatomic factors are favorable. A proximal neck length of at least 2 cm is needed to insert the stent graft. Indications for ESG in thoracic aortic aneurysm and dissection are similar to those for surgery. Endovascular stent grafting is particularly appropriate in patients with multiple traumas to the thoracic aorta in whom concomitant lesions are a contraindication to open surgery. Endovascular stent graft repair can only be done in public or private centers with expertise in both endovascular and surgical procedures and with adequate technical facilities. Patients should be informed of the advantages and drawbacks of both methods. A multidisciplinary discussion should address risks of converting to open surgery and possible need for a cardiopulmonary bypass. Patients should be monitored annually by computed tomography scan or magnetic resonance imaging and plain radiographs because long-term results are uncertain (possible stent graft deterioration, onset of aortic disease). They should be told of the need for surveillance and possible further treatment. CONCLUSIONS: A prospective registry of all thoracic aorta procedures (endovascular treatment, open surgery, thoracic ESG plus extra-anatomic bypass) needs to be set up. All practitioners and stent graft manufacturers should contribute to this registry. It should include information on patient monitoring in order to (1) select patients who could be treated by ESG repair, (2) assess the feasibility of a randomized controlled study comparing ESG and surgery, (3) assess the medium-term outcome of different devices, and (4) obtain a better understanding of the health economics aspects.

Long-term results of carotid stenting are competitive with surgery.

OBJECTIVE: The feasibility of carotid stenting (CS) is no longer questionable, although its indications remain debatable. Until the results of randomized trials are available, personal series and registries should help in the comparison of long-term results of CS with those of endarterectomy. We report here the long-term results of a large series of CS in our department with a long follow-up. This retrospective study reviews a single surgeon's 11-year experience with CS. Our results are compared with those of conventional surgery emanating from our own series and the North American Symptomatic Carotid Endarterectomy Trial (NASCET), European Carotid Surgery Trial (ECST), and Asymptomatic Carotid Atherosclerosis Study (ACAS). MATERIALS AND METHODS: CS has been performed in our department in a single, semi-private institution for 12 years. Patients with high lesions, and postradiotherapy and postendarterectomy stenoses were treated with CS, as were patients at high risk for surgery. The others were operated on with conventional endarterectomy. During the study, we performed 221 CS procedures on 193 patients (150 men and 43 women). The average follow-up was 2.7 years (1 month to 9.3 years). We analyzed the late results in terms of prevention from stroke, the freedom from new neurologic events, and also patency rates of the treated carotid vessels. We also identified predictors for neurologic complication and in-stent restenosis by using univariate analysis. RESULTS: Life-table analyses at 10 years gave a 96% (confidence interval [CI] = 3%) rate for stroke freedom, a 98% (CI = 2%) rate for fatal stroke freedom, and a primary assisted patency rate of 95% (CI = 3%). Predictors for neurologic complication were [corrected] age >70 ( P = .041), and [corrected] potential renal insufficiency ( P = .056 [corrected] In-stent restenosis occurrence extended from 2 months to 4.5 years after the procedure. The restenosis rates at 6 months, 1, 2, and 4.5 years were, respectively, 1.4%, 2.3%, 3.7%, and 5.9% (13/221). No factors were found to be strong predictors of in-stent restenosis [corrected] CONCLUSION: These long-term results show that CS is competitive with conventional surgery. A more accurate selection for CS or surgery might reduce the rate of complications after carotid stenosis repair.

Long-term results of endovascular exclusion of extracranial internal carotid artery aneurysms and dissecting aneurysm.

OBJECTIVES: Surgery remains the standard option to treat symptomatic or complicated aneurysms of the extracranial internal carotid arteries (EICA). When located more distally to the EICA, surgery appears to be very invasive and disabling. Endovascular treatment of high aneurysmal EICA has been poorly reported. We report our experience in this particular field. METHODS: We treated five EICA endovascularly, using covered stents and stentgrafts in four patients, two males and two females. One male was treated bilaterally. The average age was 59.2 years (39-80). Three patients were symptomatic (two transient ischemic attack and one stroke). Patients were followed by duplex scan, CT scan, or angio MR. RESULTS: Protecting devices were used in two cases. No in-hospital complication was observed. During follow-up (3.6 +/- 1.3 years), no adverse event was observed and all devices remained patent at duplex scan and angiography. One early endoleak was observed and treated with covered stent extension. No sign of in-stent stenosis was observed. All the aneurysmal sacs thrombosed. CONCLUSION: Covered stents and stentgrafts allow a less invasive approach to treat highly located internal carotid aneurysms. Larger series are needed to assess the role of covered stents in treating aneurysmal EICA as first choice.