Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel

Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rβ, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. © 2013 Jilaveanu et al

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840

Radiation-induced skin injury after complex endovascular procedures

BackgroundRadiation-induced skin injury is a serious potential complication of fluoroscopically guided interventions. Transient erythema occurs at doses of 2 to 5 Gy, whereas permanent epilation, ulceration, and desquamation are expected at doses above this level. Complex endovascular procedures (CEPs), such as fenestrated endovascular aortic aneurysm repair (FEVAR), are associated with high radiation doses, yet the prevalence of radiation-induced skin injury is unknown. We hypothesized that skin injury after these exposures is likely to be underrecognized and underreported. This study examined the frequency and severity of deterministic effects and evaluated patient characteristics that might predispose to radiation injury in CEP.MethodsCEP was defined as a procedure with a radiation dose ≥5 Gy (National Council on Radiation Protection and Measurements threshold for substantial radiation dose level [SRDL]). Radiation dose and operating factors were recorded for all CEPs performed in a hybrid room during a 30-month period. Patient medical records were retrospectively reviewed for evidence of skin injury. Patients were seen in follow-up daily until discharge and then at weeks 2 and 6, months 3 and 6, and 1 year. Phone interviews were conducted to determine the presence of any skin-related complaints. Peak skin dose (PSD) distributions were calculated for FEVARs with custom software employing input data from fluoroscopic machine logs. These calculations were validated against Gafchromic film (Ashland Inc, Covington, Ky) measurements. Dose was summed for the subset of patients with multiple procedures within 6 months of the SRDL event, consistent with Joint Commission recommendations.ResultsSixty-one CEPs reached a reference air kerma (RAK) of 5 Gy (50 FEVARs, six embolizations, one thoracic endovascular aortic repair, one endovascular aneurysm repair, one carotid intervention, and two visceral interventions). The patient cohort was 79% male and had a mean body mass index of 31. The average RAK was 8 ± 2 Gy (5.0-15.9 Gy). Sixteen patients had multiple CEPs within 6 months of the SRDL event, with a mean cumulative RAK of 12 ± 3 Gy (7.0-18.4 Gy). The mean FEVAR PSD was 6.6 ± 3.6 Gy (3.7-17.8 Gy), with a mean PSD/RAK ratio of 0.78. Gafchromic film dose measurements were not statistically different from PSD estimations, with a constant of proportionality of 0.99. Three patients were lost to follow-up before their first postoperative visit. No radiation skin injuries were found.ConclusionsThis study represents the largest analysis of deterministic skin injury after CEPs, and our results suggest that it is less frequent than expected and not increased in CEPs

Aneurysmal iliac arteries do not portend future iliac aneurysmal enlargement after endovascular aneurysm repair for abdominal aortic aneurysm.

OBJECTIVES: The purpose of this study was to examine the fate of aneurysmal iliac arteries managed during endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). METHODS: We analyzed data from the Cook Zenith trial. Follow-up was at 1 month, 6 months, 12 months, and then annually for 5 years. Patients were evaluated according to the largest iliac artery diameter: group A (≥ 20 mm) and group B (\u3c 20 mm). These groups were further subdivided based on iliac artery growth ≥ 5 mm during follow-up. The Fisher exact test and χ(2) test were used. RESULTS: Of 736 patients treated, 671 had a follow-up examination (group A = 274). In group A, 220 (80%) were treated with flared limbs in the common iliac artery. Group A did not demonstrate increased iliac growth as compared to group B. Furthermore, both groups had a similar percentage of patients that experienced iliac artery expansion of 32.1% and 31.5%, respectively. Extension to the external iliac artery did not affect growth (P = .4). No difference was noted in the need for secondary interventions between groups. However, group A patients that did not experience growth were more likely to develop a distal type I endoleak than group B patients who did not develop growth (P = .03). There was no difference in serious adverse events (SAEs) between groups (P = .51). However, patients that developed iliac artery growth in either group were less likely to have an SAE compared to patients who did not experience growth (P = .035). There was no difference in the mean percent oversizing of the iliac limbs between groups A and B. However, the mean percent oversizing in groups A and B that had iliac artery growth was significantly higher than in those that demonstrated no growth (P \u3c .01). CONCLUSION: Aneurysmal iliac arteries managed by flared limbs or external iliac extensions at the time of EVAR for AAA do not demonstrate future iliac growth, increased rate of secondary interventions, or SAEs compared to patients with normal iliac arteries. This suggests that aneurysmal iliac arteries can be safely treated with appropriately sized limbs landed in the common or external iliac artery

Thoracic aortic endograft explant: a single-center experience.

OBJECTIVES: We report our experience following thoracic aortic endovascular repair (TEVAR) explant. METHODS: A total of 500 TEVARs were performed from 1999 to 2009, with 4 requiring explant. Chart review was performed to identify the indications of explant, operative technique, and perioperative morbidity and mortality. RESULTS: Indications of graft removal included device maldeployment, type I endoleak, aortoenteric fistula, and retrograde type A dissection necessitating aortic root replacement. Reconstruction was achieved with aortic homograft, Dacron, or explant of the proximal component with incorporation of the distal stent into the suture line. Mean follow-up was 13 months (0-50 months). Paraplegia and perioperative death occurred in 1 patient who underwent intraoperative conversion to open repair. There were no other major complications, and graft removal was achieved in all patients. CONCLUSIONS: Although rare, familiarity with TEVAR explant is imperative as it is increasingly performed for broader indications. Our limited data suggest that explant can be performed successfully albeit with morbidity

Lower limb revascularization for PAD using a heparin-coated PTFE conduit.

OBJECTIVE: To assess the patency of the PROPATEN Graft in lower extremity bypasses. METHODS: We retrospectively reviewed all lower extremity bypasses with the PROPATEN Graft from 2007-2009 at a single institution. There were 68 implants--56% male; mean age 69. Comorbidities included hypertension (HTN; 81%), hyperlipidemia (72%), coronary artery disease (CAD; 74%), and smoking (59%). Most patients were Rutherford category 4 or higher. A total of 34% of patients had only 1 runoff vessel; 10% of patients required a complex concomitant procedure with sequential extremity revascularization. Statistics were via Kaplan Meier. RESULTS: Mean follow-up was 10.4 ± 8.0 months (0-30). Patency was excellent in all positions. Primary patency for all patients was 94.0% and 86.0% at 30 days and 18 months, respectively. Limb salvage at 30 days was 95%, and at 18 months was 90%. No patients developed HIT. Ten patients lost graft patency. These patients had severe peripheral vascular disease (PVD), with rest pain or tissue loss, poor runoff (no runoff or single vessel runoff), compromised inflow, and restored competitive flow. Fifty percent of the failed grafts were in the infrapopliteal position. Endovascular intervention and graft thrombectomy to restore patency was attempted in 2 patients and was unsuccessful. CONCLUSION: The GORE PROPATEN Vascular Graft demonstrates excellent patency in all arterial positions and may be the conduit of choice for all prosthetic bypasses