Severe Arterial Occlusive Disease Research Articles

Results of the Simultaneous Combination of Ponatinib and Blinatumomab in Philadelphia Chromosome-Positive ALL.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

Chelation Therapy in Patients With Cardiovascular Disease: A Systematic Review.

BackgroundEDTA is an intravenous chelating agent with high affinity to divalent cations (lead, cadmium, and calcium) that may be beneficial in the treatment of cardiovascular disease (CVD). Although a large randomized clinical trial showed benefit, smaller studies were inconsistent. We conducted a systematic review of published studies to examine the effect of repeated EDTA on clinical outcomes in adults with CVD.Methods and ResultsWe searched 3 databases (MEDLINE, Embase, and Cochrane) from database inception to October 2021 to identify all studies involving EDTA treatment in patients with CVD. Predetermined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and quality of life. Twenty‐four studies (4 randomized clinical trials, 15 prospective before/after studies, and 5 retrospective case series) assessed the use of repeated EDTA chelation treatment in patients with preexistent CVD. Of these, 17 studies (1 randomized clinical trial) found improvement in their respective outcomes following EDTA treatment. The largest improvements were observed in studies with high prevalence of participants with diabetes and/or severe occlusive arterial disease. A meta‐analysis conducted with 4 studies reporting ankle‐brachial index indicated an improvement of 0.08 (95% CI, 0.06–0.09) from baseline.ConclusionsOverall, 17 studies suggested improved outcomes, 5 reported no statistically significant effect of treatment, and 2 reported no qualitative benefit. Repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe peripheral arterial disease. Differences across infusion regimens, including dosage, solution components, and number of infusions, limit comparisons across studies. Additional research is necessary to confirm these findings and to evaluate the potential mediating role of metals.RegistrationURL: https://www.crd.york.ac.uk/; Unique identifier: CRD42020166505.

Chelation Therapy in Patients with Cardiovascular Disease: A Systematic Review

BACKGROUND AND AIM: Ethylenediaminetetraacetic acid (EDTA) is an intravenous chelating agent with high affinity to divalent cations (e.g. lead, cadmium, calcium) that may be beneficial in the treatment of cardiovascular disease (CVD). While a large randomized clinical trial (RCT) funded by the National Institutes of Health showed benefit, other smaller studies were inconsistent. We performed a systematic review of published studies to examine if EDTA improves clinical outcomes in adults with CVD. METHODS: We conducted a systematic search of 3 databases (MEDLINE, Embase and Cochrane) from database inception to November 5, 2019 to identify all studies involving EDTA chelation treatment in patients with CVD. Predetermined outcomes included mortality, disease severity, plasma biomarkers of disease chronicity, and quality of life. RESULTS:We found 23 studies (4 RCTs and 19 before/after studies) that assessed the use of repeated EDTA chelation treatment in patients with pre-existent CVD. Of these, 16 studies (1 RCT) found improvement in their respective outcomes following EDTA treatment. The largest improvements were observed in studies with high prevalence of participants with diabetes and/or severe occlusive arterial disease, including peripheral artery disease (PAD). CONCLUSIONS:Repeated EDTA for CVD treatment may provide more benefit to patients with diabetes and severe PAD. EDTA excretes metals from the body that are known to induce inflammatory and oxidative processes involved in the progression of diabetes and atherosclerosis. Research is necessary to confirm these findings and to evaluate the potential mediating role of metals. KEYWORDS: Cardiovascular Diseases, Heavy Metals

Cardiovascular Scoring and Age-Related Mutations Predict the Occurrence of Adverse Vascular Events in CML Patients during Nilotinib Therapy

Although otherwise considered a relatively safe drug, the BCR/ABL1 tyrosine kinase inhibitor nilotinib has recently been associated with the occurrence of progressive arterial occlusive disease (AOD). In most of the affected patients, cardiovascular risk factors have been identified. However, AOD may even occur in patients without known risk factors. The aim of this project was to identify clinical and molecular risk factors predicting AOD development in CML patients receiving nilotinib. A total number of 36 consecutive nilotinib-treated patients with Ph+ CML (median age: 49 years; m/f ratio: 1.25, all seen at our department between 2006-2013) were examined. With the exception of one case, none of these patients had developed an AOD before nilotinib-therapy. During nilotinib therapy, AOD events were found to accumulate over time. After 2.0 years, 29.4% of our patients had developed one or more AOD events. After 3.0 years, the frequency of AOD increased to 38.9%, and after 3.7 years, it reached 47.2%. After 3.7 years, a total number of 39 symptomatic AOD events were recorded, resulting in 32 AOD-events per 100 patient-years and a 1-year hazard ratio of 4.72 compared to the AOD-risk of healthy individuals (p<0.01). No venous thromboembolic events were recorded. The frequency of patients with severe AOD did not further increase after 3.0 years which may be due to better patient-selection, drug-discontinuation, and co-medication consisting of aspirin, statins (hypercholesterolemia) and anti-diabetic drugs (diabetes mellitus). In a first step, we applied the European Society of Cardiology (ESC) SCORE. A substantial number of our patients were at high risk for AOD-development according to this score (ESC-SCORE ≥5: 5/36=13.9%). As expected we found a positive correlation between a high ESC-SCORE (≥5) and the development of AOD (AOD+: 4/5 patients; AOD-: 1/5 patients). In an attempt to identify additional risk factors, molecular and serologic studies were performed. First, we screened for well-established classical molecular risk factors. In these studies, no Factor-V Leiden- and no prothrombin mutations were detected. The median levels of protein C and protein S were found to be lower in patients with AOD compared to those without AOD (protein C, AOD: 103% vs non-AOD: 132%; protein S, AOD: 67% vs non-AOD: 105%). We also detected a correlation between the blood group status and the occurrence of AOD: non-0 status in AOD patients: 73.3% vs non-0 status in non-AOD patients: 52.9%. Next we examined our patients for the presence of age-related somatic mutations (ARCH) as recent data have shown that such mutations (in TET2, ASXL1, DNMT3A, ZRSR2, CEBPA, and SF3B1) are associated with an increased risk of healthy individuals to develop a myeloid neoplasm but also to develop a severe cardiovascular disease (Jaiswal et al, N Engl J Med 2014;371:2488-2498). In our study, we found that these ARCH mutations, especially mutations in TET2, ASXL1, and DNMT3A, are more frequently detected in CML patients who developed AOD during nilotinib-treatment compared to those who did not develop AOD (AOD in mutation-positive patients: 11/17=65% vsAOD in mutation-negative patients: 6/19=32%, p<0.05) (Figure). These mutations were detected at the time of partial or complete molecular response but also in patients with residual CML (BCR-ABL1 mRNA >1%-44%). The allele burden of age-related mutations ranged between 2% and 68%. In one patient without AOD, low levels (1.6% allele-frequency) of JAK2 V617F were detected. In conclusion, multiple clinical and molecular risk factors predict the occurrence of AOD development in nilotinib-treated patients with CML. Based on our results the major recommended tool for prognostication is the ESC-SCORE. However, additional factors, like protein C and S, the blood group and age related mutations detected by NGS after debulking of the dominant BCR-ABL1+ sub-clones, should also be taken into account. Together with optimal metabolic control and co-medication, these recommendations may lead to optimal patient-selection and better control and management of vascular side-effects in nilotinib-treated patients with CML. [Display omitted] DisclosuresHadzijusufovic:Novartis: Honoraria. Hoermann:Gilead: Honoraria, Research Funding; Ariad: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Sperr:Amgen: Consultancy, Honoraria, Research Funding; Meda: Research Funding; Celgene: Consultancy, Honoraria; Phadia: Research Funding; Teva: Honoraria; Novartis: Other: Register. Jilma:Biomed: Research Funding; Arsanis: Research Funding; Baxalta: Research Funding; Emcools: Research Funding; Bayer: Research Funding; Syntheract: Research Funding; Valneva: Research Funding; Boehringer Ingelheim: Research Funding; TrueNorth Therapeutics Inc.: Consultancy; Octapharma: Research Funding; Prediction Biosciences: Research Funding; Recardio: Research Funding; Themis: Research Funding; TrueNorth Therapeutics: Research Funding; Bioverativ: Research Funding; JHL: Research Funding; VitaerisBios: Research Funding. Schernthaner:Amgen: Honoraria; Astra Zeneca: Honoraria; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Elli Lilly: Honoraria; Merck: Honoraria; Novo-Nordisk: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Sanofi-Aventis: Honoraria. Valent:Teva: Honoraria; Ariad: Honoraria, Research Funding; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Hybrid-based iliofemoral endarterectomy for severe and complete iliofemoral occlusive disease

ObjectivePrimary endovascular approaches are now the dominant modality for the treatment of iliac occlusive disease. However, stenting of the external iliac artery is plagued with high in-stent restenosis rates. This hybrid approach with fluoroscopic, retrograde iliofemoral endarterectomy combined with stenting was previously demonstrated to be both a safe and effective alternative to bypass and primary stenting alone for TransAtlantic Inter-Society Consensus (TASC) II C and D lesions. In this study, early outcomes and hemodynamic improvements of this hybrid approach are evaluated with an expanded patient population. MethodsThis was a single-institution, retrospective review of all hybrid-based retrograde iliofemoral endarterectomies from the common femoral artery extending to the proximal external iliac artery from January 1, 2010, to November 15, 2017. Data were collected from the electronic medical record and analyzed using standard quantitative statistical techniques. All preprocedure and postprocedure imaging was independently reviewed by two vascular surgeons. Variables included patient demographics, degree of ischemia, and stent characteristics. The primary outcomes were mortality and freedom from amputation, with secondary outcomes including changes in the ankle-brachial index and toe pressure. ResultsThe procedure was performed on 63 limbs in 51 total patients. In 33 limbs, the indication was critical limb ischemia (tissue loss/gangrene = 17, rest pain = 16) and 30 for lifestyle-limiting claudication. The cohort consisted of 84% TASC D and 16% TASC C. External iliac stenting was required in 68% (modal diameter, 10 mm) and ipsilateral common iliac stenting was completed in 75% (modal diameter, 9 mm). The ankle-brachial index significantly improved from 0.42 ± 0.25 to 0.73 ± 0.27 (P < .001) as did toe pressure from 29 ± 27 mm Hg to 59 ± 34 mm Hg (P < .001). Thirteen limbs ultimately required an infrainguinal procedure. One patient experienced an intraoperative iliac perforation that resolved with stenting. One death occurred within 90 days. Ninety-five percent of patients remained free from amputation. ConclusionsExtensive hybrid-based, retrograde iliofemoral endarterectomy with stenting is a safe and efficacious approach to severe iliac arterial occlusive disease, with excellent early outcomes. This series promulgates the hypothesis that extensive endarterectomy with selective iliac stenting yields superior results to external iliac stenting alone. Given the superb hemodynamic improvements in a larger patient population, this hybrid-based, extensive iliofemoral endarterectomy should be recommended as a minimally invasive, first-line treatment for severe iliac occlusive disease.

Further Evaluation of Pro-Atherogenic and Anti-Angiogenic Effects of Nilotinib in Mice and in Patients with Ph-Chromosome+ CML

Abstract Nilotinib, an inhibitor of BCR/ABL1 is increasingly used to treat patients suffering from chronic myeloid leukemia (CML). However, treatment with nilotinib is associated with the occurrence of vascular adverse events, including progressive atherosclerosis resulting in arterial occlusive disease (AOD). We have recently shown that these events are recurrent and severe and accumulate over time in our patients (n=36). The percentage of patients developing i) one or more clinically overt (symptomatic) AOD-related events and ii) one or more clinically severe AOD events requiring surgical intervention and/or prolonged hospitalization increased from 26.5% and 17.6% at a median observation time (MOT) of 24 months to 44.4% and 19.4% after a MOT of 44 months. The frequency of AOD was lower in all control cohorts examined, including risk factor- and age-matched CML patients treated with imatinib, patients suffering from myelodysplastic syndromes, patients with JAK2-mutated myeloproliferative neoplasms and patients with lymphoid neoplasms. In order to explore the potential pro-atherogenic potential of nilotinib, we employed ApoE knock-out mice. In these mice, treatment with nilotinib (75 mg/kg/day p.o. for 8 weeks) was found to promote plaque formation and thus atherosclerosis when compared to control-mice (percent aortic plaque-area: vehicle-control: 16±3.2%; imatinib: 19.4±8.2%; nilotinib: 22.4±2.9%; p&lt;0.005 for nilotinib vs control). To evaluate the effects of nilotinib on vascular repair processes following stenosis, we also employed a mouse model of hindlimb ischemia. Here, nilotinib (75 mg/kg/day p.o. for 28 days) was found to decrease reperfusion after induction of ischemia whereas imatinib (100 mg/kg/day p.o. for 28 days) showed no comparable effect as determined by laser Doppler perfusion imaging. The decreased perfusion seen in the nilotinib-treated mice was accompanied by an increased rate of limb necrosis as well as a decrease in microvessel density when compared to imatinib-treated mice or control-mice (p&lt;0.05). In addition, we found that the pro-atherogenic cytoadhesion molecule VCAM-1 is expressed at higher levels in vascular cells in nilotinib-treated mice compared to imatinib-treated mice or control animals (cells/high power field: control: 13.9±11.9; imatinib: 14.9±11; nilotinib: 22.6±9.3). In a next step, we examined the in vitro effects of nilotinib on cultured human umbilical vein endothelial cells (HUVEC). In these experiments, we found that nilotinib (between 1-10 µM), but not imatinib (1-10 µM) promotes the expression of the cytoadhesion molecules ICAM-1, VCAM-1 and E-Selectin on HUVEC, confirming our data obtained in mice. In addition, we were able to confirm the anti-angiogenic effects of nilotinib seen in mice by our in vitro experiments. In particular, nilotinib was found to inhibit the migration of HUVEC in a wound-scratch assay as well as angiogenesis in a tube-formation assay whereas imatinib showed no comparable effect. Moreover, nilotinib was found to inhibit the proliferation of HUVEC in a dose-dependent manner (IC50: 1.0 µM) whereas imatinib showed no substantial effect up to 5 µM. Finally, we examined bone marrow (BM) microvessel density in 8 CML patients before and during treatment with nilotinib (800 mg/day for at least 1 year). In these experiments, we found that the numbers of CD34+ endothelial cells per high power field decreases substantially during treatment with nilotinib (before nilotinib: 12.3±2 versus post-nilotinib: 5.5±2.6, p&lt;0.05). In summary, nilotinib exerts direct proatherogenic and growth-inhibitory and thus anti-angiogenic effects on vascular endothelial cells. Whether these effects contribute to nilotinib-associated vasculopathy in patients with CML is currently under investigation. Disclosures Wolf: BMS: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Valent:Pfizer: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Stent Graft Treatment of AAA With Preservation of the Inferior Mesenteric Artery

Coverage of the inferior mesenteric artery is standard in stent graft treatment of an infrarenal abdominal aortic aneurysm (AAA). Complications of colonic ischemia are rare, but risk factors include poor collateral flow from prior colonic surgery or from severe pelvic arterial occlusive disease. Preservation of inferior mesenteric artery (IMA) flow may prevent such complications in patients deemed to be at high risk for intestinal/pelvic ischemic complications. We have performed two unique cases of aortic stent grafting with preservation of IMA flow, comprising one IMA fenestration and one IMA snorkel. Record reviews of these two patients with details on the indications, technical details, and outcomes were recorded. A 53-year-old woman with a recent right hemicolectomy for cecal cancer also an enlarging AAA at 4.5 cm and a right iliac aneurysm of 3.8 cm. Given the recent colonic resection, the need to occlude the right internal iliac artery, and a stenotic left internal iliac artery, her risk for colonic ischemia was thought to be significantly higher than the average. To avoid this, a single fenestration was made with a back table modification of a Zenith graft (Cook Inc, Bloomington, Ind) and a Viabahn stent (W. L. Gore, Flagstaff, Ariz) and was used to fenestrate the IMA. On follow-up, the patient had no complications with no evidence of colonic ischemia and successful treatment of her AAA (Fig 1). The second patient was a 61-year-old man with a history a left iliac stent placed previously for calf claudication who developed severe, progressive hip claudication and impotence. Computed tomography angiography showed 3.5-cm iliac aneurysms and a 3.7-cm distal aortic aneurysm with preocclusive right and totally occluded left internal iliac arteries. There was a 7-mm-diameter inferior mesenteric artery coming off the AAA with severe stenosis at its origin. An Endologix AFX stent graft (Endologix, Irvine, Calif) was used to treat the aortoiliac aneurysmal disease with a long Viabahn snorkel stent placed into the IMA. Both iliac limbs were extended to the externals. Follow-up computed tomography showed complete exclusion of the aortoiliac aneurysms with no endoleak, and the patient had resolution of his hip claudication and impotence (Fig 2). Preservation of IMA flow with modified stent graft techniques is feasible and may reduce complications of colonic and pelvic ischemia in highly selected patients.Fig 1Fenestration technique. CTA, Computed tomography angiography; IMA, inferior mesenteric artery.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Octogenarians Develop Infrapopliteal Arterial Occlusive Disease in the Absence of Traditional Risk Factors

With increasing longevity, a growing proportion of patients who present with lower extremity peripheral arterial disease (LE-PAD) are ≥80years old. While smoking and diabetes mellitus (DM) have traditionally been the main risk factors associated with PAD, we noted a pattern of severe infrapopliteal PAD in patients ≥80years old in the absence of these traditional risk factors. As recognition of patterns of disease affects decisions regarding diagnostic and therapeutic approach, we sought to confirm this observation. A single-center retrospective review was performed on all patients who underwent lower extremity arteriography between March 2007 and September 2009. Arteriograms were scored in a blinded fashion. Any infrapopliteal PAD was defined as one or more infrapopliteal arteries with either >50% stenosis or total occlusion. Severe infrapopliteal PAD was defined as 2 or more infrapopliteal arteries with >50% stenosis or total occlusion. Fisher's exact test and 2-sample t-test or Wilcoxon rank-sum test were used for analysis. Two hundred ninety-seven patients comprised the study population. Eighty-two percent (= 145/176) of those ≤70years old versus 96% (= 46/48) of those ≥80years old had any infrapopliteal PAD (P=0.02). Thirty percent of patients ≥80years old with infrapopliteal PAD had no history of DM or smoking, while only 5% of younger patients had infrapopliteal PAD in the absence of DM or smoking (P<0.0001). A similar pattern was seen for severe infrapopliteal PAD. Tissue loss was an indication for lower extremity arteriography in 45% of those ≤70years of age versus 65% of those ≥80 (P=0.022). A significant proportion of patients ≥80years of age with PAD develop arterial disease in the infrapopliteal pattern in the absence of the traditional risk factors of smoking and DM. Our data also showed that this pattern of disease is significantly associated with tissue loss and critical limb ischemia, particularly in patients ≥80years of age. Primary care providers need to be educated to suspect ischemic etiology for foot pain and ulcers in elderly patients not otherwise thought to have risk factors associated with PAD. Vascular specialists need to anticipate this pattern of disease when planning interventions. As smoking becomes less prevalent and as the population ages, octogenarians with severe infrapopliteal arterial occlusive disease will become a larger proportion of the patients treated by vascular specialists.

Nilotinib Exerts Direct Pro-Atherogenic and Anti-Angiogenic Effects On Vascular Endothelial Cells: A Potential Explanation For Drug-Induced Vasculopathy In CML

The BCR/ABL1 inhibitor nilotinib is increasingly used to treat patients with chronic myeloid leukemia (CML). However, nilotinib apparently induces metabolic changes, including an increase in the fasting glucose level. In addition, vascular adverse events, including progressive atherosclerosis with peripheral arterial occlusive disease (AOD) have been reported in nilotinib-treated CML patients. We reviewed and updated AOD events in our CML patients receiving nilotinib (n=34) and initiated preclinical in vitro and in vivo studies in order to dissect potential targets and mechanisms. After a median observation time (MOT) of 24 months, the frequency of AOD (26.5%) and severe AOD requiring surgical intervention and/or prolonged hospitalization (17.6%) was higher in nilotinib-treated patients compared to risk factor-, observation time-, and age-matched controls (34 imatinib-treated patients with CML, 34 with myelodysplastic syndromes, 34 with JAK2-mutated MPN and 34 with lymphoid neoplasms; <5% AOD, p<0.05). After a MOT of 36 months, the frequency of AOD amounted to 36.1% and the frequency of severe AOD was 19.4%. We next examined the in vitro effects of nilotinib on cultured human umbilical vein endothelial cells (HUVEC), human coronary artery-derived endothelial cells (HCAEC), and the human microvascular endothelial cell line HMEC-1. As determined by 3H-thymidine incorporation, nilotinib was found to inhibit the proliferation of endothelial cells in a dose-dependent manner, with pharmacologically relevant IC50 values obtained in HUVEC (1.0 µM), HCAEC (100 nM), and HMEC-1 (1.0 µM), whereas imatinib showed little effect up to 5 µM. Moreover, nilotinib was found to inhibit the migration of HUVEC in a wound-scratch assay as well as angiogenesis in a tube-formation assay (relative capillary tubes: VEGF+control: 1.8±0.1, VEGF+nilotinib (100 nM): 1.3±0.1, VEGF+imatinib (100 nM): 1.7±0.05; n=3, p<0.01 for VEGF alone vs VEGF+nilotinib). In a mouse model of hindlimb ischemia, nilotinib (75 mg/kg/day p.o. for 28 days) was found to slow blood flow-recovery after induction of ischemia whereas imatinib (100 mg/kg/day p.o. for 28 days) showed no comparable effect (laser Doppler perfusion imaging ratio ischemic/control leg: control mice: 0.81±0.03, imatinib-treated mice: 0.79±0.04, nilotinib-treated mice: 0.68±0.04; n=13/group; p<0.05 for nilotinib vs control and for nilotinib vs imatinib). The decreased blood perfusion was accompanied by an increased rate of limb necrosis (necrosis score: control: 1.15±0.08, imatinib: 1.17±0.05, nilotinib: 1.54±0.18; p<0.05 for nilotinib vs control and nilotinib vs imatinib). Moreover, microvessel density was significantly lower in the affected hind limb in nilotinib-treated mice compared to imatinib-treated mice or control-mice (p<0.05). In addition, we found that nilotinib (between 1-10 µM), but not imatinib (1-10 µM) promotes the expression of pro-atherogenic cytoadhesion molecules (CAM) on HUVEC, including ICAM-1 (CD54), VCAM-1 (CD106) and E-Selectin (CD62E). By contrast, nilotinib (up to 10 µM) showed no effects on expression of plasminogen activators or uPA receptor (CD87) in cultured endothelial cells. As assessed by chemical proteomics profiling and phospho-array analysis, several angiogenesis-related and other endothelial antigens, including Tie-2/TEK, JAK1, BRAF and EPHB2 were identified as molecular targets of nilotinib, whereas imatinib did not bind to these vascular targets in endothelial cells. As assessed by immunohistochemistry using antibodies against KIT and mast cell tryptase, we also found that in our CML patients, nilotinib induces an almost complete depletion of KIT+ mast cells, a cell type that serves as unique source of heparin and uncomplexed tPA and has been implicated as a major repair cell in vascular disorders. However, imatinib was also found to induce mast cell depletion in our patients with CML. Neither nilotinib nor imatinib showed in vitro or in vivo effects on platelet adhesion or platelet aggregation. In conclusion, nilotinib exerts multiple effects on vascular endothelial cells and other perivascular cells such as mast cells, presumably through multiple mechanisms and targets. We hypothesize that these effects may contribute to nilotinib-induced vasculopathy in CML. Disclosures:Wolf:Bristol-Meyers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Valent:Novartis: Consultancy, Honoraria, Research Funding.

Noninvasive monitoring of blood pressure in the critically ill

In the critically ill, blood pressure measurements mostly rely on automated oscillometric devices pending the intra-arterial catheter insertion or after its removal. If the arms are inaccessible, the cuff is placed at the ankle or the thigh, but this common practice has never been assessed. We evaluated the reliability of noninvasive blood pressure readings at these anatomic sites. Prospective observational study. Medical-surgical intensive care unit. Patients carrying an arterial line with no severe occlusive arterial disease. Each patient underwent a set of three pairs of noninvasive and intra-arterial measurements at each site (arm, ankle, thigh [if Ramsay sedation scale >4]) and, in case of circulatory failure, a second set of measurements after a cardiovascular intervention (volume expansion, change in catecholamine dosage). In 150 patients, whatever the cuff site, the agreement between invasive and noninvasive readings was markedly higher for mean arterial pressure than for systolic or diastolic pressure. For mean arterial pressure measurement, arm noninvasive blood pressure was reliable (mean bias of 3.4 ± 5.0 mm Hg, lower/upper limit of agreement of -6.3/13.1 mm Hg) contrary to ankle or thigh noninvasive blood pressure (mean bias of 3.1 ± 7.7 mm Hg and 5.7 ± 6.8 mm Hg and lower/upper limits of agreement of -12.1/18.3 mm Hg and -7.7/19.2 mm Hg, respectively). During acute circulatory failure (n = 83), arm noninvasive blood pressure but also ankle and thigh noninvasive blood pressure allowed a reliable detection of 1) invasive mean arterial pressure <65 mm Hg (area under the receiver operating characteristic curve of 0.98 [0.92-1], 0.93 [0.85-0.97], and 0.93 [0.85-0.98] for arm, ankle, and thigh noninvasive blood pressure, respectively); and 2) a significant (>10%) increase in invasive mean arterial pressure after a cardiovascular intervention (area under the receiver operating characteristic curve of 0.99 [0.92-1], 0.90 [0.80-0.97], and 0.96 [0.87-0.99], respectively). In our population, arm noninvasive mean arterial pressure readings were accurate. Either the ankle or the thigh may be reliable alternatives, only to detect hypotensive and therapy-responding patients.

Vascular Imaging of the Foot: The First Step toward Endovascular Recanalization

In the past 5 years, with the introduction of new techniques and dedicated materials, endovascular recanalization of distal tibial and pedal vessels has become a valid alternative to inframalleolar bypass for limb salvage in patients with severe arterial occlusive disease, particularly diabetics. Revascularization of the foot is now often performed by using percutaneous transluminal angioplasty; over a 4-year period, the authors performed more than 2500 antegrade interventional procedures in patients with critical limb ischemia, diabetes, and infrainguinal arterial disease. Intraprocedural angiography of the foot is crucial for successful planning and guidance of percutaneous transluminal angioplasty in tibial and pedal arteries, and its effective use requires both anatomic knowledge and technical skill. To select the best revascularization strategy and obtain optimal clinical results, interventional radiologists, cardiologists, and vascular surgeons performing below-the-knee endovascular procedures also must be familiar with the functional aspects of circulation in the foot. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.316115511/-/DC1.

Phenol lumbar sympathectomy for severe arterial occlusive disease in the elderly.

Phenol chemical lumbar sympathectomy is an additional aid in the management of ischaemic rest pain and incipient gangrene. This technique was used in 132 elderly patients in Bath between September 1972 and March 1975 and the results are presented here. The patients were unfit for reconstructive arterial surgery. In this series an image intensifier was used in order to make the procedure safer. One hundred and twenty-six patients were available for review, their average age being 71.5 years. The average period of follow-up was 16.3 months. Of the 126 patients, 111 were not diabetic, and of these 45 (41 per cent) had satisfactory results while 17 (15.4 per cent) had persistent symptoms but had avoided amputation. Thirty (27 per cent) patients required amputation and 12 of these died as a direct result of this procedure. A further 19 patients in the non-diabetic group died during the period of follow-up. However, of the 15 diabetic patients, only 3 (20 per cent) improved whilst one patient with persistent symptoms avoided amputation. The remainder either died (8) or had an amputation (5) during the period of follow-up. Two died after amputation.

Die „Beckenkammspan-Interpositionsarthrodese“ des oberen Sprunggelenks

Bony fusion of the ankle in a functionally favorable position for restitution of a painless weight bearing while avoiding a leg length discrepancy.Disabling, painful osteoarthritis of the ankle with extensive bone defect secondary to trauma, infection, or serious deformities such as congenital malformations or diabetic osteoarthropathies.Acute joint infection. Severe arterial occlusive disease of the involved limb.Lateral approach to the distal fibula. Fibular osteotomy 7 cm proximal to the tip of the lateral malleolus and posterior flipping of the distal fibula. Exposure of the ankle. Removal of all articular cartilage and debridement of the bone defect. Determination of the size of the defect and harvesting of a corresponding tricortical bone graft from the iliac crest. Also harvesting of autogenous cancellous bone either from the iliac crest or from the lateral part of the proximal tibia. Insertion of the tricortical bone graft and filling of the remaining defect with cancellous bone. Fixation with three 6.5-mm titanium lag screws. Depending on the extent of the defect additional stabilization of the bone graft with a titanium plate. Fixation of the lateral fibula on talus and tibia with two 3.5-mm titanium screws for additional support. Wound closure in layers. Split below-knee cast with the ankle in neutral position.Between January 2002 and January 2004 this technique was used in five patients with extensive bone defects (four women, one man, average age 57 years [42-77 years]). No intra- or early postoperative complications. The AOFAS (American Orthopedic Foot and Ankle Society) Score was improved from 23 points preoperatively to 76 points postoperatively (average follow-up time of 25 months). Two patients developed a nonunion and underwent a revision with an ankle arthrodesis nail. A valgus malposition after arthrodesis in one patient was corrected with a supramalleolar osteotomy.

Finger pricking

A 59-year-old man with diabetes mellitus and end-stage renal disease requiring peritoneal dialysis was admitted for amputation of the right lower leg because of severe arterial occlusive disease. During his recovery, he started glucose self-monitoring and a few days later, complained of pain and purple discolouration of the fourth finger of his left hand. Examination showed multiple small, well circumscribed areas of skin necrosis around recent finger pricking sites. Despite treatment with iloprost infusions, the lesions progressed to necrosis of the distal phalange.

Outcome of Venous Stasis Ulceration when Complicated by Arterial Occlusive Disease

Objective: to report the outcome of patients with venous stasis ulceration (VSU) and severe arterial occlusive disease (AOD).Design: retrospective study.Methods: using the International Classification of Diseases (ICD-9), codes for VSU and AOD were cross-matched to identify patients from 1989 to 1999 at two tertiary hospitals. Entry into the study required the presence of a VSU and an ipsilateral procedure to improve AOD or major amputation during the same hospitalisation.Results: fourteen patients (15 extremities) with a mean age of 80 years (range: 47–93) were identified as having VSU and AOD. Mean duration of VSU up to the time of revascularisation or amputation was 6.4 years (range: 4 months–21 years). The mean number of VSUs per extremity was 2.1 and mean wound area was 71cm2. Mean ankle–brachial index was 0.46 (range: 0.10–0.78). Nine extremities (60%) had a bypass procedure, 3 (20%) had an interventional procedure, 1 (0.6%) had a lumbar sympathectomy, and 2 (13%) had an amputation. Over a mean follow-up of 2.8 years, 3 extremities (23%) healed of which 2 recurred. On last review, 11 patients with 12 afflicted extremities had expired. Nine of the remaining 10 extremities were not healed at the time of death. Eight of nine bypass grafts remained patent in follow-up or at death and subsequent limb salvage was 100%.Conclusions: combined VSU and AOD represents a rare condition predominantly found in elderly patients with multiple comorbidities. Few patients had complete healing despite an arterial inflow procedure and mortality was high over the short term.

Magnetic resonance angiography unmasks reliable target vessels for pedal bypass grafting in patients with diabetes mellitus

Objective: The purpose of this study was to evaluate the performance of pedal bypass grafts to foot vessels detected by magnetic resonance angiography (MRA) that were occult in conventional angiography in patients with diabetes mellitus and severe arterial occlusive disease. Methods: Vascular surgery and radiology registries were reviewed for patients with pedal bypass grafts to arteries that were not detected with digital subtraction angiography but unmasked with MRA. From December 1997 to March 1999, 15 patients (mean age, 73 ± 8 years) were identified and analyzed retrospectively. All the patients were diabetic, with 60% being insulin-dependent. Advanced tissue loss was the operative indication in all the cases. Distal anastomosis was performed to the dorsalis pedis artery in 10 cases and to the plantar artery in five cases, with ipsilateral greater saphenous vein as graft material in all the cases. Results: The perioperative mortality rate was 7% (1 of 15 cases). One graft occlusion resulted in a secondary patency rate of 93.1%. During a mean follow-up examination period of 22 months, no graft occlusions and one major amputation were noted, which resulted in a secondary patency rate of 93.1% and a limb salvage rate of 89.5% at 36 months. Conclusion: Foot vessels that were occult in conventional angiography but could be detected with MRA were shown to be suitable target vessels for pedal bypass grafting with promising results.( J Vasc Surg 2002;35:766-72.)

Severe digital arterial occlusive disease and acute parvovirus B19 infection

We report a case of arterial occlusive disease and digital ischaemia associated with acute parvovirus B19 infection. Treatment with intravenous epoprostanol improved her symptoms.

Management of the Femoral Artery After Transluminal Repair of Abdominal Aortic Aneurysms

Catheter-based treatment of abdominal aortic aneurysms (AAA), in which an endograft is placed into the aneurysmal aorta through one or more femoral arteriotomies, is gaining acceptance rapidly. This technique has the advantage of avoiding the morbidity and prolonged recovery of conventional repair, but subjects the femoral arteries to significant surgical and catheter trauma that may compromise the outcome of the procedure. We review our experience with management of the femoral arteries following endovascular aneurysmal repair. Thirty patients undergoing endovascular repair of their AAA with the modular bifurcated Aneu Rxg (Medtronic AneuRx, Sunnyvale, CA) endovascular prosthesis had their femoral arteries exposed through bilateral groin incisions to permit insertion of the device. Proximal and distal control of the femoral arteries was achieved, and guidewire passage and sheath access obtained using standard angiographic techniques. The endovascular components, ensheathed in a 22F (primary device) or 16F (secondary device) catheter were positioned and deployed from bilateral common femoral arteriotomies. The 22F insertion system was used in the right femoral artery in 18 and left femoral artery in 12 of the 30 procedures. Repair of the femoral arteriotomies was accomplished following standard vascular surgical principles, and femoral and pedal pulses and ankle-brachial indices (ABI) recorded postoperatively. All 30 patients were men (mean age: 73 ±8 years), and all had evidence of extra-aortic atherosclerosis. The endovascular prosthesis was deployed successfully in 29 of the 30 patients. One limb was lost in the postoperative period secondary to severe pre-existing arterial occlusive disease in the popliteal and tibial arteries, and one patient thrombosed an associated popliteal aneurysm requiring emergent repair on the first postoperative day. No patient experienced a permanent change in the pulse examination or reduction in the ABI. Thirteen of the 60 (22%) arteries required repair other than simple closure of the arteriotomy to restore arterial continuity. Complex repair was more common in the initial 15 (10 of 30 arteries, 33%) patients than in the latter 15 (3 of 30 arteries, 10%, p=0.01) and on the side of the larger, primary device (8 of 30 arteries, p=NS). Technically successful repair was achieved in all vessels. Although associated with shorter recovery times and brief hospital stays, endovascular repair of AAA, not unexpectedly, may require complex management of the sites of access for the prosthesis. The need for complex repair appears to diminish both with increasing experience with the device and smaller device size. Simplifying management of the femoral artery requires significant advances in the design of the currently available devices.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Femorodistal Bypass Using Cryopreserved Venous Allografts for Limb Salvage

Critical ischemia due to extensive femoropopliteal occlusive disease often leads to amputation in patients in whom an autologous vein is unavailable for reconstruction. The purpose of this nonrandomized prospective study is to evaluate the usefulness of cryopreserved venous allografts (CPVA) as an arterial substitute in these cases. Between October 1990 and March 1993, long bypass to a tibial or a foot artery using a CPVA was performed in 25 consecutive patients with ulcerations or gangrene. There were 19 women and six men with a mean age of 72 years (range: 51-90). The indication for allograft reconstruction was absence (17 cases) or unsuitability (eight cases) of an autologous vein graft. Greater saphenous vein allografts were harvested from multiple organ donors and frozen at -80 degrees C with 12% dimethylsulfoxide (DMSO). Sixteen patients had undergone one or more previous unsuccessful limb salvage attempts. The plantar arch was absent or incomplete in 16 patients (64%). Patients were followed up prospectively for a mean of 21 months (range: 3-32). One patient died early (32 days) and three patients died late with patent bypasses. Cumulative survival rate was 77% at 1 year and 72% at 2 years. Cumulative secondary patency rate (Kaplan-Meier) was 88% at 1 months, 72% at 6 months, and 52% at 1 year. The cumulative limb salvage rate was 78% at 2 years. When an autologous vein is unavailable, long bypass using a CPVA is a simple, quick, minimally traumatic, economical, and effective method to achieve limb salvage in patients with severe distal arterial occlusive disease. However, CPVA causes immunoreaction and there is a risk of proximal postanastomotic stenosis. Doppler ultrasound surveillance of a subcutaneous graft allows accurate assessment and repair of the abnormalities with no increase in mortality or morbidity.