Super-selective intra-arterial dissolution therapy for lingual artery occlusion resulting due to the use of hyaluronic acid for chin augmentation: The first reported case.

As a consequence of the current trend of performing minimally invasive surgery, the use of injectable fillers has progressively increased in aesthetic surgery. Vascular complications resulting due to the filling of hyaluronic acid (HA) in the chin have been previously reported. However, clinical evidence regarding the results of treatment of lingual artery occlusion with super-selective intra-arterial dissolution is lacking. Herein, we reported a case of lingual artery occlusion resulting due to HA filling for which tongue arteriography and catheter-directed dissolution were implemented via femoral artery intubation for the first time in the literature. The aim of this paper was to discuss the rare complications arising due to chin augmentation and their treatment to provide a deeper understanding of the use and side effects of HA in this procedure.

Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee.

BACKGROUND: The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. METHODS: To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. RESULTS: A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. CONCLUSIONS: This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 ( https://clinicaltrials.gov/ct2/show/NCT01207440 ).

Cancer Therapy-Associated Thrombosis.

[Figure: see text].

Arterial Thrombotic Complications of Tyrosine Kinase Inhibitors.

Abnormal expression or function of several classes of kinases contribute to the development of many types of solid and hematologic malignancies. TKs (tyrosine kinases) in particular play a role in tumor growth, metastasis, neovascularization, suppression of immune surveillance, and drug resistance. TKIs (tyrosine kinase inhibitors) targeted to TKs such as BCR-ABL1, VEGF receptors, PDGF receptors, have transformed therapy of certain forms of cancer by providing excellent efficacy with relatively low adverse event rates. Yet some of these agents have been associated with high rates of vascular events, presumably from prothrombotic complications that result in myocardial infarction, stroke, and critical limb ischemia. This review describes the scope of the problem evidenced by clinical experience with some of the most commonly used TKIs, with a focus on TKIs targeted to the BCR-ABL1 (breakpoint cluster region-Abelson 1) translocation. We also discuss the potential mechanisms responsible for arterial thrombotic complications that could lead to mitigation strategies or unique TK targeting strategies to reduce adverse event rates without compromising efficacy.

Surgical outcomes of strabismus after iatrogenic ophthalmic artery occlusion caused by cosmetic filler injections.

BACKGROUND: To investigate the surgical outcomes of strabismus related to iatrogenic occlusion of the ophthalmic artery and its branches from cosmetic facial filler injection. METHODS: A retrospective study was performed on 6 patients who underwent strabismus surgery among 23 patients who had suffered occlusion of the ophthalmic artery and its branches after cosmetic facial filler injection. Initial, preoperative and final ocular motility examinations, the type of surgery and surgical outcomes were evaluated. RESULTS: At initial presentation, visual acuity was no light perception in 5 patients and hand motion in one patient. Five out of 6 patients showed initial ophthalmoplegia. Among these 5 patients, eye motility fully recovered in 3 patients although sensory strabismus developed during follow-up, while the remaining 2 patients had persistent ocular motility limitations. Strabismus surgery was performed at 2.2 ± 1.5 years after iatrogenic ophthalmic artery occlusion. Preoperatively, 5 of the 6 patients showed exotropia, and one patient had esotropia. Vertical deviation was found in 3 out of 6 patients in addition to the horizontal deviation. Successful outcome was achieved only in the 4 patients without persistent ophthalmoplegia after 1.4 ± 1.0 years from surgery. The other two patients with persistent ocular motility limitations failed to achieve successful alignment after surgery, and one patient eventually underwent evisceration due to phthisis bulbi. CONCLUSIONS: In our study, surgical outcomes of strabismus caused by cosmetic facial filler injection were successful only in patients without persistent ophthalmoplegia at the time of surgery.

Management of Intracranial Stenotic Disease in Cancer Patients Treated With Vasotoxic Agents.

OBJECTIVE: To summarize the characteristics of and therapeutic options for cancer patients whose treatments may be vasotoxic and cause intracranial arterial stenotic disease and stroke. METHODS: We describe 3 patients with symptomatic cerebrovascular pathology that were being actively treated for cancer. RESULTS: Two of the patients were being treated with tyrosine kinase inhibitors (TKIs); and the third was being treated with 2 monoclonal antibodies, one of which was targeting an endothelial growth factor. These agents have been associated with vascular adverse events. Surgical revascularization was done in the first 2 patients, as they were suffering from cerebral ischemia. The third patient had suffered a significant brain hemorrhage, and therapeutic options were limited. In the first 2 patients, treatments also included antiplatelet agents and stopping/changing the TKI. In one of these patients we demonstrated regression of arterial stenosis after changing the TKI. CONCLUSIONS: Possibilities for treatment in this population, beyond the usual medical and surgical administrations, may include stopping or changing cancer drugs that may be related to the development of arterial pathology. Collaboration with oncologists is essential in this subset of patients. While aware of the potential for vascular toxicity, oncologists are often not fully appreciative of the fact that their therapeutic agents can cause stroke.

Experimentally Induced Arterial Embolism by Hyaluronic Acid Injection: Clinicopathologic Observations and Treatment.

BACKGROUND: Although major complications of hyaluronic acid injection rarely occur, with the rapidly growing number of procedures performed and their expanding applications, such complications warrant greater attention. Our study was designed to explore optimal treatment methods for hyaluronic acid-related vascular occlusion. METHODS: In the first part of the study, 60 rats were given intraarterial hyaluronic acid injected into the bilateral inferior epigastric arteries to establish an animal model, and were euthanized at different postinjection time points. The inferior epigastric artery was retrieved for pathologic examination. In the second part of the study, bilateral abdominal flaps supplied by the inferior epigastric artery were elevated in six groups of rats, and hyaluronic acid was injected into the right side, with each group receiving a different intervention. The flap survival rate was calculated and analyzed. RESULTS: In the first part of the study, pathologic examination revealed that the composition of the emboli caused by arterial hyaluronic acid-induced occlusion changed from pure hyaluronic acid to a hyaluronic acid-thrombus mixture. In the second part of the study, flap survival rates (mean percentages) were as follows: group A, 43.29 ± 9.28 percent; group B, 54.17 ± 10.86 percent; group C, 59.27 ± 13.40 percent; group D, 64.37 ± 8.61 percent; group E, 71.92 ± 19.06 percent; and group F, 57.47 ± 13.64 percent. Group A differed significantly from groups B, C, D, and E (p < 0.001). No significant difference was observed between groups A and F (p > 0.05). CONCLUSIONS: The combined use of intravenous or subcutaneous hyaluronidase and urokinase was most effective in treating hyaluronic acid injection-related arterial embolism after 45 minutes and 24 hours. This treatment may be ineffective after 48 hours.

Chemotherapeutic Agents and the Risk of Ischemia and Arterial Thrombosis.

PURPOSE OF REVIEW: Numerous chemotherapeutic agents have been associated with the development of ischemia and arterial thrombosis. As newer therapies have been developed to treat cancer, some of these chemotherapy drugs have been implicated in the development of vascular disease. In this review, we will summarize the most common chemotherapeutic drug classes that may play a role in the development of ischemic heart disease. RECENT FINDINGS: Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors have a number of cardiovascular toxicities. The possible mechanisms of action of these drugs leading to ischemic complications are varied but include endothelial dysfunction, platelet aggregation, reduced levels of nitrous oxide (NO), and elevated levels of reactive oxygen species (ROS), and vasospasm. While some drugs act through multiple pathways that result in the development of ischemic heart disease, others such as the antimetabolites and antimicrotubules appear to primarily cause vasospasm. Furthermore, while aromatase inhibitors increase the risk of heart disease in comparison to tamoxifen in large studies, this finding likely occurs because of a protective role of tamoxifen on cardiovascular risk factors rather than a direct effect of aromatase inhibitors. Angiogenesis inhibitors, alkylating agents, antimetabolites, antimicrotubules, and proteasome inhibitors can lead to ischemic complications in patients with cancer. Many of these drugs have proven to be effective in improving cancer prognosis, but their possible cardiovascular effects have to be carefully monitored and treated. Treatment of ischemic complications in the setting of cancer therapy should focus on the optimal medical management of known cardiovascular risk factors and follow an evidence-based approach.

Reversible Alopecia with Localized Scalp Necrosis After Accidental Embolization of the Parietal Artery with Hyaluronic Acid.

Hyaluronic acid (HA) filler injection is widely used for soft-tissue augmentation. Complications associated with HA filling are not uncommon; however, HA-induced alopecia is a rarely reported complication that could result in severe secondary psychological trauma. The etiology, clinical traits, treatment strategies, outcomes, and possible reversibility of HA-induced alopecia have not been characterized. Here, we report a case in which bilateral temple injections of 6.5 mL of HA led to persistent pain over the left scalp for several days. Although the pain was relieved at day 9 after 600 U of hyaluronidase were injected in the left temple, the patient developed localized alopecia at the left temporoparietal region with central skin necrosis at day 15. After topical applications of recombinant bovine basic fibroblast growth factor gel and 2% minoxidil spay, the necrotic skin wound was healed at day 42. Hair regrowth and normal hair density were restored at day 74. Analyses of Doppler ultrasound examinations and histopathology of the skin biopsy suggested that mild ischemia of the left temporoparietal region led to reversible alopecia, while the permanent hair loss in the left parietal area was associated with severe skin ischemia. Therefore, the key to treatment would be to focus on the effective correction of severe ischemia-induced skin necrosis to prevent permanent hair loss. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Dermal fillers: pathophysiology, prevention and treatment of complications.

Dermal fillers are increasingly used for soft tissue augmentation of the face and hands. The widespread use of dermal fillers for rejuvenation has led to a rise in reports of associated complications. Although the majority of complications are mild and transient, serious and long-lasting complications have been observed. This article discusses the key complications including pigmentary changes, hypersensitivity reactions, infections, nodule formation, granulomatous reactions, vascular occlusion and migration of filler material. A thorough literature review was performed in addition to the combined extensive authors' (GP and FA) experience. Complications from fillers are increasingly being recognized and highlighted in the literature partly reflecting the growth in the market. This article provides a comprehensive overview of the filler complications with mechanisms of prevention and treatment per complication. A thorough understanding of the preventative and management strategies for the associated dermal filler complications will help the physician to prepare the patient well, and deal with complications that may arise effectively.

A RARE COMPLICATION OF POSTERIOR SUBTENON INJECTION.

PURPOSE: To report a case of posterior ciliary artery occlusion after posterior subtenon injection. METHODS: Clinical examination and fundus fluorescein angiography was performed to confirm diagnosis. A 49-year-old female who was on treatment for bilateral chronic sclerokeratouveitis was given posterior subtenon injection for cystoid macular edema. RESULTS: Posterior ciliary artery occlusion occurred after posterior subtenon injection. CONCLUSION: Choroidal vascular occlusion is a rare complication of posterior subtenon injection.

Role of the CD39/CD73 Purinergic Pathway in Modulating Arterial Thrombosis in Mice.

OBJECTIVE: Circulating blood cells and endothelial cells express ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5'-nucleotidase (CD73). CD39 hydrolyzes extracellular ATP or ADP to AMP. CD73 hydrolyzes AMP to adenosine. The goal of this study was to examine the interplay between CD39 and CD73 cascade in arterial thrombosis. APPROACH AND RESULTS: To determine how CD73 activity influences in vivo thrombosis, the time to ferric chloride-induced arterial thrombosis was measured in CD73-null mice. In response to 5% FeCl3, but not to 10% FeCl3, there was a significant decrease in the time to thrombosis in CD73-null mice compared with wild-type mice. In mice overexpressing CD39, ablation of CD73 did not inhibit the prolongation in the time to thrombosis conveyed by CD39 overexpression. However, the CD73 inhibitor α-ß-methylene-ADP nullified the prolongation in the time to thrombosis in human CD39 transgenic (hC39-Tg)/CD73-null mice. To determine whether hematopoietic-derived cells or endothelial cell CD39 activity regulates in vivo arterial thrombus, bone marrow transplant studies were conducted. FeCl3-induced arterial thrombosis in chimeric mice revealed a significant prolongation in the time to thrombosis in hCD39-Tg reconstituted wild-type mice, but not on wild-type reconstituted hCD39-Tg mice. Monocyte depletion with clodronate-loaded liposomes normalized the time to thrombosis in hCD39-Tg mice compared with hCD39-Tg mice treated with control liposomes, demonstrating that increased CD39 expression on monocytes protects against thrombosis. CONCLUSIONS: These data demonstrate that ablation of CD73 minimally effects in vivo thrombosis, but increased CD39 expression on hematopoietic-derived cells, especially monocytes, attenuates in vivo arterial thrombosis.

Retinal Branch Artery Embolization Following Hyaluronic Acid Injection: A Case Report.

Injection of hyaluronic acid (HA) filler is a common aesthetic procedure. Impairment of vision, although rare, is a devastating complication of this procedure, which may not be reversible. We report on a patient who experienced visual acuity impairment and ischemic oculomotor nerve palsy after injection of HA into the nasal dorsum. In this case, clinical signs improved within 14 days of treatment. We also provide a review of the mechanism, clinical features, risk factors, and prevention and treatment strategies relating to embolization of ocular circulation after injection of HA. Vision loss is a rare but devastating complication of injection of hyaluronic acid (HA) in the face. Visual acuity seldom recovers completely. We report on a 22-year-old Asian woman who experienced obstruction of a branch of the retinal artery after injection of HA to augment her nose. The patient's visual acuity declined shortly after the procedure, and ophthalmoplegia occurred. Combination treatment was administered to restore the perfusion and oxygen supply to the retina and optic nerve. Within 14 days of rigorous treatment, the patient experienced improvement in visual acuity, extraocular movement, and visual field defects. LEVEL OF EVIDENCE 5: Risk.

Platelet activation independent of pulmonary inflammation contributes to diesel exhaust particulate-induced promotion of arterial thrombosis.

BACKGROUND: Accelerated thrombus formation induced by exposure to combustion-derived air pollution has been linked to alterations in endogenous fibrinolysis and platelet activation in response to pulmonary and systemic inflammation. We hypothesised that mechanisms independent of inflammation contribute to accelerated thrombus formation following exposure to diesel exhaust particles (DEP). METHODS: Thrombosis in rats was assessed 2, 6 and 24 h after administration of DEP, carbon black (CB; control carbon nanoparticle), DQ12 quartz microparticles (to induce pulmonary inflammation) or saline (vehicle) by either intra-tracheal instillation (0.5 mg, except Quartz; 0.125 mg) or intravenous injection (0.5 mg/kg). Thrombogenicity was assessed by carotid artery occlusion, fibrinolytic variables and platelet-monocyte aggregates. Measures of inflammation were determined in plasma and bronchoalveolar lavage fluid. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI)-1 were measured following direct in vitro exposure of human umbilical vein endothelial cells (HUVECs) to DEP (10-150 µg/mL). RESULTS: Instillation of DEP reduced the time to thrombotic occlusion in vivo, coinciding with the peak of DEP-induced pulmonary inflammation (6 h). CB and DQ12 produced greater inflammation than DEP but did not alter time to thrombotic occlusion. Intravenous DEP produced an earlier (2 h) acceleration of thrombosis (as did CB) without pulmonary or systemic inflammation. DEP inhibited t-PA and PAI-1 release from HUVECs, and reduced the t-PA/PAI-1 ratio in vivo; similar effects in vivo were seen with CB and DQ12. DEP, but not CB or DQ12, increased platelet-monocyte aggregates. CONCLUSION: DEP accelerates arterial thrombus formation through increased platelet activation. This effect is dissociated from pulmonary and systemic inflammation and from impaired fibrinolytic function.

Cardiovascular risk profile of patients with peripheral arterial occlusive disease during nilotinib therapy.

BACKGROUND: Over the past few years, data have suggested that severe peripheral arterial occlusive disease (PAOD) is associated with nilotinib exposure. However, the characteristics of this adverse drug reaction are poorly described since its frequency is low. As far as we know, no study using a spontaneous adverse drug reactions reporting system was performed to describe the characteristics of cases of PAOD related to nilotinib. OBJECTIVE: We performed a study to describe the cardiovascular risk profile of cases of PAOD in patients treated with nilotinib spontaneously reported to the French Pharmacovigilance Database (FPVD). PATIENTS/METHODS: We selected all cases of "vascular disorders," as the System Organ Class in MedDRA®, in which nilotinib was "suspected" and recorded in the French Pharmacovigilance Database between 2007 and 21 October 2014. We then identified cases of PAOD with a Low Level Term and through a detailed summary of the clinical description. RESULTS: We identified 25 cases of POAD. Most of the patients were older than 60 years (84 %) or had another cardiovascular risk factor such as hypercholesterolemia, arterial hypertension, overweight/obesity, smoking, or diabetes mellitus (72 %). Females (13 cases) and males (12 cases) were equally represented, but the presence of cardiovascular risk factors was more frequent in females than in males. The mean time from initiation of nilotinib to PAOD onset was 24 months and was significantly longer in patients aged less than 60 years compared with those aged over 60 years (33.8 ± 24.6 months vs. 22.6 ± 17.5 months, p = 0.002). Pre-existing cardiovascular risk factors, especially diabetes mellitus, also seem to accelerate its occurrence. CONCLUSIONS: The FPVD is a useful tool in describing the cardiovascular risk profile of patients with PAOD during nilotinib exposure. Physicians have to be particularly vigilant in patients older than 60 years of age; in patients younger than 60 years of age, long-term surveillance has to be maintained.