Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.

BACKGROUND: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia. METHODS: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events. RESULTS: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia. CONCLUSIONS: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.

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.

Cancer Therapy-Associated Thrombosis.

[Figure: see text].

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.

Arterial Occlusion and Necrosis Following Hyaluronic Acid Injection and a Review of the Literature

With the rising popularity of fillers for facial rejuvenation coupled with the paucity of regulations on credentialing of qualified injectors, the number of filler related complications is increasing. Although the majority of complications are mild, vascular occlusion is the most feared and dangerous. Minimizing risk of vascular complications through a comprehensive understanding of vascular anatomy and careful technique is important. Physicians who perform filler injections should also be able to promptly recognize complications and manage them. We report a case of vascular occlusion successfully managed using high dose hyaluronidase and provide a review of the literature including incidence, management, and techniques to prevent vascular complications. J Drugs Dermatol. 2019;18(6):587-591.

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.

Ocular and cerebral infarction from periocular filler injection.

A 20-year-old woman presented with loss of vision in her right eye and a "black nose" after receiving hyaluronic acid filler injections in her right glabella 1 month prior. Her vision was no light perception, and external examination revealed resolving skin necrosis at the nasal tip. A dilated fundus exam showed a fibrotic membrane emanating from a pale optic nerve and a diffusely atrophic retina with sclerotic vessels. An MRI demonstrated scattered right-sided parietal lobe infarcts. These findings were consistent with inadvertent cannulation of the supraorbital artery, followed by injection of filler into the internal carotid circulation. The product traveled in a retrograde fashion, occluding the right ophthalmic artery, right dorsal nasal artery, and arterial segments to the Circle of Willis. This case highlights the importance of understanding the complex vascular architecture of the periorbita and the mechanism by which such occlusions occur.

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.

An age dependent response to hydroxyurea in pediatric sickle cell anemia patients with alpha thalassemia trait.

Hydroxyurea (HU) is a key drug therapy for individuals with sickle cell anemia (SCA), yet its clinical and hematologic responses can be variable. Various studies have reported the role of α-thalassemia as one of the most prevalent heritable traits that may modify HU response. We provide data from 62 pediatric and adolescent patients with SCA, 26 with co-inherited α-thalassemia trait. Our data suggest that altered hematologic and clinical responses to HU therapy are noted in adolescent SCA individuals with co-inherited α-thalassemia trait. Adolescent patients who co-inherited α-thalassemia trait had a greater reduction in vaso-occlusive episodes compared to those without α-thalassemia, despite a less robust fetal hemoglobin induction as well as a lower maximum HU dose. This clinical improvement was associated with a lower MCH and higher RBC count. Responses to HU in younger SCA children (ages 5-11years) with co-inherited α-thalassemia trait, compared to those without α-thalassemia trait, did not show any difference in number vaso-occlusive episodes, fetal hemoglobin induction and change in MCH and RBC count.

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.

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.

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 .

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.

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.

Choroid vascular occlusion and ischemic optic neuropathy after facial calcium hydroxyapatite injection- a case report.

BACKGROUND: We reported a case of sudden monocular vision loss after calcium hydroxyapatite (CaHA) injection into the nasal tip and dorsum with detailed retina images. CASE PRESENTATION: A healthy, 35-year-old woman received CaHA filler injection for nose augmentation. Ten minutes after the procedure, she developed nausea, vomiting, headache, ptosis, and left periorbital pain. After 30 minutes, she complained of progressively blurring vision in the left eye. The best-corrected visual acuity (BCVA) in her left eye was 30 cm ahead of hand motion. Left exotropia was noted in primary gaze. Limitations in adduction, supraduction, and infraduction of the left eye were also observed. Slit lamp examination of the left eye revealed a pink conjunctiva, a clear cornea, a mild anterior chamber reaction, a sluggish papillary light reflex, and a semi-dilated pupil. A positive relative afferent pupillary defect was observed in the left eye. Fundus examination revealed optic disc edema and some linear whitish opacity over the superior and temporal sites in the left eye, suggesting multiple CaHA emboli in the choroid vessels. CONCLUSIONS: Although the majority of adverse reactions are mild and transient, surgeons should be alert about extremely rare serious adverse events such as visual loss.

Oral contraceptives in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age and combined oral contraceptives (OCs) are often the first-line treatment of the syndrome by improving hyperandrogenism and regulating menstrual cycles. Oral contraceptives have some cardiovascular and metabolic effects that varies among different formulations depending upon the dose and type of the both estrogen and progestin components. These cardiometabolic effects of OCs raise some concerns about their long-term use in PCOS, but available data suggest that the benefits outweigh the risks. More studies are needed to clarify the safety of long-term use of OCs in PCOS.

Risk of venous and arterial thromboembolic events in cancer patients treated with gemcitabine: a systematic review and meta-analysis.

AIMS: Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (ATEs and VTEs), although the overall risk remains unclear. As indications for its use in oncology are expanding, a comprehensive characterization of these complications becomes imperative. METHODS: Pubmed was searched for articles published from 1 January 1990 to 31 December 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine based vs. non-gemcitabine based chemotherapy in patients with solid tumours. Data on VTEs and ATEs were extracted. Overall incidence rates, odds ratio (OR), and 95% confidence intervals (CIs) were calculated employing fixed or random effects models depending on the heterogeneity of included trials. RESULTS: A total of 4845 patients from 19 trials were included. Among patients treated with gemcitabine based chemotherapy, the overall incidence of VTEs (13 studies comprising 3823 patients) and ATEs (eight studies consisting of 2431 patients) was 2.1% (95% CI 1.2%, 3.8%) and 2.2% (95% CI 1.4%, 3.2%). The associated ORs of VTEs and ATEs were 1.56 (95% CI 0.86, 2.83, P = 0.15) and 1.82 (95% CI 0.89, 3.75, P = 0.10) compared with non-gemcitabine based therapy. A tendency to increase the risk of ATE and VTEs was also detected in any prespecified subgroup. CONCLUSION: The use of gemcitabine does not significantly increase the risk of VTEs and ATEs in patients with solid tumours when compared with non-gemcitabine based chemotherapy.

[Injectable fillers: adverse reactions and their management]. / Injizierbare Füllmaterialien: Nebenwirkungen und Management.

Injectable fillers are one of the corner stones of aesthetic medicine. In general they are safe to use. However, adverse reactions may occur. These reactions may be acute, subacute or delayed, e.g. after decades. It is important to know these reactions and to be prepared so that they can be adequately treated, in view of the clinical symptoms, the injected material and if applicable other diseases/treatments that might trigger these reactions. Last but not least, all reactions should be reported either to specialized registries or regulatory agencies. Only then we are able to learn more about these reactions and their best possible treatment.

Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials.

PURPOSE: Anti-epidermal growth factor receptor (EGFR) agents [monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)] are targeted therapies used in advanced cancers. Arterial and venous thromboembolic events (ATEs and VTEs excluding catheter-related events) were not investigated with these agents, and the risk of these events is still unknown. PATIENTS AND METHODS: We have carried out a meta-analysis in order to determine the incidence and the relative risk (RR) of VTEs and ATEs associated with these agents. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies. RESULTS: A total of 13 studies (7611 patients) was selected for this meta-analysis. The associated RRs of VTEs (11 studies comprising 7073 patients) and ATEs (5 studies consisting of 3030 patients) were 1.32 (95% CI 1.07-1.63; P equals 0.01) and 1.34 (95% CI 0.94-1.9; P equals 0.11) compared with control patients. The analysis of VTEs was also stratified by class of agents: MoAbs (RR 1.34; P equals 0.01) and oral TKIs (RR 1.16; P equals 0.65). CONCLUSION: Anti-EGFR agents are associated with a significant increase in the risk of VTEs. In particular, the risk is significant with cetuximab and panitumumab in settings where these drugs are currently approved.