Rebound Growth Research Articles

Abstract 4127: Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks

Abstract Preclinical and clinical studies have suggested that stopping antiangiogenic therapy may lead to rapid revascularization and rebound tumor growth in certain instances. However, the implications for these findings remain unclear. It is possible that treatment rebounds may impact disease progression following neoadjuvant therapy, where drugs are administered for short periods and then halted prior to surgical removal of a primary tumor. Indeed, recent retrospective clinical studies have suggested that neoadjuvant antiangiogenic treatment discontinuation increases vascular proliferation and, in turn, might increase post-surgical disease progression and metastasis. However, this hypothesis has not been studied experimentally in clinically relevant mouse models of metastatic disease. We examined the effect of treatment discontinuation in the neoadjuvant setting using approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) such as sunitinib. Our studies utilized models of spontaneous metastatic breast, melanoma, and kidney cancer following surgical removal of orthotopically grown primary tumors. Neoadjuvant sunitinib treatment periods were 14 days in duration (60 mg/kg) with treatment breaks of 0, 3, 7, and 11 days compared. Pre-surgical molecular and cellular biomarkers were investigated as potential surrogates for post-surgical metastatic disease progression. These included tumor and vascular cell Ki67 and CD31 expression, as well as circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs). Our results show that VEGF RTKI neoadjuvant treatment benefits observed pre-surgically (such as reduction in primary tumor growth) did not consistently correlate with post-surgical survival and reduced metastatic recurrence. The addition of treatment breaks prior to surgery had positive or negative impact on post-surgical survival depending on the tumor model used. Interestingly, high-dose bolus (3 day) neoadjuvant sunitinib (120 mg/kg) treatment consistently improved post-surgical benefits when compared to sustained treatments, despite gaps in therapy. Finally, our results show that tumoral CD31+/Ki67+ cells, CTCs, and MDSCs may serve as surrogate markers of metastatic potential and predict the impact of treatment cessation on disease recurrence. Citation Format: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos. Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2015-4127

Rebound growth after hemiepiphysiodesis: An animal-based experimental study of incidence and chronology.

Rebound growth after hemiepiphysiodesis may be a normal event, but little is known about its causes, incidence or factors related to its intensity. The aim of this study was to evaluate rebound growth under controlled experimental conditions. A total of 22 six-week-old rabbits underwent a medial proximal tibial hemiepiphysiodesis using a two-hole plate and screws. Temporal growth plate arrest was maintained for three weeks, and animals were killed at intervals ranging between three days and three weeks after removal of the device. The radiological angulation of the proximal tibia was studied at weekly intervals during and after hemiepiphysiodesis. A histological study of the retrieved proximal physis of the tibia was performed. The mean angulation achieved at three weeks was 34.7° (standard deviation (sd) 3.4), and this remained unchanged for the study period of up to two weeks. By three weeks after removal of the implant the mean angulation had dropped to 28.2° (sd 1.8) (p < 0.001). Histologically, widening of the medial side was noted during the first two weeks. By three weeks this widening had substantially disappeared and the normal columnar structure was virtually re-established. In our rabbit model, rebound was an event of variable incidence and intensity and, when present, did not appear immediately after restoration of growth, but took some time to appear.

Fertility rebound and economic growth. New evidence for 18 countries over the period 1970–2011

Long-run impact of economic growth on fertility trends is ambiguous and sensitive for in-time variations. Noticeably, over last decades, economic growth has led to significant falls in total fertility rates in many countries. However, recently, in high-income economies a kind of ‘fertility rebound’ emerged (Goldstein, 2009; Luci and Thevenon, 2011; Day, 2012), which supports the hypothesis that reversal trends in total fertility rates are mainly attributed to economic growth. The paper unveils the relationship between total fertility rate changes and economic growth in 18 selected countries with fertility rebound observed, over the period 1970–2011, and detects the GDP-threshold at which the fertility rebound emerged. To report on the relationship we deploy longitudinal data analysis assuming non-linearity between examined variables. The data applied are exclusively derived from World Development Indicators 2013. Our main findings support the hypothesis on U-shaped relationship between the total fertility rate and economic growth in analyzed countries in 1970-2011. Along with the previous, we project the minimum level of GDP per capita (GDP-threshold) when the fertility rebound takes place.

A novel topical nano-propranolol for treatment of infantile hemangiomas

Topical propranolol has been used for the therapy of superficial infantile hemangiomas (IH). A retrospective investigation was conducted in 50 patients to evaluate the clinical effect of a new type of topical nano-propranolol-dispersed hydrogel. Participants were treated 3 times per day for 2 weeks to 11 months. 68% of patients were female and 12% had received other treatments before therapy. The nano-propranolol 0.5% hydrogel was initiated at a mean age of 5.010 months and for a mean duration of 3.610 months. The response rate was 86%. No recurrence and rebound growth occurred after withdrawal of hydrogel. Slight side effects (application site itching, erosion and crusting) were observed in only 2 cases. All the local irritations were evaluated as mild and were tolerated without discontinuing the medication. We suggest that topical nano-propranolol hydrogel could be an alternative option for the treatment of uncomplicated superficial IH with satisfactory tolerability and optimal effectiveness. From the Clinical EditorThe current recommended treatment for infantile hemangiomas is oral propranolol. Nonetheless, a small proportion of patients will have systemic side effects. In this article, the authors developed topical nano-propranolol hydrogel and tested this on clinical patients and found favorable response.

Childhood Body Mass Index Trajectories Predicting Cardiovascular Risk in Adolescence

PurposeThe present study compared growth parameters of girls' and boys' body mass index (BMI) trajectories from infancy to middle childhood and evaluated these parameters as predictors of cardiovascular disease (CVD) risk in adolescence. MethodsUsing 657 children from the NICHD Study of Early Child Care and Youth Development, quadratic growth curve analyses were conducted to establish growth parameters (intercept, slope, and quadratic term) for girls and boys from age 15 months to 10.5 years. Parameters were compared across gender and evaluated as predictors of a CVD risk index at the age of 15 years, controlling for characteristics of the adiposity rebound (AR) including age at which it occurred and children's BMI at the rebound. ResultsBoys had more extreme trajectories of growth than girls with higher initial BMI at age 15 months (intercept), more rapid declines in BMI before the AR (slope), and sharper rebound growth in BMI after the rebound (quadratic term). For boys and girls, higher intercept, slope, and quadratic term values predicted higher CVD risk at the age of 15 years, controlling for characteristics of the AR. ConclusionsFindings suggest that individuals at risk for developing CVD later in life may be identified before the AR by elevated BMI at 15 months and slow BMI declines. Because of the importance of early intervention in altering lifelong health trajectories, consistent BMI monitoring is essential in identifying high-risk children.

Abstract PR16: Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance

Abstract Tumor growth is a complex evolutionary process driven by dynamic feedback between a heterogeneous cell population and selection pressures from the tumor microenvironment. Spatio-temporal heterogeneity in the microenvironment can create physical niches that facilitate cellular adaptation as seen in regions of hypoxia and acidosis where cells may up-regulate glycolysis and become resistant to acid-meditated toxicity in order to survive. In recent studies, using clinically prevalent subtypes of EGFR-related non-small cell lung cancer (NSCLC), we observe that nutrient and drug gradients resulting from a cells' proximity to vasculature, can produce selective pressures driving tumor evolution. We provide a detailed examination of the microenvironmental impact (i.e. oxygen, glucose, and drug) on growth rates of NSCLC cell lines that are either sensitive or resistant to the EGFR TKI, erlotinib. Often we consider drug resistance to be associated with a fitness cost to the cell in the absence of drug. However, here we demonstrate that the situation is more complex, with the local tumor microenvironment influencing the magnitude and the directionality of the selective effect. In fact, the resistant cells actually gain a selective advantage in nutrient-stressed environments compared to the sensitive cells. The resulting growth dynamics were used to inform a stochastic compartment-based tumor model of pre-existing drug resistance where each compartment represents a specific tumor environmental niche. This integrative modeling framework was then used to predict rebound growth kinetics and tumor composition (i.e. % resistance) and in particular, provide insight into the magnitude by which the microenvironment influences these results. These investigations strongly suggest that ignoring the microenvironment or using laboratory environmental conditions to inform tumor dynamics can lead to inaccurate conclusions. Therefore, knowledge of the selective advantage/disadvantage of different cell populations within different regions of the tumor will better guide model predictions, influence overall tumor dynamics, and impact treatment strategies. This abstract is also presented as Poster A80. Citation Format: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick. Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR16. doi:10.1158/1538-7445.CHTME14-PR16

Treatment of rapidly proliferating haemangiomas in newborns with propranolol and review of the literature

Aim: Infantile haemangiomas (IH) are neoplastic proliferations of endothelial cells which occur with an incidence of 10–12%. IH rapidly growing and found in cosmetically sensitive areas or complicated with ulcerations are of special concern of parents.Methods: A review of medical charts was performed for newborns treated with propranolol because of IH between 2012 and 2013. There were two boys and two girls, referred to our department at the age of 2–3 weeks. Children were commenced on propranolol 0.5 mg/kg daily and closely monitored. The dosage was increased up to a maximum of 2 mg/kg/d and was maintained until the lesion had involuted or showed good result.Results: The minimal dosage required to achieve involution was 1.5–2.0 mg/kg/d. No rebound growth or complications were observed. Three patients showed excellent response with resolution of the lesion. Fourth patient showed good result with >50% reduction of IH.Conclusions: Propranolol at 1.5–2.0 mg/kg/d is effective and safe for treating IH in our series of newborn patients. Treatment should be maintained until the lesion is involuted or shows good cosmetic result. Still there is need for larger scale studies confirming the safety and efficacy of propranolol in treatment of haemangiomas in newborns.

Management of infantile haemangioma

Abstract Infantile haemangioma (IH) are benign vascular tumours affecting 4–5% of infants. Natural history is of rapid growth in the first few months of life followed by stabilisation and gradual resolution. IH are usually an isolated cutaneous problem. Occasionally they may be associated with internal haemangioma or other abnormalities of cardiovascular and neurological systems. Treatment is required in the first few months of life for IH which are threatening life or function, become ulcerated, or are likely to cause residual problems due to site or large size. First line treatment in most centres is oral propranolol, despite it being unlicensed for this indication. Treatment is continued until 12–16 months of age; there is a small risk of rebound growth after stopping. Other treatments that may be considered in specific situations include oral or intra-lesional steroids, vincristine, pulsed dye laser, embolisation and surgery. A multi-disciplinary approach involving paediatricians, dermatologists and other organ specialists is required to ensure consistent and optimum management for this common condition.

Abstract 2996: Sunitinib withdrawal uncovers complementary stromal- and tumor-mediated mechanisms of resistance and rebound growth in metastatic mouse models

Abstract Background: Despite the clinical approval of VEGF pathway targeted agents in the treatment of late-stage metastatic disease, sustained benefits are not seen in the majority of patients, and eventual relapse occurs. Understanding mechanisms of intrinsic and acquired drug resistance has taken on increasing importance as both host- and tumor-mediated pathways may contribute to treatment failure. However, few studies have aimed to assess resistance in clinically-relevant spontaneous metastatic disease after surgical resection of the primary tumor. Methods: Here we describe the derivation of spontaneous metastatic human kidney, breast, and melanoma cell lines following long-term in vivo sunitinib treatment. Re-exposure of selected tumor and stromal cells to drug in vitro for extended periods allowed evaluation of reversible and irreversible gene expression changes. Cells were implanted orthotopically and then surgically removed to assess primary and metastatic growth potential following treatment cessation. Results: Our results show that metastatic sunitinib-resistant cells retained treatment sensitivity when re-implanted orthotopically regardless of in vitro drug exposure conditions, suggesting a predominant host-mediated role in treatment failure. However, sunitinib treatment withdrawal elicited significant increases in tumor growth and metastatic potential, a finding which was enhanced when non-tumor bearing mice were ‘conditioned’ with drug prior to i.v. tumor cell inoculation. Parallel studies in vitro show increased proliferation and migration following therapy removal. Results from gene and protein expression analysis of cells in different sunitinib treatment conditions will be presented showing that coordinated tumor and host reactions can contribute to changes in metastatic phenotype upon therapy removal. Conclusions: Taken together, clinically relevant models of drug-resistant spontaneous metastatic disease may have the potential to distinguish tumor- and stromal-responses to treatment that can alter in vivo disease progression both on (and off) therapy. Citation Format: Michalis Mastri, Amanda Tracz, Christina R. Lee, Derya Deveci, John M. L. Ebos. Sunitinib withdrawal uncovers complementary stromal- and tumor-mediated mechanisms of resistance and rebound growth in metastatic mouse models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2996. doi:10.1158/1538-7445.AM2014-2996

A multilayer grow-or-go model for GBM: effects of invasive cells and anti-angiogenesis on growth.

The recent use of anti-angiogenesis (AA) drugs for the treatment of glioblastoma multiforme (GBM) has uncovered unusual tumor responses. Here, we derive a new mathematical model that takes into account the ability of proliferative cells to become invasive under hypoxic conditions; model simulations generate the multilayer structure of GBM, namely proliferation, brain invasion, and necrosis. The model is able to replicate and justify the clinical observation of rebound growth when AA therapy is discontinued in some patients. The model is interrogated to derive fundamental insights int cancer biology and on the clinical and biological effects of AA drugs. Invasive cells promote tumor growth, which in the long run exceeds the effects of angiogenesis alone. Furthermore, AA drugs increase the fraction of invasive cells in the tumor, which explain progression by fluid-attenuated inversion recovery (FLAIR) signal and the rebound tumor growth when AA is discontinued.

Comprehensive Therapy for Hemangioma Presenting With Kasabach-Merritt Syndrome in the Maxillofacial Region

To summarize the characteristics of Kasabach-Merritt syndrome (KMS) and to evaluate the therapeutic effect of drug therapy combined with transarterial embolization. From 2007 to 2011, 6 cases of KMS that underwent drug therapy and transarterial embolization were retrospectively analyzed, comprising of 3 male and 3 female patients; the ages of the patients ranged from 3 to 40 days. The lesions were located in the temporal region (1 of 6, 16.7%), parotid region (2 of 6, 33.3%), or submandibular region and neck (3 of 6, 50%). All the patients were followed for 12 to 18 months. Therapeutic outcomes were assessed by evaluating the platelet count, coagulation parameters, and size of the lesion. Positive responses were visible shrinkage of the hemangioma or lightening of the skin color of the cutaneous tumor (or both) within 8 to 72 hours in 4 patients (66.67%). These occurred within 1 week in 5 patients (83.33%) and within 2 weeks in all patients (100%). The mean platelet count before treatment was 18,000/L (range, 8,000 to 33,000/L). After the first week of medical treatment, the mean platelet count increased to above 80,000/L in 5 patients (83.33%); it began to increase on the second day after embolization and reached 102,000/L in 1 patient (16.67%). All 6 cases (100%) showed good results with treatment. A 12- to 18-month follow-up evaluation was obtained for all treated patients, and no rebound growth or platelet count decreases were observed. No severe or obvious adverse complications were noted during all treatment courses. For most hemangiomas presenting with KMS, good results can be obtained with systemic medical treatment. Transcatheter arterial embolization with polyvinyl alcohol particles combined with systemic medical treatment should be considered an efficacious and important therapeutic option for challenging cases.

Management of problematic infantile hemangioma using intralesional triamcinolone: Efficacy and safety in 100 infants

Intralesional corticosteroid is one method used to limit the rapid growth of infantile hemangiomas. The purpose of this study was to determine the efficacy and safety of triamcinolone injection using a standardized protocol. The study comprised infants managed with intralesional corticosteroid between 2007 and 2013. Tumors ≤3 cm in diameter were injected with triamcinolone, not to exceed 3 mg/kg, and followed every 4-6 weeks to determine whether additional injections were indicated. Predictive variables were patient age and tumor location, depth, and size. Treatment response was defined as regression, stabilization, or failure. Rebound growth and drug morbidity were recorded. Seventy-three females and 27 males had lesions located on the lip (29%), cheek (20%), nose (16%), periorbital area (13%), forehead (7%), scalp (4%), chin (2%), ear (2%), trunk (2%), extremity (2%), and neck (2%). Mean tumor size was 2.1 cm(2) (range 0.15-9.0). Treatment began at an average age of 11 weeks (range 3-30). The mean number of injections was 1.8 (range 1-5), and the average dose per injection was 1.6 mg/kg (range 0.76-2.66). All tumors responded: 63% regressed and 37% stabilized. Rebound growth affected 40% of tumors at a median of 3 weeks (IQR 3-4) following injection. Age, location, size, and depth did not affect treatment response (p = 0.7). None of the patients exhibited systemic side-effects and 2% had atrophy at the site of injection. Intralesional triamcinolone is an effective treatment for small, localized proliferating infantile hemangiomas. Therapy is safe and infants are at minimal risk for systemic side-effects when low doses of corticosteroid are used.

Chemoprevention for neurofibromatosis 2: just over the horizon?

Chemoprevention for neurofibromatosis 2: just over the horizon?

Propranolol in Treatment of Huge and Complicated Infantile Hemangiomas in Egyptian Children

Background. Infantile hemangiomas (IHs) are the most common benign tumours of infancy. Propranolol has recently been reported to be a highly effective treatment for IHs. This study aimed to evaluate the efficacy and side effects of propranolol for treatment of complicated cases of IHs. Patients and Methods. This prospective clinical study included 30 children with huge or complicated IHs; their ages ranged from 2 months to 1 year. They were treated by oral propranolol. Treatment outcomes were clinically evaluated. Results. Superficial cutaneous hemangiomas began to respond to propranolol therapy within one to two weeks after the onset of treatment. The mean treatment period that was needed for the occurrence of complete resolution was 9.4 months. Treatment with propranolol was well tolerated and had few side effects. No rebound growth of the tumors was noted when propranolol dosing stopped except in one case. Conclusion. Propranolol is a promising treatment for IHs without obvious side effects. However, further studies with longer follow-up periods are needed.

Treatment of periorbital infantile haemangiomas: a systematic literature review on propranolol or steroids.

The aim of this study was to compare the efficacy and safety of propranolol versus corticosteroids for the treatment of periorbital infantile haemangiomas (IHs). A literature review using PubMed, Ovid Medline, EBSCO, Springer, Web of Knowledge, Cochrane Library, CNKI and associated references before 2 March 2013 was conducted. The main outcomes were distribution of locations, response rate, rebound growth rate, spherical and cylinder power before and after treatment, amblyopia rate and adverse events. Thirty-one studies including 425 patients met the inclusion criteria. A total of 70.6% of patients were female, 89.6% of the periorbital IHs were located in the upper or lower eyelid area. The most common administration routes involved oral propranolol and intralesional injection of corticosteroids. The mean response rate was 94.0% for propranolol and 82.3% for corticosteroid (P = 0.001). The rebound growth rate was 13.9% for propranolol and 12.0% for steroids (P = 0.71). Astigmatism was reduced in both propranolol and steroid studies (P < 0.0001, P < 0.0001), but a significant reduction in spherical power was only demonstrated in propranolol studies (P = 0.005). A total of 31.1% of patients treated with corticosteroids developed post-operative amblyopia compared with 16.7% of patients treated with propranolol (P = 0.04). Oral propranolol seemed to induce more temporary adverse events than intralesional corticosteroids administration (24.0% vs. 9.6%, P = 0.006). Propranolol may represent an effective therapy for periorbital IHs compared with the use of corticosteroids; however, further randomised control studies are needed to compare adverse events.

Propranolol for the treatment of infantile haemangiomas: our experience with 44 patients

Propranolol is an effective, safe treatment for complicated infantile haemangiomas (IH). We evaluated all patients (n = 44) with IH treated with propranolol in our department. Of the 44 patients who were begun on propranolol therapy, 26 patients have completed the treatment to date and all had a good response. The mean duration of treatment was 45.7 weeks. Four patients developed rebound growth of their IH, which responded to the reintroduction of propranolol. Two patients with PHACES (posterior fossa malformations, haemangiomas, arterial anomalies, coarctation of the aorta/cardiac abnormalities, eye anomalies and sternal defects/supraumbilical raphe) syndrome were treated with lower than standard doses, because of concern about possible cerebrovascular compromise. Adverse effects were minor in most patients. Three patients discontinued propranolol because of vomiting, wheeze, and hypoglycaemia, respectively. Our duration of treatment was longer than that of other series, and may be due to our group having higher rates of hypotension, recorded in 27.3% of patients, precluding an increase in propranolol dose. Our experience supports that propranolol is an effective first-line agent for complicated IH.

UNC1666, a Dual Mer and Flt-3 Tyrosine Kinase Small Molecule Inhibitor In Acute Myeloid Leukemia

The identification of novel biologically targeted agents for the treatment of acute myeloid leukemia (AML) could potentially augment therapeutic outcome, decrease toxicity to normal tissues, and/or provide a therapy option for those who are not able to tolerate conventional therapy. Previously, Flt-3 and Mer have been identified as potential targets in the treatment of acute myeloid leukemia. Flt-3 internal tandem duplication (ITD) has been described in ∼30-40% of AML patient samples and Mer overexpression has been detected in ∼80-100% of AML patient samples. Here we describe a novel first-in-class small molecule inhibitor that has dual inhibition of these two tyrosine kinases with effective killing of myeloblasts in preclinical evaluation.UNC1666 is an ATP competitive reversible small molecule inhibitor which potentially inhibits Mer (IC50: 0.55 nM) and Flt-3 (IC50: 0.69 nM), preventing phosphorylation of the kinase and resultant downstream signaling. In these studies, UNC1666 was analyzed in AML cell lines which were either known to be Mer-positive (Nomo-1, Kasumi-1 and U937) or positive for the Flt3-ITD (Molm-13 and MV4;11). Short term exposure of these cell lines to UNC1666 resulted in decreased AKT and STAT6 activation in a dose dependent manner compared to equivalent concentration of drug vehicle (DMSO). AML cell lines were treated with nanomolar doses of UNC1666 or equivalent concentration of vehicle for 72 hours, stained with Yo-Pro-1 iodide and propidium iodide, and were assessed for apoptosis by flow cytometry. Compared to AML cells treated with vehicle, treatment of Mer-positive cell lines with UNC1666 resulted in a two to five-fold induction of apoptosis (mean of 20±10% apoptosis after treatment with vehicle versus 66±10% after treatment with UNC1666, p<0.01). Treatment of Flt3-ITD cell lines with UNC1666 resulted in a nine-fold induction of apoptosis (mean of 10±2% apoptosis after treatment with vehicle versus 90±6% after treatment with UNC1666, p<0.001). To further evaluate for sustained effects of UNC1666 on cell growth and survival after drug removal, AML cell lines were treated with UNC1666 for 72 hours, then washed and replated in normal growth conditions to assess for possible rebound growth. Viable cell count was performed on a Cedex analyzer using trypan blue exclusion over the course of six days. Cells treated with UNC1666 continued to have a significant decrease in their ability to proliferate even after the drug was removed (day six viable cell count of 1.9 x 106 cells previously treated with vehicle versus 0.04 x 106 cells previously treated with UNC1666, p<0.01). Furthermore, when these AML cell lines were plated in equal number in soft agar, and then treated with medium containing nanomolar doses of UNC1666 for 10 days, cell lines treated with the dual inhibitor demonstrated decreased colony formation compared to cells treated with medium containing vehicle only (relative colony count of 100 with vehicle treatment versus 34±15 colonies with Mer-positive cell lines and 15±12 with Flt3-ITD cell lines after treatment with UNC1666, p<0.01).In summary, UNC1666 is novel first-in-class small molecule with ability to inhibit kinase activity and activation of both Mer and Flt-3 tyrosine kinases. Inhibition using this molecule effectively prevented downstream activation of several intracellular signaling molecules including AKT and STAT6, induced apoptosis and decreased myeloblast proliferative capacity. These data validate dual Mer/Flt-3 inhibition as a new and attractive potentially clinically applicable therapeutic in the treatment of AML. Disclosures:Liu:University of North Carolina: inventor on a patent application relevant to this work, inventor on a patent application relevant to this work Patents & Royalties. Wang:University of North Carolina at Chapel Hill: This author is an inventor on patent application relevant to this work, This author is an inventor on patent application relevant to this work Patents & Royalties. Frye:University of North Carolina at Chapel Hill: This author is an inventor on a patent application relevant to this work, This author is an inventor on a patent application relevant to this work Patents & Royalties.

Failure of Intralesional Propranolol in Infantile Hemangiomas

The purpose of this study was to evaluate the use of intralesional propranolol injection in the management of small, noncomplicated infantile hemangiomas (IHs) located in areas of cosmetic concern. A prospective study was performed in six female infants with small, non-complicated IHs in areas of cosmetic concern. The parents had refused oral propranolol or the patients had no response to topical timolol or had relapsed after oral propranolol and the parents refused further systemic treatment. All six patients were treated with 1 mg/mL propranolol solution at a dose of 0.2 mL/cm(2). The size, color, and growth of the hemangiomas were monitored and recorded every 4 weeks. Treatment response was evaluated using a 5-point scale: much better (+2), better (+1), same (0), worse (-1), and much worse (-2). Heart rate and blood pressure were measured before and 1 hour after each injection. Adverse effects after medication were evaluated and managed accordingly. All hemangiomas stopped growing during therapy, but no significant changes in size or color were observed, even after repeated injections, and all patients were evaluated as 0 (same). One patient whose hemangioma stopped growing during treatment presented rebound growth after therapy cessation. No changes in heart rate or blood pressure were observed after intralesional propranolol injection. Adverse effects observed were pain and redness after injection. Intralesional propranolol seems safe but is not effective for the treatment of IH.

Late Rebound of Infantile Hemangioma after Cessation of Oral Propranolol

Propranolol has become the first line of treatment for infantile hemangiomas (IHs), with a high response rate, but rebound growth after cessation of propranolol has been reported, primarily in the first year of life. We sought to determine the frequency and associated factors leading to late regrowth after successful treatment at an age when the proliferative phase has usually ceased. We retrospectively reviewed the clinical charts, serial photographs, and radiologic images of children with rebound IH occurring after the age of 15 months after a successful course of oral propranolol averaging 2.6 mg/kg/day (range 2-3 mg/kg/day). Thirteen (10 female, 3 male) of 212 patients (6%) treated with oral propranolol since 2008 were evaluated. The mean age at the start of treatment was 5.3 months (range 1.8-13 months), and an average of 10.3 months (range 4.5-16 months) of treatment was given. It took an average of 5.3 months (range 1-13.8 months) for a significant rebound to appear. Late rebound after successful propranolol indicates a prolonged proliferation phase of IH even after 15 months of age. This is compared with previous reports of rebound, which occurred primarily in infants younger than 1 year old. Late proliferation can occur in localized, small, mixed, and deep IH, even after several months of a positive response to propranolol. A second course of propranolol readily controlled the recurrence.

Beta-blockers for the treatment of problematic hemangiomas

To examine treatment indications, efficacy and side effects of oral beta-blockers for the treatment of problematic hemangiomas. A retrospective review of patients with hemangiomas presenting to the Alberta Children's Hospital Vascular Birthmark Clinic (Calgary, Alberta) between 2009 and 2011 was conducted. The subset of patients treated with oral beta-blockers was further characterized, investigating indication for treatment, response to treatment, time to resolution of indication, duration of treatment, occurrence of rebound growth and side effects of therapy. Between 2009 and 2011, 311 new patients with hemangiomas were seen, of whom 105 were treated with oral beta-blockers. Forty-five patients completed beta-blocker treatment while the remainder continue to receive therapy. Indications for treatment were either functional concerns (68.6%) or disfigurement (31.4%). Functional concerns included ulceration (29.5%), periocular location with potential for visual interference (28.6%), airway interference (4.8%), PHACES syndrome (3.8%), auditory interference (0.95%) and visceral location with congestive heart failure (0.95%). The median age at beta-blocker initiation was 3.3 months; median duration of therapy was 10.6 months; and median maximal treatment dose was 1.5 mg/kg/day for propranolol and 1.6 mg/kg/day for atenolol. Ninety-nine patients (94.3%) responded to therapy with size reduction, colour changes, softened texture and/or healing of ulceration. Rebound growth requiring an additional course of therapy was observed in 23 patients. Side effects from beta-blockers included cool extremities (26.7%), irritability (17.1%), lower gastrointestinal upset (14.3%), emesis (11.4%), hypotension (10.5%), poor feeding (7.6%), lethargy (4.8%), bronchospasm (0.95%) and rash (0.95%). Side effects did not result in complete discontinuation of beta-blocker treatment in any case; however, they prompted a switch to a different beta-blocker preparation in some cases. Resolution of the primary indication, requiring a median time of three months, occurred in 87 individuals (82.9%). Treatment of infantile hemangiomas with oral beta-blocker therapy is highly effective and well tolerated, with more than 94% of patients demonstrating a response to treatment and 90% showing resolution of the primary functional indication for treatment.