Retrospective cross-sectional analysis of concurrent VTE diagnosis in hospitalised socially excluded individuals in Ireland.

OBJECTIVE: Social exclusion (such as that experienced by people who are homeless, incarcerated or use drugs) increases morbidity across a range of diseases but is poorly captured in routine data sets. The aim of this study was to use a novel composite variable in a national-level hospital usage dataset to identify social exclusion and to determine whether social exclusion is associated with concurrent venous thromboembolism (VTE) in hospitalised patients in Ireland. Identifying and characterising this association in people who are socially excluded will inform VTE prevention and treatment strategies. DESIGN: Retrospective cross-sectional study. SETTING: Irish Hospital Inpatient Enquiry (HIPE) system, which collects diagnostic information by International Classification of Diseases Tenth Revision code on all hospital admission episodes in the Ireland. PARTICIPANTS: All hospital admission episodes involving a VTE diagnosis (in a primary 'Dx 1' or secondary 'Dx 2-30' coding position) during a 12-month period in the Ireland were identified from consolidated, national-level datasets derived from the Irish HIPE system. Social exclusion was defined as the presence of one or more indicators of homelessness, drug use, incarceration, health hazards due to socioeconomic status or episodes of healthcare terminated prematurely. RESULTS: Of 5701 admission episodes involving a VTE diagnosis (in a primary or secondary position) during the study period, 271 (4.8%) related to an individual affected by social exclusion. Among hospitalised individuals identified as being socially excluded based on the novel composite variable, the likelihood of having a concurrent VTE diagnosis was over twofold greater than that observed in the general population (OR 2.14, 95% CI 1.79 to 2.26; p<0.001). CONCLUSION: These data suggest that VTE (primary and secondary) is over-represented in hospitalised socially excluded persons in Ireland and that the development of strategies to address this potentially life-threatening accompanying condition in this vulnerable patient group must be prioritised.

COVID-19 incidence and outcome by affluence/deprivation across three pandemic waves in Ireland: A retrospective cohort study using routinely collected data.

BACKGROUND: Since the pandemic onset, deprivation has been seen as a significant determinant of COVID-19 incidence and mortality. This study explores outcomes of COVID-19 in the context of material deprivation across three pandemic waves in Ireland. METHODS: Between 1st March 2020 and 13th May 2021, 252,637 PCR-confirmed COVID-19 cases were notified in Ireland. Cases were notified to the national Computerised Infectious Disease Reporting (CIDR) system. Each case was geo-referenced and assigned a deprivation category according to the Haase-Pratschke (HP) Deprivation Index. Regression modelling examined three outcomes: admission to hospital; admission to an intensive care unit (ICU) and death. RESULTS: Deprivation increased the likelihood of contracting COVID-19 in all age groups and across all pandemic waves, except for the 20-39 age group. Deprivation, age, comorbidity and male gender carried increased risk of hospital admission. Deprivation was not a factor in predicting ICU admission or death, and diagnosis in wave 2 was associated with the lowest risk of all three outcomes. CONCLUSIONS: Our study suggests that COVID-19 spreads easily through all strata of society and particularly in the more deprived population; however this was not a consistent finding. Ireland is ethnically more homogenous than other countries reporting a larger deprivation gradient, and in such societies, structural racial differences may contribute more to poor COVID outcomes than elements of deprivation.

Social Connectedness and Smoking among Adolescents in Ireland: An Analysis of the Health Behaviour in Schoolchildren Study.

Continuing progress with preventing smoking initiation is a key to the tobacco endgame. Home- and school-based social networks shape the health behaviour of children and adolescents. This study described the relationship between social connectedness and smoking behaviour in school-aged children in Ireland. The 2014 Irish Health Behaviour in School-aged Children (HBSC) surveyed self-reported smoking status and measured perceptions of social connectedness and support with validated and reliable questions across a random stratified sample of 9623 schoolchildren (aged 10-19). Overall, 8% of school-aged children reported smoking, in the last 30 days 52% reported smoking daily, and prevalence increased with age (p < 0.001). Compared with schoolchildren who did not smoke, perceptions of social connectedness and perceptions of support at home, from peers, and at school were significantly poorer for schoolchildren who smoked across all measures examined (p < 0.001). The poorest rated measures were for school connectedness and teacher support for smokers. Policies and practices that build and support positive environments for schoolchildren must continue to be prioritised if progress on preventing smoking initiation is to be sustained.

Multisystem inflammatory syndrome in the context of paediatric COVID-19 infection in the Republic of Ireland April 2020 to April 2021.

AIM: Our aim was to describe the epidemiology of multisystem inflammatory syndrome in children (MIS-C) in the Republic of Ireland, in the context of all cases of COVID-19 in children, during the first year of the SARS-CoV-2 pandemic. METHODS: Cases of MIS-C were identified by prospective surveillance in Irish hospitals from April 2020 to April 2021. Paediatric COVID-19 cases and outbreaks in schools or childcare facilities were notified to and routinely investigated by Public Health. Univariate and bivariate analyses were carried out in Excel, Stata and JMP statistical package. RESULTS: Fifty-four MIS-C cases (median age 7.58 years; males 57%) were identified over the study period. MIS-C incidence was higher in certain ethnicities ('black' 21.3/100,000 [95% CI 4.3-38.4]; and 'Irish Traveller' 14.7/100,000 [95% CI -5.7-35.1]) than those of 'white' ethnicity (3.4 /100,000). MIS-C cases occurred in three temporal clusters, which followed three distinct waves of community COVID-19 infection, irrespective of school closures. Formal contact tracing identified an epidemiological link with a COVID-19-infected family member in the majority of MIS-C cases (77%). In contrast, investigation of COVID-19 school outbreaks demonstrated no epidemiological link with MIS-C cases during the study period. CONCLUSION: Efforts at controlling SARS-CoV-2 transmission in the community may be a more effective means to reduce MIS-C incidence than school closures. Establishing a mandatory reporting structure for MIS-C will help delineate the role of risk factors such as ethnicity and obesity and the effect of vaccination on MIS-C incidence.

Hypertension in pregnancy: Prevalence, risk factors and outcomes for women birthing in Ireland.

OBJECTIVES: The purpose of this study was to identify the number of pregnancies affected by hypertension in Ireland and report on possible risk factors and adverse pregnancy outcomes for women and their babies. STUDY DESIGN: Data on maternity hospital discharges for women giving birth in Ireland in 2016 were extracted from the national Hospital In-Patient Enquiry data system. Women with a diagnosis of a hypertensive disorder of pregnancy were identified using relevant ICD codes. Descriptive statistics were used to present prevalence, and Pearson's Chi-square and multivariable regression analyses were conducted to identify risk factors and pregnancy outcomes. Differences between proportions were analysed by Pearson's Chi-squared test of independence. RESULTS: Of 60,188 maternities reported for the year 2016, 5.9% of women (n = 3531) had a hypertensive disorder of pregnancy and 4.6% (n = 2790) had pre-eclampsia. Rates were higher among women with pre-existing diabetes, gestational diabetes, obesity and those aged ≥40 years. After adjusting for maternal age, pre-existing DM, GDM, obesity and tobacco use, obesity (AOR 4.3; 95% CI: 3.2-5.7; p < 0.001), pre-existing diabetes (AOR 3.5; 95% CI: 2.5-4-9; p < 0.001), gestational diabetes (AOR 1.5; 95% CI: 1.3-1.8; p < 0.001) and being aged ≥40 years (AOR 1.5; 95% CI: 1.3-1.7; p < 0.001) remained significantly associated with being diagnosed with a hypertensive disorder of pregnancy in the Republic of Ireland. CONCLUSION: In Ireland where maternal age at childbirth is increasing, the association of hypertension with advancing age will undoubtedly contribute to a greater prevalence of hypertensive disorders of pregnancy and their potential adverse outcomes for pregnant women and their babies. This retrospective study highlights the prevalence rates in Ireland while also identifying possible risk factors and associated adverse pregnancy outcomes. They pinpoint the need for further research to look in more detail at risk factors and adverse outcomes for the 79% (n = 2790) of women presenting with pre-eclampsia among this large nationally representative sample of women.

Drug-related medical hospital admissions during and after a period of head shop expansion.

BACKGROUND: New psychoactive substance (NPS) use can negatively impact health and may result in drug-related hospital admissions (DRHAs). Irish youth reported very high rates of NPS use by international standards, the most common being synthetic cannabinoids and cathinones. There was a rapid expansion in specialist shops, called head shops, selling NPS in 2010. Government responded to public protests about head shops by enacting legislation in May and August 2010 to end this trade. Many academics argued that such actions would prove futile. We sought to determine if changes in head shop activity coincided with changes in DRHA. METHODS: The national database on admissions to general hospitals hospital in-patient enquiry was examined focusing on young adults admitted from 2008 to 2012, and all emergency admissions with an International Classification of Diseases-10 diagnosis of mental disorder related to any drug (F11-F19) were identified. Joinpoint regression analysis was utilized to explore for the presence of trend changes in DRHA. RESULTS: Joinpoint regression analysis identified a significant downward trend change which occurred in June 2010 (95% CI February 2010 to January 2011). DRHA increased by 0.5% (95% CI 0.1-0.9) per month prior to this and then fell by 2.6% (95% CI -1.4 to -3.8) per month over the next 16 months. CONCLUSIONS: Cessation of NPS sale by head shops coincided with a reversal in the upward trend of emergency hospital admissions related to drugs. Although correlation does not confirm causation, legislation which successfully curtails the commercial sale of NPS may result in reduced hospitalizations.

Comparison of the health and well-being of smoking and non-smoking school-aged children in Ireland.

BACKGROUND: Although most young people are aware of the long-term consequences of smoking, it has been shown that young smokers expect to give up before any health damage occurs. Little is known in an Irish context about the association between smoking and young people's current health. This could be helpful to help reduce smoking initiation and encouraging quitting. The study aimed to determine the association between smoking and health and well-being indicators among Irish school-aged children. METHODS: The 2014 Irish Health Behaviour in School-aged Children study was analysed, which comprised a random stratified sample of 9,623 schoolchildren (aged 10-18). The prevalence of eight self-reported health complaints and two subjective well-being measures were compared across strata classified by self-reported smoking status using Pearson's chi square and independent t tests. Logistic regression and ordinal regression were used to control for age, gender, and social class. RESULTS: A significantly larger proportion of smokers (p < .001) reported fair to poor health (32% versus 11% for non-smokers), lower mean life satisfaction scores (6.2 compared with 7.5), and each of eight health complaints at least once a week (range = 25-50% compared with 15-21%). These patterns remained significant after adjusting for differences in age, gender, and social class profile (p < .001). CONCLUSIONS: The study demonstrates the potential of developing initiatives, which target smoking in adolescence as opposed to the longer term health effects of smoking which are well known. The findings can be utilized to counteract positive perceptions of smoking among schoolchildren. This, combined with providing supports to help children quit, may help achieve government targets to reduce smoking prevalence.

A multi-faceted intervention to reduce alcohol misuse and harm amongst sports people in Ireland: A controlled trial.

INTRODUCTION AND AIMS: Alcohol misuse and harm are more prevalent amongst sports people than non-sports people. Few studies have trialled interventions to address alcohol misuse for this group. The study aimed to test the effectiveness of an intervention to reduce alcohol misuse and related harms amongst amateur sports people in Ireland. DESIGN AND METHODS: A controlled trial was conducted in two counties in Ireland. A random selection of sports clubs in one county received a 4 month multi-faceted intervention. All sports clubs in a non-adjacent county acted as control sites. Consumption of more than 21 units of alcohol per week and six or more standard drinks on a single occasion at least once per week was the primary study outcome. Alcohol Use Disorders Identification Test scores and number of alcohol-related harms were also reported. Outcomes were assessed for cross-sectional samples of players at pre-intervention and post-intervention and paired samples of players who completed surveys at both times. Generalised linear mixed model analysis was used. RESULTS: There was no evidence of effect for the primary outcomes or Alcohol Use Disorders Identification Test scores. There was a statistically significant difference in the median number of alcohol-related harms reported by intervention group players compared with control group players at post-intervention for the paired samples [intervention: 0; control: 3; incident rate ratio 0.56 (0.37, 0.84); P = 0.005]. DISCUSSION AND CONCLUSIONS: Intervention in community sports clubs may be effective in reducing the number of alcohol-related harms. Low levels of intervention participation and inadequate intervention dose are possible reasons for lack of a broader intervention effect. [O'Farrell A, Kingsland M, Kenny S, Eldin N, Wiggers J, Wolfenden L, Allwright S. A multi-faceted intervention to reduce alcohol misuse and harm amongst sports people in Ireland: A controlled trial. Drug Alcohol Rev 2018;37:14-22].

Child Health Care in Ireland.

The Irish health care system is based on a complex and costly mix of private, statutory, and voluntary provisions. The majority of health care expenditure comes from the state, with a significant proportion of acute hospital care funded from private insurance, but there are relatively high out-of-pocket costs for most service users. There is free access to acute hospital care, but not for primary care, for all children. About 40% of the population have free access to primary care. Universal preventive public health services, including vaccination and immunization, newborn blood spot screening, and universal neonatal hearing screening are free. Major health challenges include poverty, obesity, drug and alcohol use, and mental health. The health care system has been dominated for the last 5 years by the impact of the current recession, which has led to very sharp cuts in health care expenditure. It is unclear if the necessary substantial reform of the system will happen. Government policy calls for a move toward a patient-centered, primary care-led system, but without very substantial transfers of resources and investment in Information and Communication Technology, this is unlikely to occur.

Trends in the incidence of lower extremity amputations in people with and without diabetes over a five-year period in the Republic of Ireland.

AIMS: To describe trends in the incidence of non-traumatic amputations among people with and without diabetes and estimate the relative risk of an individual with diabetes undergoing a lower extremity amputation compared to an individual without diabetes in the Republic of Ireland. METHODS: All adults who underwent a nontraumatic amputation during 2005 to 2009 were identified using HIPE (Hospital In-patient Enquiry) data. Participants were classified as having diabetes or not having diabetes. Incidence rates were calculated using the number of discharges for diabetes and non-diabetes related lower extremity amputations as the numerator and estimates of the resident population with and without diabetes as the denominator. Age-adjusted incidence rates were used for trend analysis. RESULTS: Total diabetes-related amputation rates increased non-significantly during the study period; 144.2 in 2005 to 175.7 in 2009 per 100,000 people with diabetes (p = 0.11). Total non-diabetes related amputation rates dropped non-significantly from 12.0 in 2005 to 9.2 in 2009 per 100,000 people without diabetes (p = 0.16). An individual with diabetes was 22.3 (95% CI 19.1-26.1) times more likely to undergo a nontraumatic amputation than an individual without diabetes in 2005 and this did not change significantly by 2009. DISCUSSION: This study provides the first national estimate of lower extremity amputation rates in the Republic of Ireland. Diabetes-related amputation rates have remained steady despite an increase in people with diabetes. These estimates provide a base-line and will allow follow-up over time.

Alcohol use among amateur sportsmen in Ireland.

BACKGROUND: The objective of this study was to establish baseline data on alcohol consumption patterns, behaviours and harms among amateur sportsmen in the Republic of Ireland. FINDINGS: The study presents findings from the baseline survey for a cluster randomised controlled trial to evaluate the effectiveness of a community intervention programme to reduce problem alcohol use among a representative sample of Gaelic Athletic Association (GAA) clubs in two counties in the Republic of Ireland. Self reported alcohol use, prevalence of binge drinking, AUDIT scores and alcohol-related harms were assessed in amateur GAA sportsmen aged 16 years and over.Nine hundred and sixty (960) players completed questionnaires (72% response rate). Mean age was 24.0 years (S.D. 5.2). Of those aged 18 years or over, 75% had post-primary education; most (864, 90%) were current drinkers and 8.2% were regular smokers. The self-reported average yearly alcohol consumption was 12.5 litres. Almost one third (31%) of current drinkers reported drinking over the recommended limit of 21 standard drinks per week and just over half (54.3%) reported drinking 6 or more standard drinks in a row at least once a week (regular binge drinking). Of those who (self) completed the Alcohol Use Disorder Identification Test (AUDIT) questionnaire, three-quarters (74.7%) had a score of 8 or more; 11.5% had a score of 20 or above warranting referral for diagnostic evaluation and treatment. Almost all (87.6%) of the 864 drinkers reported experiencing at least one harm due to their drinking. These alcohol misuse outcomes were higher than those found in a nationally representative sample of males of a similar age. There were strong associations between regular binge drinking and reporting harms such as being in a fight (adjusted odds ratio (OR) 2.02, p < 0.001), missing time from work or college (adjusted OR 1.39, p = 0.04) or being in an accident (adjusted OR 1.78, p = 0.04). CONCLUSIONS: These male amateur sportsmen reported high rates of alcohol consumption and alcohol-related harm.

SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity.

Receptor tyrosine kinases (RTK), such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and fms-like tyrosine kinase 3 (FLT3), are expressed in malignant tissues and act in concert, playing diverse and major roles in angiogenesis, tumor growth, and metastasis. With the exception of a few malignancies, seemingly driven by a single genetic mutation in a signaling protein, most tumors are the product of multiple mutations in multiple aberrant signaling pathways. Consequently, simultaneous targeted inhibition of multiple signaling pathways could be more effective than inhibiting a single pathway in cancer therapies. Such a multitargeted strategy has recently been validated in a number of preclinical and clinical studies using RTK inhibitors with broad target selectivity. SU14813, a small molecule identified from the same chemical library used to isolate sunitinib, has broad-spectrum RTK inhibitory activity through binding to and inhibition of VEGFR, PDGFR, KIT, and FLT3. In cellular assays, SU14813 inhibited ligand-dependent and ligand-independent proliferation, migration, and survival of endothelial cells and/or tumor cells expressing these targets. SU14813 inhibited VEGFR-2, PDGFR-beta, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion. The plasma concentration required for in vivo target inhibition was estimated to be 100 to 200 ng/mL. Used as monotherapy, SU14813 exhibited broad and potent antitumor activity resulting in regression, growth arrest, or substantially reduced growth of various established xenografts derived from human or rat tumor cell lines. Treatment in combination with docetaxel significantly enhanced both the inhibition of primary tumor growth and the survival of the tumor-bearing mice compared with administration of either agent alone. In summary, SU14813 inhibited target RTK activity in vivo in association with reduction in angiogenesis, target RTK-mediated proliferation, and survival of tumor cells, leading to broad and potent antitumor efficacy. These data support the ongoing phase I clinical evaluation of SU14813 in advanced malignancies.

A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease.

Fifteen patients with refractory AML were treated in a phase 1 study with SU11248, an oral kinase inhibitor of fms-like tyrosine kinase 3 (Flt3), Kit, vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) receptors. Separate cohorts of patients received SU11248 for 4-week cycles followed by either a 2- or a 1-week rest period. At the starting dose level of 50 mg (n = 13), no dose-limiting toxicities were observed. The most frequent grade 2 toxicities were edema, fatigue, and oral ulcerations. Two fatal bleedings possibly related to the disease, one from a concomitant lung cancer and one cerebral bleeding, were observed. At the 75 mg dose level (n = 2), one case each of grade 4 fatigue, hypertension, and cardiac failure was observed, and this dose level was abandoned. All patients with FLT3 mutations (n = 4) had morphologic or partial responses compared with 2 of 10 evaluable patients with wild-type FLT3. Responses, although longer in patients with mutated FLT3, were of short duration. Reductions of cellularity and numbers of Ki-67(+), phospho-Kit(+), phospho-kinase domain-containing receptor-positive (phospho-KDR(+)), phospho-signal transducer and activator of transcription 5-positive (phospho-STAT5(+)), and phospho-Akt(+) cells were detected in bone marrow histology analysis. In summary, monotherapy with SU11248 induced partial remissions of short duration in acute myeloid leukemia (AML) patients. Further evaluation of this compound, for example in combination with chemotherapy, is warranted.

Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells.

Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results.

Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia.

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy trial in the US, where partial responses were observed in two of 33 patients. Since AML provides a unique platform to evaluate mechanism of action of small molecule inhibitors, investigation of the effect of SU5416 on FLT3 expression and phosphorylation in blood and bone marrow was an additional focus of this trial. Phosphorylated FLT3 was detected by immunoprecipitation/Western analysis in peripheral blood samples from 17 of 22 patients, and seven exhibited strong inhibition of phosphorylation immediately following a 1h SU5416 infusion, demonstrating that SU5416 can modulate RTK phosphorylation in humans. Although no clear correlation with clinical response was observed, analysis of patient plasma drug levels suggested that a threshold SU5416 concentration of 15 microM was associated with FLT3 inhibition. This observation was supported by data from an ex vivo model where AML cells were spiked into human blood, established to mimic the clinical setting and enable more rigorous analysis of effect of SU5416. In addition, FLT3 protein levels were downregulated in patient bone marrow samples, analyzed by an RIA assay. To identify putative predictors of response, patient plasma was analyzed for levels of secreted ligands of SU5416 targets; SCF and FLT3 ligand. Baseline levels of SCF in patients with stable or progressive disease were significantly higher than those in normal donors, whereas FLT3 ligand levels in patients who exhibited progressive disease were significantly lower than those in normal donors. The translational and clinical analyses described in this report provide some insights into the mechanism and duration of action of SU5416.

An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients.

PURPOSE: Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor alpha/beta, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML. EXPERIMENTAL DESIGN: Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels. RESULTS: Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3-wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in >50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition. CONCLUSIONS: This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics.

A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia.

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification.

BACKGROUND: Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. METHODS: Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC) samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF) receptor tyrosine kinase (RTK) inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. RESULTS: Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9) as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. CONCLUSIONS: These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes.

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.