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Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric liver disease in the developed world, with primary care providers caring for many at-risk children. The prevalence of NAFLD varies widely by race and ethnicity.To explore racial differences in screening and referral patterns for NAFLD among a high-risk pediatric population.This retrospective cohort study studied primary care patients at Children's of Alabama aged 5-17 years with BMI ≥ 85th percentile from 2008 to 2018. The main outcomes of interest were screening for NAFLD with alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and referral to Hepatology, Endocrinology, or Weight Management clinics.Of 666 children with BMI ≥ 85th percentile, 65% were screened at least once for NAFLD during the designated study period. Liver enzyme screening was performed in 54% of Hispanic Whites, 50% of non-Hispanic Whites, and 74% of African Americans (p-value 0.001). African American patients had the lowest rate of abnormal liver enzymes (defined as ALT and/or AST 1 × upper limit of normal). Among all patients with abnormal liver enzymes, 87% of non-Hispanic Whites, 92% of Hispanic Whites, and 17% of African Americans were referred (p-value 0.0001).Significant differences exist in NAFLD screening and referral practices by race/ethnicity. African Americans were far less likely to be referred for abnormal screening labs than their counterparts of other races. Awareness of these differences may allow for more intentional efforts to standardize practices, ensuring all patients receive care according to established guidelines.

Objectives To compare contraception use in 18–30-year-old women living with and without HIV. We also explored factors associated with contraceptive use. Study design We reviewed outpatient medical records for women living with HIV aged 18–30 years seen in one of two university-affiliated HIV-subspecialty clinics in Birmingham, Alabama, between July 2015 and June 2016. We selected an age-matched sample of women living without HIV seen in one of two university-affiliated non-HIV primary care clinics as the comparator group and focused our analysis on women with a documented discussion of contraception in clinic. For women with more than one clinic visit during the 1-year study period, the most recent visit was used for analysis. Multinominal and binary logistic regressions were used to identify factors associated with contraception use, and models were adjusted for HIV status. Results This study included 197 women (58 HIV-positive, 139 HIV-negative). Short-acting contraception methods were the most common methods used by women with (41.4%) and without HIV (47.5%, p=.43). Long-acting reversible contraception (LARC) use was 14% among women with HIV and 32% among women without HIV (p=.12). Contraception use predictors included HIV status, mental health comorbidities, obesity and number of pregnancies. Conclusion Documented contraceptive method use among 18–30-year -old women seen in clinics in urban Alabama varied by HIV status. Women with HIV were less likely to use LARC methods compared to women without HIV. Implications Future studies should focus on identifying factors that influence contraceptive choice and which methods are offered to young women in the South. Providers should document contraception discussions at each visit and remove any barriers to LARC provision.

The etiology of late-onset Alzheimer's disease is unknown. Recent epidemiological studies suggest that exposure to high levels of ozone (O3) may be a risk factor for late-onset Alzheimer's disease. Nonetheless, whether and how O3 exposure contributes to AD development remains to be determined. In this study, we tested the hypothesis that O3 exposure synergizes with the genetic risk factor APOE e4 and aging leading to AD, using male apolipoprotein E (apoE)4 and apoE3 targeted replacement mice as men have increased risk exposure to high levels of O3 via working environments and few studies have addressed APOE e4 effects on males. Surprisingly, our results show that O3 exposure impairs memory in old apoE3, but not old apoE4 or young apoE3 and apoE4, male mice. Further studies show that old apoE4 mice have increased hippocampal activities or expression of some enzymes involved in antioxidant defense, diminished protein oxidative modification, and neuroinflammation following O3 exposure compared with old apoE3 mice. These novel findings highlight the complexity of interactions between APOE genotype, age, and environmental exposure in AD development.

Summary Background The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events. Methods We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed. Findings Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 [SD 3·87] vs 9·34 [5·08]; p=0·0007) and mean alternate-day prednisone doses (24 mg [SD 21] vs 48 mg [29]; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase. Interpretation At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis. Funding National Institutes of Health, National Institute of Neurological Disorders and Stroke.

Asthma is one of the most common respiratory diseases. Although progress has been made in our understanding of airway pathology and many drugs are available to relieve asthma symptoms, there is no cure for chronic asthma. Plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue-type and urokinase-type plasminogen activators, has pleiotropic functions besides suppression of fibrinolysis. In this study, we show that administration of TM5275, an orally effective small-molecule PAI-1 inhibitor, 25 days after ovalbumin (OVA) sensitization-challenge, significantly ameliorated airway hyperresponsiveness in an OVA-induced chronic asthma model. Furthermore, we show that TM5275 administration significantly attenuated OVA-induced infiltration of inflammatory cells (neutrophils, eosinophils, and monocytes), the increase in the levels of OVA-specific IgE and Th2 cytokines (IL-4 and IL-5), the production of mucin in the airways, and airway subepithelial fibrosis. Together, the results suggest that the PAI-1 inhibitor TM5275 may have therapeutic potential for asthma through suppressing eosinophilic allergic response and ameliorating airway remodeling.

Importance Despite a high disease burden, there is no effective treatment for respiratory syncytial virus (RSV) infection. Objectives To determine whether administration of azithromycin (AZM) to children with RSV-induced respiratory failure is safe and to define the effect of AZM therapy on nasal matrix metalloproteinase 9 (MMP-9) levels. Design, Setting, and Participants This randomized, double-blind, placebo-controlled phase 2 trial was conducted at a single tertiary pediatric intensive care unit from February 2016 to February 2019. The study included children with RSV infection who were admitted to the pediatric intensive care unit and required respiratory support via positive pressure ventilation (invasive and noninvasive). A total of 147 children were screened; 90 were excluded for not meeting inclusion criteria, having an absent legal guardian, lacking pharmacy support, or having a language barrier and 9 declined participation, resulting in 48 patients enrolled in the study. Intervention Receipt of standard dose AZM (10 mg/kg/d), high-dose AZM (20 mg/kg/d), or a matching placebo of normal saline intravenously for 3 days. Main Outcomes and Measures Nasal and endotracheal samples were collected at baseline as well as at 24 hours and 48 hours after start of treatment. The secondary outcome was to determine treatment effect on clinical outcome measures, including days of positive pressure ventilation and length of hospital stay. Results A total of 48 patients were enrolled in the trial, with a median (range) age at randomization of 12 (1 to 125) months; 36 participants (75.0%) were younger than 2 years. Overall, 26 participants (54.2%) were boys, and 29 (60.4%) had a comorbidity. A total of 16 patients were randomized into each trial group (ie, placebo, standard-dose AZM, and high-dose AZM). Baseline demographic characteristics were comparable among the 3 groups. Both doses of AZM were safe, with no adverse events observed. No difference in nasal MMP-9 levels were observed between treatment groups. Among those who required mechanical ventilation and received high-dose AZM, endotracheal active and total MMP-9 levels were lower on day 3. Compared with baseline, active and total MMP-9 levels in endotracheal aspirates were 1.0 log lower in the high-dose AZM group (active MMP-9: 99.8% CI, −1.28 to −0.64;P Conclusions and Relevance In this phase 2 randomized clinical trial, both doses of AZM were safe. While nasal MMP-9 levels were unchanged among treatment groups, endotracheal MMP-9 levels were lower among those who received high-dose AZM. The positive secondary clinical outcome, while exploratory, provides insight for end points in a multicenter randomized trial. Trial Registration ClinicalTrials.gov Identifier:NCT02707523

Fluid resuscitation is the cornerstone of treatment for pediatric shock caused by conditions such as sepsis, dehydration, trauma, and anaphylaxis. Children presenting to the Emergency Department (ED) in shock have a high risk of mortality, and each hour of delay in shock reversal doubles the odds of death1,2. Pediatric Advanced Life Support (PALS) guidelines emphasize the importance of providing rapid fluid resuscitation to prevent the progression to hypotensive or refractory shock3. PALS and other septic shock guidelines recommend that patients receive a 20 mL/kg bolus of crystalloid immediately upon recognition of hypovolemic or distributive shock, with 20 mL/kg to be delivered within 5 minutes and up to 60 mL/kg within the first 15-60 minutes3-6. Studies based on these guidelines show that earlier fluid delivery directed at reversal of shock reversal leads to decreased morbidity7-9, mortality2,7,9-12, and hospital length of stay (LOS)9,11-13. Unfortunately, timely fluid delivery is often not achieved due to the technical challenges of obtaining adequate vascular access and delivering fluid boluses quickly in patients with shock or hypotension11,14-16. Current methods of fluid bolus delivery in the pediatric emergency care setting include infusion pumps, gravity drip, pressure bags, rapid infusers, and the push-pull syringe technique17,18. Each of these methods are limited by speed, ease of use, or safety concerns. Infusion pumps provide a maximum rate of 999 mL per hour, which for a 25kg child would provide a 60 mL/kg bolus in 90 minutes. In most patients, infusion pumps are therefore too slow to provide adequate fluid resuscitation. Gravity drip rates are unpredictable and inadequate for the treatment of shock and hypotension. For example, up to 50 minutes are required for one liter of fluid to flow through a 22G intravenous (IV) line, and up to 200 minutes via the intraosseous (IO) route19-22. A pressure cuff may speed flow modestly, but requires constant re-inflation, makes volume of infusion difficult to track, and carries the risk of inadvertent air embolism3,20,22-25. Rapid infusers can deliver fluids very quickly but are expensive, require frequent training, are not readily available in many emergency care settings, and importantly do not provide adequate flow with the small gauge IV or intraosseous (IO) access typical of pediatric resuscitation19,26. Due to the limitations of these common fluid delivery methods, pediatric emergency providers commonly use a syringe and 3-way stopcock to repeatedly draw fluid from the container of crystalloid and then deliver to the patient. This technique is referred to as the “push-pull” method and is recommended in the PALS guidelines3. An alternate technique involves disconnecting and reconnecting multiple pre-filled 60mL syringes, which often requires two providers18. Both methods may be associated with increased risk of nosocomial infection due to the difficulty of maintaining syringe sterility27-31. The LifeFlow® infuser (410 Medical, Inc; Durham, NC) is a new manually operated device for rapid fluid bolus delivery that overcomes some of these common barriers. The device is currently FDA-cleared for infusion of crystalloid and colloid fluids, and is in use at our center for emergency resuscitation. Using common IV gauges LifeFlow can deliver fluid 2 to 4 times faster than standard techniques, and allows providers to observe a clinical response immediately by improvements in vital signs, mental status and skin perfusion29,32-34. This study describes the use of the LifeFlow device in a busy academic children’s hospital ED with 74,000 patient visits per year.

BackgroundViral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear.MethodsPost hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy.ResultsHigher baseline VL was associated with central nervous system involvement (3.82 log, range 1–5.65 vs 3.32 log, range 1–5.36; P = .001), thrombocytopenia (3.68 log, range 1–5.65 vs 3.43 log, range 1–5.36; P = .03), and transaminitis at presentation (3.73 log, range 1–5.60 vs 3.39 log, range 1–5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing.ConclusionsIn infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes.

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain.

Background Sensorineural hearing loss (SNHL) and neurodevelopmental (ND) outcomes are favorably impacted by antiviral therapy in infants with symptomatic cCMV disease. We correlated blood VL before and during therapy with clinical findings at presentation and follow-up in this population. Methods Post-hoc analysis of two clinical trials conducted by the CASG from 2002 to 2013 evaluating valganciclovir therapy. 120 subjects (73 treated × 6 weeks, 47 treated × 6 months) were included. Whole blood VL was determined by real-time PCR at a central laboratory before therapy (baseline, BL) and periodically for 6 months. Results In subjects treated for 6 months, increases in BL VL correlated with decreased probability of better hearing outcomes at 12 months (Figure 1), but clinically meaningful VL thresholds that predict SNHL were not identified (Table 1). Subjects treated for 6 weeks had no correlation between BL VL and SNHL. No correlation was found between BL VL and Bayley ND testing at 12 and 24 months for subjects receiving either treatment duration. Subjects treated for 6 months who achieved and sustained VL suppression (3 symptoms of congenital CMV at presentation had higher BL VL than subjects with ≤3 symptoms (3.75 log, range 1.00–5.65, vs. 3.38 log, range 1.00–5.36; P = 0.005). Conclusion Blood VL at BL and during therapy has little clinically meaningful predictive value for long-term outcomes in symptomatic congenital CMV. Disclosures J. Englund, Gilead: Consultant and Investigator, Research support; Chimerix: Investigator, Research support; Alios: Investigator, Research support; Novavax: Investigator, Research support; MedImmune: Investigator, Research support; GlaxoSmithKline: Investigator, Research support

The etiology of Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is unknown. Recent epidemiology studies suggest that exposure to unhealthy levels of ozone (O3), a highly reactive oxidant and one of most abundant urban pollutant, may be responsible. Whether O3 acts alone or synergizes with other risk factors, such as aging and APOEe4, leading to AD remains to be determined. To test whether O3 exposure, APOEe4, and aging negatively interact leading to AD, we exposed otherwise healthy male apoE4 targeted replacement (TR) mice to a cyclic O3 exposure protocol, which mimics human exposure scenarios, and compared the results to male apoE3 TR mice, which represent the majority of the human population who carries the APOE e3 gene. The results show, surprisingly, that O3 exposure impairs memory of old male apoE3, but not apoE4, mice nor young apoE3 or apoE4 mice. Further studies show that glutathione concentration decreases with increased age and with O3 exposure in the hippocampus of male apoE3 mice, although its concentration is low in male apE4 mice since young age. Cysteine concentration, on the other hand, increases with age in apoE4 mice. The activities of several antioxidant enzymes including thioredoxin 1 are also increased in the hippocampus of old apoE4 mice, compared to old apoE3 mice. This is associated with diminished lipid and protein oxidation, astrocyte activation/inflammation, and neurogenesis in O3 exposed old apoE4 mice. Our results show, for the first time, that APOEe4, a genetic risk factor for AD, actually protects old male mice from O3-induced memory impairment, probably because old apoE4 male mice have developed compensatory mechanisms to combat O3-induced oxidative stress

Congenital cytomegalovirus (CMV) affects 0.6% to 0.7% of live births in industrialized nations. It is the leading viral causeof mental retardation and can also result in sensorineural hearing loss. Accepted treatment for patients with symptomatic congenital CMV involving the central nervous system includes intravenous ganciclovir, but the benefits of intravenous ganciclovir may wane over time. Oral therapy with valganciclovir has also been used in the treatment of congenital CMV, and the benefit of longer therapy was studied in this randomized controlled trial. A total of 40 sites participated in the study, and newborns were eligible if they had symptomatic congenital CMV disease, without or without central nervous system involvement. All patients received valganciclovir for 6 weeks, and 1 group continued the treatment for 4.5 months, whereas the rest received a placebo. Change in hearing in the better ear was measured as the primary end point. From 31 study sites, a total of 96 participants were randomized, with 47 participants receiving 6 months of treatment and 49 receiving placebo. A total of 12 stopped taking the blinded medication before the end of the study, but none did so because of adverse events. At 6 months, hearing in the better ear was similar between the 2 groups, with 2 having improvement in the 6-month group and 3 having improvement in the 6-week group, and 5 and 3, respectively, worsening (P = 0.41). At 12 months, total-ear hearing was more likely to be improved or remain normal in patients in the 6-month group than in the 6-week group (73% vs 57%, P = 0.001). The 6-month group scored better on the Bayley Scales of Infant and Toddler Development than did the 6-week group after 24 months on the receptive-communication scale (P = 0.003) and the language-composite scale (P = 0.004).Grade 3 or 4 neutropenia was not different in the 6-month versus the 6-week group (21% vs 27% after 6 months, P = 0.64).These findings suggest 6 months, compared with 6 weeks, of oral valganciclovir among infants with symptomatic congenital CMV disease modestly improved hearing, not in the short term, but in the long term. The prolonged treatment also appearedto improve developmental outcomes modestly.

The cause for the late-onset (sporadic) Alzheimer’s disease (AD), which accounts for 95% of AD cases, is unknown and most likely conferred by complex interactions between genetic and environmental risk factors plus aging. How the genetic and environmental risk factors as well as aging interact, leading to AD, however, is unknown. In this study, we explored the potential interactions between ApoE4, a genetic risk factor, O3, an environmental risk factor, and aging in the induction of memory impairment, using human ApoE4 and ApoE3 (the majority of human population carry the ApoE3 gene) targeted replacement (TR) male mice. The results show that exposure to O3 following a cyclic exposure protocol, which mimics human exposure scenarios, impairs memory of old ApoE3 TR mice, although it has no significant effect on the memory of young ApoE3 and ApoE4 or old ApoE4 TR mice. The concentrations of glutathione (GSH), an important antioxidant, decrease with age and with O3 exposure in frontal cortex (FC) and hippocampus, two brain areas affected mainly in AD, in ApoE3 TR mice, but only in FC of ApoE4 TR mice. The GSH and GSSG redox potentials decrease with age in the FC and hippocampus of ApoE3, but not ApoE4, TR mice; O3 exposure, on the other hand, reduces the redox potential in young ApoE3 and old ApoE4 TR mice. Cysteine concentrations decrease with age and with O3 exposure in both FC and hippocampus in ApoE3, but not in ApoE4, TR mice. The cysteine/cystine redox potentials, a major extracellular redox couple, decrease with O3 exposure in both brain areas in young and old ApoE3 TR mice, but only in the frontal cortex of young ApoE4 TR mice. Together, the results suggest that male ApoE3 TR mice are more sensitive to aging- and O3-induced oxidative stress than ApoE4 TR mice, although young ApoE4 mice per se experience increased level of oxidative stress, compared to young ApoE3 TR mice. The results also suggest that increased sensitivity to oxidative stress may underlie memory loss in O3 exposed old ApoE3 TR mice. As ApoE4 mainly affects females, interactions between ApoE4, O3, and aging in modulation of brain oxidative stress levels and memory in females warrant further investigation.

G207, a mutant herpes simplex virus (HSV) type 1, is safe when inoculated into recurrent malignant glioma. We conducted a phase 1 trial of G207 to demonstrate the safety of stereotactic intratumoral administration when given 24 hours prior to a single 5 Gy radiation dose in patients with recurrent malignant glioma. Nine patients with progressive, recurrent malignant glioma despite standard therapy were included. Patients received one dose of G207 stereotactically inoculated into the multiple sites of the enhancing tumor margin and were then treated focally with 5 Gy radiation. Treatment was well tolerated, and no patient developed HSV encephalitis. The median interval between initial diagnosis and G207 inoculation was 18 months (mean: 23 months; range: 11–51 months). Six of the nine patients had stable disease or partial response for at least one time point. Three instances of marked radiographic response to treatment occurred. The median survival time from G207 inoculation until death was 7.5 months (95% confidence interval: 3.0–12.7). In conclusion, this study showed the safety and the potential for clinical response of single-dose oncolytic HSV therapy augmented with radiation in the treatment of malignant glioma patients. Additional studies with oncolytic HSV such as G207 in the treatment of human glioma are recommended.

The matricellular protein osteopontin (OPN), expressed in various cancer types and elevated in the blood of cancer patients, is thought to have different functions when derived from host versus cancer cells. To assess the effect of host-derived OPN on growth of cancers of epithelial origin, we established a line of cutaneous squamous cell carcinoma (SCC) cells, named ONSC, which lacks the OPN gene and develops SCC in syngeneic wild-type (WT) and OPN-null mice. At 8 and/or 10 week after subcutaneous injection of ONSC cells in mice, however, there was a lower tumor incidence in WT mice, suggesting that host-derived OPN is associated with suppression of early growth of extrinsic cancer cells. Histological, immunohistochemical, biochemical and hematological analyses were performed on the tumor microenvironment and blood from tumor-bearing mice during the first week after implantation. Host-derived OPN suppression of extrinsic ONSC cell progression is likely mediated through elicitation of an early innate inflammatory response, through its function as a chemoattractant and/or by enhancing survival of inflammatory cells. Further, consistent with a previous report, the serum levels of host-derived OPN, which are elevated during the early phase of tumor growth in mice implanted with ONSC, appear to reflect an anti-tumor progression effect.

Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease.We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy.A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09).Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Objective To determine the maximum tolerated dose of ABT-510, a thrombospondin-1 mimetic drug with antiangiogenic properties, when used concurrently with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. Design Phase 1 dose-escalation clinical trial. Setting Comprehensive Cancer Center, University of Alabama at Birmingham. Patients A total of 23 patients with newly diagnosed, histologically verified glioblastoma enrolled between April 2005 and January 2007. Interventions Four cohorts of 3 patients each received subcutaneous ABT-510 injection at doses of 20, 50, 100, or 200 mg/d. The maximum cohort was expanded to 14 patients to obtain additional safety and gene expression data. The treatment plan included 10 weeks of induction phase (temozolomide and radiotherapy with ABT-510 for 6 weeks plus ABT-510 monotherapy for 4 weeks) followed by a maintenance phase of ABT-510 and monthly temozolomide. Main Outcome Measures Patients were monitored with brain magnetic resonance imaging and laboratory testing for dose-limiting toxicities, defined as grades 3 or 4 nonhematological toxicities and grade 4 hematological toxicities. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression, survival statistics, and gene expression arrays were analyzed. Results There were no grade 3 or 4 dose-limiting toxicity events that appeared related to ABT-510 for the dose range of 20 to 200 mg/d. A maximum tolerated dose was not defined. Most adverse events were mild, and injection-site reactions. The median time to tumor progression was 45.9 weeks, and the median overall survival time was 64.4 weeks. Gene expression analysis using TaqMan low-density arrays identified angiogenic genes that were differentially expressed in the brains of controls compared with patients with newly diagnosed glioblastoma, and identified FGF-1 and TIE-1 as being downregulated in patients who had better clinical outcomes. Conclusions ABT-510, at subcutaneous doses up to 200 mg/d, is tolerated well with concurrent temozolomide and radiotherapy in patients with newly diagnosed glioblastoma, and low-density arrays provide a useful method of exploring gene expression profiles.

2023 Background: ABT-510 (Abbott Laboratories, Abbott Park, IL, USA) is a Thrombospondin-1 (TSP-1) mimetic drug with anti-angiogenic properties. This phase I dose escalation trial was designed to study the maximum tolerated dose (MTD) of ABT 510 when used concurrently with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma multiforme (GBM). Methods: A total of 23 patients with newly diagnosed, histologically verified GBM were enrolled between April 2005 and January 2007, after obtaining written consent. The study was approved by the University of Alabama at Birmingham (UAB) Institutional Review Board. Four cohorts with three patients in each, receiving subcutaneous ABT 510 injection at doses of 20, 50, 100, and 200 mg/day were studied. The starting dose was primarily based on preclinical findings from animal studies and phase I studies on healthy subjects and cancer patients. Treatment plan included 10 weeks of induction phase (TMZ and RT with ABT 510) followed by a maintenance phase (ABT 510 and TMZ) of 14 cycles each consisting of 28 days. Patients were monitored with brain MRI along with laboratory values for dose limiting toxicities (DLT) defined as grades 3–4 non-hematological toxicities and grade 4 hematological toxicities (neutropenia or thrombocytopenia). In the absence of a DLT in at least two of the three patients, the dose was increased by 50% in the next cohort of patients. Therapy was discontinued if 14 maintenance cycles were completed, disease progression occurred, or if the patient requested withdrawal. Disease progression and survival statistics were analyzed. Results: During this trial, grade 3/4 DLT were not observed even after the dose was increased to 200 mg/day, hence, the last cohort was expanded to include 14 patients. A MTD was not defined. The median time to tumor progression (TTP) was 220 days and the median overall survival was 422 days. Gene expression analysis of the tumor pathology will be performed to evaluate the relationship between the expression of TSP-1, TSP-2, and patient response to the drug. Conclusions: ABT 510, at subcutaneous doses up to 200 mg/day, is tolerated well with concurrent TMZ and RT in patients with newly diagnosed GBM. No significant financial relationships to disclose.