Terzah Horton - Academia.edu (original) (raw)

Papers by Terzah Horton

Journal of Pediatric Hematology Oncology, Mar 31, 2003

Thrombotic thrombocytopenic purpura (TTP) is a well-described entity in adults but is rarely obse... more Thrombotic thrombocytopenic purpura (TTP) is a well-described entity in adults but is rarely observed in children. The authors describe a series of seven children with suspected acquired TTP. Clinical findings included petechiae, purpura, or jaundice ( 6), central nervous system events ( 5), fever ( 3), diarrhea ( 3), renal insufficiency ( 2), and hematuria ( 2). Significant central nervous system events included cerebral vascular accidents ( 2), altered mental status ( 2), seizures ( 1), and hemiparesis ( 1). Patients were treated with daily plasma infusions (1/7) or plasma exchange (5/7). Response was prompt, although relapses were frequent. Decreased vWF-protease activity was found in four of five cases and vWF-protease inhibitors were found in three of five cases. Although rare, TTP is a life-threatening illness that does occur in children and should be considered in the differential diagnosis of thrombocytopenia with hemolytic anemia.

Journal of Virology

A 14.7-kilodalton protein (14.7K protein) encoded by the E3 region of group C adenoviruses has be... more A 14.7-kilodalton protein (14.7K protein) encoded by the E3 region of group C adenoviruses has been shown to protect virus-infected fibroblasts from lysis by tumor necrosis factor (TNF) (L.R. Gooding, L.W. Elmore, A.E. Tollefson, H.A. Brady, and W.S.M. Wold, Cell 53:341-346, 1988). In this study we show that adenoviruses of other groups are also protected from TNF-induced cytolysis. Representative serotypes of groups A, B, D, and E produce a protein analogous to the 14.7K protein found in human group C adenoviruses. Deletion of this protein in group C viruses permits virus infection to induce cellular susceptibility to TNF killing. As with group C adenoviruses, cells infected with wild-type adenoviruses of other serotypes are not killed by TNF and are protected from lysis induced by TNF plus cycloheximide. However, cells are susceptible to TNF-induced lysis when infected with adenovirus type 4 mutants from which the 14.7K gene has been deleted. Although all known adenovirus serotype...

Journal of Virology

We have reported that the E3 14,700-dalton protein (E3 14.7K protein) protects adenovirus-infecte... more We have reported that the E3 14,700-dalton protein (E3 14.7K protein) protects adenovirus-infected mouse C3HA fibroblasts against lysis by tumor necrosis factor (TNF) (L. R. Gooding, L. W. Elmore, A. E. Tollefson, H. A. Brady, and W. S. M. Wold, Cell 53:341-346, 1988). We have also observed that the E1B 19K protein protects adenovirus-infected human but not mouse cells against TNF lysis (L. R. Gooding, L. Aquino, P. J. Duerksen-Hughes, D. Day, T. M. Horton, S. Yei, and W. S. M. Wold, J. Virol. 65:3083-3094, 1991). We now report that, in the absence of E3 14.7K, the E3 10.4K and E3 14.5K proteins are both required to protect C127 as well as several other mouse cell lines against TNF lysis. The 14.7K protein can also protect these cells from TNF in the absence of the 10.4K and 14.5K proteins. This protection by the 10.4K and 14.5K proteins was not observed in the C3HA cell line. These conclusions are based on 51Cr release assays of cells infected with virus E3 mutants that express the...

Lymphoma, 2012

ABSTRACT Constitutively active nuclear factor- κ B (NF- κ B) is integral to the survival of Hodgk... more ABSTRACT Constitutively active nuclear factor- κ B (NF- κ B) is integral to the survival of Hodgkin/Reed-Sternberg cells (H/RS) in Hodgkin lymphoma (HL). To investigate NF- κ B pathway proteins in pediatric HL, we utilized a tissue microarray compiled from 102 children enrolled in the Children's Oncology Group intermediate-risk clinical trial AHOD0031 (56 male, 78 Caucasian, median age 15 years (range 1–20 years), 85 nodular sclerosing subtype, 23 Epstein-Barr virus (EBV) positive, and 24 refractory/relapsed disease). We examined the intensity, localization, and pathway correlations of NF- κ B pathway proteins (Rel-A/p65, Rel-B, c-Rel, NF- κ B1, NF- κ B2, I κ B- α , IKK- α , IKK- β , IKK- γ /NEMO, NIK, and A20), as well as their associations with EBV status and clinical outcome. NF- κ B pathway proteins were overexpressed in pediatric HL patients compared to controls. Patients with EBV− tumors, or with rapid early therapy response, had tightly coordinated regulation of NF- κ B pathway proteins, whereas patients with EBV+ tumors, or slow early therapy response, had little coordinated NF- κ B pathway regulation. High NIK expression was associated with a slow response to therapy and decreased EFS. Elevated Rel-B, NIK, and the NF- κ B inhibitor A20 were associated with decreased EFS in multivariate analysis. These studies suggest a pivotal role for the NF- κ B pathway in therapy response and patient survival in Hodgkin lymphoma.

British journal of haematology, 2015

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the... more A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0·32). Although not statistically different, results suggest IVB may be a promising combination.

Journal of virology, 1993

The 14,700-Da protein (14.7K protein) encoded by the E3 region of adenovirus has previously been ... more The 14,700-Da protein (14.7K protein) encoded by the E3 region of adenovirus has previously been shown to protect mouse cells from cytolysis by tumor necrosis factor (TNF). Delineating the sequences in the 14.7K protein that are required for this activity may provide insight into the mechanism of protection from TNF by 14.7K as well as the mechanism of TNF cytolysis. In the present study, we examined the ability of 14.7K mutants to protect cells from lysis by TNF. In-frame deletions as well as Cys-to-Ser mutations in the 14.7K gene were generated by site-directed mutagenesis and then built into the genome of a modified adenovirus type 5 (dl7001) that lacks all E3 genes. dl7001, which replicates to the same titers as does adenovirus type 5 in cultured cells, has the largest E3 deletion analyzed to date. 51Cr release was used to assay TNF cytolysis. Our results indicate that most mutations in the 14.7K gene result in a loss of function, suggesting that nearly the entire protein rather...

Pediatric Blood & Cancer, 2010

A workshop at the 2008 ASPHO Annual Meeting functioned as the first step in a systematic needs as... more A workshop at the 2008 ASPHO Annual Meeting functioned as the first step in a systematic needs assessment of the particular challenges to satisfaction and success in the middle and senior phases of career development for pediatric hematologist/oncologists (PHOs). The 61 ASPHO members who attended were randomly distributed to small discussion groups based on self-identified career stage. Groups completed challenge forms for each issue identified as pertinent to their own stage of professional development. A total of 71 forms with useable data were generated by the groups. The largest number of challenges described (26) clustered around themes of Work-Life Bal-ance followed by Transition and Succession (18), Management and Finances (15), and Keeping up to Date (13). Mid-career groups were more likely to identify Work-Life Balance challenges while senior stage groups were more likely to articulate Succession and Management challenges. The article describes the demographics of the workshop participants, summarizes the content of challenge themes and the associated suggestions for management. It is hoped that this effort will assist educational and career planning efforts by individuals, institutions, and ASPHO as a professional society.

Pediatric Blood & Cancer, 2014

This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction c... more This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. Patients with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B). Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.

The Pediatric Infectious Disease Journal, 2001

Cytarabine was temporally associated with aseptic meningitis syndrome in an 8-year-old Hispanic g... more Cytarabine was temporally associated with aseptic meningitis syndrome in an 8-year-old Hispanic girl being treated for acute lymphoblastic leukemia.

Pediatric Hematology-Oncology, 2012

Despite the favorable outcome of most pediatric patients with Hodgkin lymphoma (HL), there is ris... more Despite the favorable outcome of most pediatric patients with Hodgkin lymphoma (HL), there is rising concern about risks of carcinogenesis from both diagnostic and therapeutic radiation exposure for patients treated on study protocols. Although previous studies have investigated radiation exposure during treatment, radiation from post-treatment surveillance imaging may also increase the likelihood of secondary malignancies. All diagnostic imaging examinations involving ionizing radiation exposure performed for surveillance following completion of therapy were recorded for 99 consecutive pediatric patients diagnosed with HL from 2000 to 2010. Cumulative radiation dosage from these examinations and the frequency of relapse detection by these examinations were recorded. In the first 2 years following completion of therapy, patients in remission received a median of 11 examinations (range 0-26). Only 13 of 99 patients relapsed, 11 within 5 months of treatment completion. No relapse was detected by 1- or 2-view chest radiographs (n = 38 and 296, respectively), abdomen/pelvis computed tomography (CT) scans (n = 211), or positron emission tomography (PET) scans alone (n = 11). However, 10/391 (2.6%) of chest CT scans, 4/364 (1.1%) of neck CT scans, and 3/47 (6.4%) of PET/CT scans detected relapsed disease. Thus, only 17 scans (1.3%) detected relapse in a total of 1358 scans. Mean radiation dosages were 31.97 mSv for Stage 1, 37.76 mSv for Stage 2, 48.08 mSv for Stage 3, and 51.35 mSv for Stage 4 HL. Approximately 1% of surveillance imaging examinations identified relapsed disease. Given the very low rate of relapse detection by surveillance imaging stipulated by current protocols for pediatric HL patients, the financial burden of the tests themselves, the high cure rate, and risks of second malignancy from ionizing radiation exposure, modification of the surveillance strategy is recommended.

Pediatric Blood & Cancer, 2009

Background-Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation... more Background-Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation that is generally fatal without immune modulating chemotherapy. At Texas Children's Hospital, we have observed significant central nervous system (CNS) toxicity in several patients treated for HLH according to the Histiocyte Society protocol HLH-2004 in which cyclosporine is given early in the treatment regimen.

Pediatric Blood & Cancer, 2013

ABSTRACT Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgki... more ABSTRACT Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgkin lymphoma. Pediatric radiation oncologists have provided critical input into the development and implementation of concepts for clinical trials to further define the modality&#39;s role and test newer methods to reduce side effects or intensify therapy. The quality of pediatric oncology clinical trials that include radiation therapy is linked to the quality of guidelines. Radiation oncology is an adult medical specialty; thus, pediatric radiation oncologists are uniquely positioned to work with adult cancer investigators in the reorganized US National Cancer Institute Clinic Trials Network. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.

Pediatric Blood & Cancer, 2008

This report summarizes a phase 1 study conducted by the Children&amp;amp;amp;amp;amp;amp;amp;... more This report summarizes a phase 1 study conducted by the Children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Cancer Group (CCG) to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and anti-leukemia activity of paclitaxel in children with advanced stage leukemias. This study examined two dose escalation schedules of intravenous paclitaxel. Doses ranged from 250 to 500 mg/m(2) every 21 days in schedule A and 105 to 200 mg/m(2) weekly x 3 every 28 days in schedule B. Serial plasma samples for pharmacokinetic studies were obtained after the first paclitaxel dose. Sixty-three patients (median 10 years) with refractory or relapsed leukemia (ALL) (n = 39), acute myeloid leukemia (AML) (n = 19), biphenotypic (n = 4), and JCML (n = 1)) were enrolled. The DLTs in schedule A were grade 4 hypertension and hyperbilirubinemia with an MTD of 430 mg/m(2) every 21 days. The DLTs in schedule B were coagulopathy, hyperkalemia, hyperbilirubinemia, elevated SGOT (n = 1, 125 mg/m(2)), peripheral neuropathy (n = 1, 200 mg/m(2)), and typhlitis (n = 1, 200 mg/m(2)) with an MTD of 182 mg/m(2) weekly x 3 every 28 days. Among 54 evaluable patients, there was one complete response (CR), three partial responses (PR), and five patients with stable disease (SD). The mean terminal elimination half-life was 9.5 +/- 3.4 hr and the mean plasma clearance was 23 +/- 11 L/hr/m(2). Paclitaxel was tolerated at 430 mg/m(2) every 21 days and at 182 mg/m(2)/dose weekly x 3 every 28 days in pediatric patients. The objective response rate across all dose levels and schedules was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10%.

Pediatric Blood & Cancer, 2013

A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting to... more A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

Neurology, 1995

To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Hun... more To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Huntington&#39;s disease (HD), we quantitated the amount of the common mitochondrial 4977 nucleotide pair deletion (mtDNA4977) in cortex and putamen of HD patients and age-matched controls by the serial dilution-polymerase chain reaction method. Cortical deletion levels were analyzed in the temporal, frontal, and occipital lobes. HD temporal lobes had an 11-fold greater mean mtDNA4977 deletion level than age-matched controls, and HD frontal lobes had fivefold greater levels. HD occipital lobe and putamen deletion levels were comparable with control levels. These results support the hypothesis that HD is associated with elevated cortical mtDNA damage.

Molecular Cancer Therapeutics, 2009

The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of te... more The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O(6)-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC(50) alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3-7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2-5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ.

Leukemia & Lymphoma, 2009

With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who r... more With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who relapse multiple times have an extremely poor prognosis. Therefore, new agents and novel therapeutic approaches are urgently needed. Antiapoptotic proteins such as Bcl-2 and Bcl-x have been associated with the growth and survival of Hodgkin Reed-Sternberg cells and are potential therapeutic targets. ABT-737 is a small molecule that inhibits the Bcl-2 family of apoptosis regulators. In this study, we show the concentration-dependent and time-dependent cytotoxicity of ABT-737 against cell lines derived from patients with HL. A concurrent reduction in a number of intracellular cell growth and survival related molecules, such as Bcl-2, Bcl-xl, NF-kB and survivin was also seen. Drug combination studies using a panel of conventional and novel therapeutic agents show that ABT-737 potentiates the activity of agents that have inherent anti-lymphoma activity and provide support for the evaluation of ABT-737 in the clinical setting.

The Journal of Pediatrics, 2004

To determine whether elective cholecystectomy is justifiable in children with sickle cell disease... more To determine whether elective cholecystectomy is justifiable in children with sickle cell disease (SCD), gallbladder abnormalities, and minimal clinical symptoms. A retrospective review comparing clinical presentations and abdominal ultrasound results with outcomes in 146 children with SCD. Ultrasound examination showed sludge or stones in 83 of 146 children (57%). This was found during a diagnostic ultrasound in 59 patients (71%) and during a screening ultrasound in 24 asymptomatic patients (29%). Fifty-four (65%) children with a positive ultrasound underwent cholecystectomy; 13 of these were initially asymptomatic patients who had subsequent development of clinical symptoms. Of the patients with cholecystectomy, 93% had histopathologic evidence of cholecystitis. Perioperative complications were rare, and there were no episodes of postoperative acute chest syndrome. Children who underwent elective surgery had an average 12-days-shorter overall hospital stay than those who underwent emergent surgery (4 vs 16 days, P &amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). Elective laparoscopic cholecystectomy may be safely performed in children with SCD. Surgery should be strongly considered at the time of gallstone diagnosis before symptoms or complications develop. Histopathologic chronic cholecystitis does not correlate with clinical symptoms.

Journal of Pediatric Hematology/Oncology, 2013

A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair yo... more A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair young investigators (mentees) with established COG members (mentors). Despite the American Academy of Pediatrics policy statement promoting mentorship programs, there are no publications describing and evaluating national mentorship programs in pediatric subspecialties. In this study, a series of internal program evaluations were performed using surveys of both mentors and mentees. Responses were deidentified and analyzed to determine the utility of the program by both participant satisfaction and selfreported academic productivity. Results indicated that mentees were generally satisfied with the program. Mentor-mentee pairs that met at least quarterly demonstrated greater academic productivity than pairings that met less frequently. This formal mentorship program appeared to have subjective and objective utility for the development of academic pediatric subspecialists. FIGURE 4. Relationship of the frequency of mentor-mentee interactions with reported predictors and productivity outcome measures. P-values shown are for Kruskal-Wallis analysis of the entire data set for each figure. Correlation of meeting frequency (and P-values for Spearman nonparametric correlation) with (A) the mentee's perceived degree of "fit" with their mentor (P = 0.0094), (B) the mentee's perceived match of program expectations with the mentor's (P = 0.0027), (C) the mentee's perceived match of time expectations with the mentor's (P = 0.0092), and (D) the mentee's reported productivity (P = 0.0059).

Journal of Pediatric Hematology Oncology, Mar 31, 2003

Thrombotic thrombocytopenic purpura (TTP) is a well-described entity in adults but is rarely obse... more Thrombotic thrombocytopenic purpura (TTP) is a well-described entity in adults but is rarely observed in children. The authors describe a series of seven children with suspected acquired TTP. Clinical findings included petechiae, purpura, or jaundice ( 6), central nervous system events ( 5), fever ( 3), diarrhea ( 3), renal insufficiency ( 2), and hematuria ( 2). Significant central nervous system events included cerebral vascular accidents ( 2), altered mental status ( 2), seizures ( 1), and hemiparesis ( 1). Patients were treated with daily plasma infusions (1/7) or plasma exchange (5/7). Response was prompt, although relapses were frequent. Decreased vWF-protease activity was found in four of five cases and vWF-protease inhibitors were found in three of five cases. Although rare, TTP is a life-threatening illness that does occur in children and should be considered in the differential diagnosis of thrombocytopenia with hemolytic anemia.

Journal of Virology

A 14.7-kilodalton protein (14.7K protein) encoded by the E3 region of group C adenoviruses has be... more A 14.7-kilodalton protein (14.7K protein) encoded by the E3 region of group C adenoviruses has been shown to protect virus-infected fibroblasts from lysis by tumor necrosis factor (TNF) (L.R. Gooding, L.W. Elmore, A.E. Tollefson, H.A. Brady, and W.S.M. Wold, Cell 53:341-346, 1988). In this study we show that adenoviruses of other groups are also protected from TNF-induced cytolysis. Representative serotypes of groups A, B, D, and E produce a protein analogous to the 14.7K protein found in human group C adenoviruses. Deletion of this protein in group C viruses permits virus infection to induce cellular susceptibility to TNF killing. As with group C adenoviruses, cells infected with wild-type adenoviruses of other serotypes are not killed by TNF and are protected from lysis induced by TNF plus cycloheximide. However, cells are susceptible to TNF-induced lysis when infected with adenovirus type 4 mutants from which the 14.7K gene has been deleted. Although all known adenovirus serotype...

Journal of Virology

We have reported that the E3 14,700-dalton protein (E3 14.7K protein) protects adenovirus-infecte... more We have reported that the E3 14,700-dalton protein (E3 14.7K protein) protects adenovirus-infected mouse C3HA fibroblasts against lysis by tumor necrosis factor (TNF) (L. R. Gooding, L. W. Elmore, A. E. Tollefson, H. A. Brady, and W. S. M. Wold, Cell 53:341-346, 1988). We have also observed that the E1B 19K protein protects adenovirus-infected human but not mouse cells against TNF lysis (L. R. Gooding, L. Aquino, P. J. Duerksen-Hughes, D. Day, T. M. Horton, S. Yei, and W. S. M. Wold, J. Virol. 65:3083-3094, 1991). We now report that, in the absence of E3 14.7K, the E3 10.4K and E3 14.5K proteins are both required to protect C127 as well as several other mouse cell lines against TNF lysis. The 14.7K protein can also protect these cells from TNF in the absence of the 10.4K and 14.5K proteins. This protection by the 10.4K and 14.5K proteins was not observed in the C3HA cell line. These conclusions are based on 51Cr release assays of cells infected with virus E3 mutants that express the...

Lymphoma, 2012

ABSTRACT Constitutively active nuclear factor- κ B (NF- κ B) is integral to the survival of Hodgk... more ABSTRACT Constitutively active nuclear factor- κ B (NF- κ B) is integral to the survival of Hodgkin/Reed-Sternberg cells (H/RS) in Hodgkin lymphoma (HL). To investigate NF- κ B pathway proteins in pediatric HL, we utilized a tissue microarray compiled from 102 children enrolled in the Children&#39;s Oncology Group intermediate-risk clinical trial AHOD0031 (56 male, 78 Caucasian, median age 15 years (range 1–20 years), 85 nodular sclerosing subtype, 23 Epstein-Barr virus (EBV) positive, and 24 refractory/relapsed disease). We examined the intensity, localization, and pathway correlations of NF- κ B pathway proteins (Rel-A/p65, Rel-B, c-Rel, NF- κ B1, NF- κ B2, I κ B- α , IKK- α , IKK- β , IKK- γ /NEMO, NIK, and A20), as well as their associations with EBV status and clinical outcome. NF- κ B pathway proteins were overexpressed in pediatric HL patients compared to controls. Patients with EBV− tumors, or with rapid early therapy response, had tightly coordinated regulation of NF- κ B pathway proteins, whereas patients with EBV+ tumors, or slow early therapy response, had little coordinated NF- κ B pathway regulation. High NIK expression was associated with a slow response to therapy and decreased EFS. Elevated Rel-B, NIK, and the NF- κ B inhibitor A20 were associated with decreased EFS in multivariate analysis. These studies suggest a pivotal role for the NF- κ B pathway in therapy response and patient survival in Hodgkin lymphoma.

British journal of haematology, 2015

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the... more A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0·32). Although not statistically different, results suggest IVB may be a promising combination.

Journal of virology, 1993

The 14,700-Da protein (14.7K protein) encoded by the E3 region of adenovirus has previously been ... more The 14,700-Da protein (14.7K protein) encoded by the E3 region of adenovirus has previously been shown to protect mouse cells from cytolysis by tumor necrosis factor (TNF). Delineating the sequences in the 14.7K protein that are required for this activity may provide insight into the mechanism of protection from TNF by 14.7K as well as the mechanism of TNF cytolysis. In the present study, we examined the ability of 14.7K mutants to protect cells from lysis by TNF. In-frame deletions as well as Cys-to-Ser mutations in the 14.7K gene were generated by site-directed mutagenesis and then built into the genome of a modified adenovirus type 5 (dl7001) that lacks all E3 genes. dl7001, which replicates to the same titers as does adenovirus type 5 in cultured cells, has the largest E3 deletion analyzed to date. 51Cr release was used to assay TNF cytolysis. Our results indicate that most mutations in the 14.7K gene result in a loss of function, suggesting that nearly the entire protein rather...

Pediatric Blood & Cancer, 2010

A workshop at the 2008 ASPHO Annual Meeting functioned as the first step in a systematic needs as... more A workshop at the 2008 ASPHO Annual Meeting functioned as the first step in a systematic needs assessment of the particular challenges to satisfaction and success in the middle and senior phases of career development for pediatric hematologist/oncologists (PHOs). The 61 ASPHO members who attended were randomly distributed to small discussion groups based on self-identified career stage. Groups completed challenge forms for each issue identified as pertinent to their own stage of professional development. A total of 71 forms with useable data were generated by the groups. The largest number of challenges described (26) clustered around themes of Work-Life Bal-ance followed by Transition and Succession (18), Management and Finances (15), and Keeping up to Date (13). Mid-career groups were more likely to identify Work-Life Balance challenges while senior stage groups were more likely to articulate Succession and Management challenges. The article describes the demographics of the workshop participants, summarizes the content of challenge themes and the associated suggestions for management. It is hoped that this effort will assist educational and career planning efforts by individuals, institutions, and ASPHO as a professional society.

Pediatric Blood & Cancer, 2014

This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction c... more This Phase 2 study tested the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for pediatric patients with relapsed, refractory or secondary acute myeloid leukemia (AML). Correlative studies measured putative AML leukemia initiating cells (AML-LIC) before and after treatment. Patients with &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;400 mg/m(2) prior anthracycline received bortezomib combined with idarubicin (12 mg/m(2) days 1-3) and low-dose cytarabine (100 mg/m(2) days 1-7) (Arm A). Patients with ≥400 mg/m(2) prior anthracycline received bortezomib with etoposide (100 mg/m(2) on days 1-5) and high-dose cytarabine (1 g/m(2) every 12 hours for 10 doses) (Arm B). Forty-six patients were treated with 58 bortezomib-containing cycles. The dose finding phase of Arm B established the recommended Phase 2 dose of bortezomib at 1.3 mg/m(2) on days 1, 4, and 8 with Arm B chemotherapy. Both arms were closed after failure to meet predetermined efficacy thresholds during the first stage of the two-stage design. The complete response (CR + CRp) rates were 29% for Arm A and 43% for Arm B. Counting additional CRi responses (CR with incomplete neutrophil recovery), the overall CR rates were 57% for Arm A and 48% for Arm B. The 2-year overall survival (OS) was 39 ± 15%. Correlative studies showed that LIC depletion after the first cycle was associated with clinical response. Bortezomib is tolerable when added to chemotherapy regimens for relapsed pediatric AML, but the regimens did not exceed preset minimum response criteria to allow continued accrual. This study also suggests that AML-LIC depletion has prognostic value.

The Pediatric Infectious Disease Journal, 2001

Cytarabine was temporally associated with aseptic meningitis syndrome in an 8-year-old Hispanic g... more Cytarabine was temporally associated with aseptic meningitis syndrome in an 8-year-old Hispanic girl being treated for acute lymphoblastic leukemia.

Pediatric Hematology-Oncology, 2012

Despite the favorable outcome of most pediatric patients with Hodgkin lymphoma (HL), there is ris... more Despite the favorable outcome of most pediatric patients with Hodgkin lymphoma (HL), there is rising concern about risks of carcinogenesis from both diagnostic and therapeutic radiation exposure for patients treated on study protocols. Although previous studies have investigated radiation exposure during treatment, radiation from post-treatment surveillance imaging may also increase the likelihood of secondary malignancies. All diagnostic imaging examinations involving ionizing radiation exposure performed for surveillance following completion of therapy were recorded for 99 consecutive pediatric patients diagnosed with HL from 2000 to 2010. Cumulative radiation dosage from these examinations and the frequency of relapse detection by these examinations were recorded. In the first 2 years following completion of therapy, patients in remission received a median of 11 examinations (range 0-26). Only 13 of 99 patients relapsed, 11 within 5 months of treatment completion. No relapse was detected by 1- or 2-view chest radiographs (n = 38 and 296, respectively), abdomen/pelvis computed tomography (CT) scans (n = 211), or positron emission tomography (PET) scans alone (n = 11). However, 10/391 (2.6%) of chest CT scans, 4/364 (1.1%) of neck CT scans, and 3/47 (6.4%) of PET/CT scans detected relapsed disease. Thus, only 17 scans (1.3%) detected relapse in a total of 1358 scans. Mean radiation dosages were 31.97 mSv for Stage 1, 37.76 mSv for Stage 2, 48.08 mSv for Stage 3, and 51.35 mSv for Stage 4 HL. Approximately 1% of surveillance imaging examinations identified relapsed disease. Given the very low rate of relapse detection by surveillance imaging stipulated by current protocols for pediatric HL patients, the financial burden of the tests themselves, the high cure rate, and risks of second malignancy from ionizing radiation exposure, modification of the surveillance strategy is recommended.

Pediatric Blood & Cancer, 2009

Background-Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation... more Background-Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation that is generally fatal without immune modulating chemotherapy. At Texas Children's Hospital, we have observed significant central nervous system (CNS) toxicity in several patients treated for HLH according to the Histiocyte Society protocol HLH-2004 in which cyclosporine is given early in the treatment regimen.

Pediatric Blood & Cancer, 2013

ABSTRACT Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgki... more ABSTRACT Radiation therapy (RT) is used to treat children with CNS tumors, solid tumors or Hodgkin lymphoma. Pediatric radiation oncologists have provided critical input into the development and implementation of concepts for clinical trials to further define the modality&#39;s role and test newer methods to reduce side effects or intensify therapy. The quality of pediatric oncology clinical trials that include radiation therapy is linked to the quality of guidelines. Radiation oncology is an adult medical specialty; thus, pediatric radiation oncologists are uniquely positioned to work with adult cancer investigators in the reorganized US National Cancer Institute Clinic Trials Network. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.

Pediatric Blood & Cancer, 2008

This report summarizes a phase 1 study conducted by the Children&amp;amp;amp;amp;amp;amp;amp;... more This report summarizes a phase 1 study conducted by the Children&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s Cancer Group (CCG) to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and anti-leukemia activity of paclitaxel in children with advanced stage leukemias. This study examined two dose escalation schedules of intravenous paclitaxel. Doses ranged from 250 to 500 mg/m(2) every 21 days in schedule A and 105 to 200 mg/m(2) weekly x 3 every 28 days in schedule B. Serial plasma samples for pharmacokinetic studies were obtained after the first paclitaxel dose. Sixty-three patients (median 10 years) with refractory or relapsed leukemia (ALL) (n = 39), acute myeloid leukemia (AML) (n = 19), biphenotypic (n = 4), and JCML (n = 1)) were enrolled. The DLTs in schedule A were grade 4 hypertension and hyperbilirubinemia with an MTD of 430 mg/m(2) every 21 days. The DLTs in schedule B were coagulopathy, hyperkalemia, hyperbilirubinemia, elevated SGOT (n = 1, 125 mg/m(2)), peripheral neuropathy (n = 1, 200 mg/m(2)), and typhlitis (n = 1, 200 mg/m(2)) with an MTD of 182 mg/m(2) weekly x 3 every 28 days. Among 54 evaluable patients, there was one complete response (CR), three partial responses (PR), and five patients with stable disease (SD). The mean terminal elimination half-life was 9.5 +/- 3.4 hr and the mean plasma clearance was 23 +/- 11 L/hr/m(2). Paclitaxel was tolerated at 430 mg/m(2) every 21 days and at 182 mg/m(2)/dose weekly x 3 every 28 days in pediatric patients. The objective response rate across all dose levels and schedules was &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;10%.

Pediatric Blood & Cancer, 2013

A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting to... more A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

Neurology, 1995

To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Hun... more To determine if somatic mtDNA mutations might contribute to the neurodegeneration observed in Huntington&#39;s disease (HD), we quantitated the amount of the common mitochondrial 4977 nucleotide pair deletion (mtDNA4977) in cortex and putamen of HD patients and age-matched controls by the serial dilution-polymerase chain reaction method. Cortical deletion levels were analyzed in the temporal, frontal, and occipital lobes. HD temporal lobes had an 11-fold greater mean mtDNA4977 deletion level than age-matched controls, and HD frontal lobes had fivefold greater levels. HD occipital lobe and putamen deletion levels were comparable with control levels. These results support the hypothesis that HD is associated with elevated cortical mtDNA damage.

Molecular Cancer Therapeutics, 2009

The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of te... more The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O(6)-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC(50) alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3-7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2-5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ.

Leukemia & Lymphoma, 2009

With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who r... more With currently available treatment, patients with refractory Hodgkin lymphoma (HL) or those who relapse multiple times have an extremely poor prognosis. Therefore, new agents and novel therapeutic approaches are urgently needed. Antiapoptotic proteins such as Bcl-2 and Bcl-x have been associated with the growth and survival of Hodgkin Reed-Sternberg cells and are potential therapeutic targets. ABT-737 is a small molecule that inhibits the Bcl-2 family of apoptosis regulators. In this study, we show the concentration-dependent and time-dependent cytotoxicity of ABT-737 against cell lines derived from patients with HL. A concurrent reduction in a number of intracellular cell growth and survival related molecules, such as Bcl-2, Bcl-xl, NF-kB and survivin was also seen. Drug combination studies using a panel of conventional and novel therapeutic agents show that ABT-737 potentiates the activity of agents that have inherent anti-lymphoma activity and provide support for the evaluation of ABT-737 in the clinical setting.

The Journal of Pediatrics, 2004

To determine whether elective cholecystectomy is justifiable in children with sickle cell disease... more To determine whether elective cholecystectomy is justifiable in children with sickle cell disease (SCD), gallbladder abnormalities, and minimal clinical symptoms. A retrospective review comparing clinical presentations and abdominal ultrasound results with outcomes in 146 children with SCD. Ultrasound examination showed sludge or stones in 83 of 146 children (57%). This was found during a diagnostic ultrasound in 59 patients (71%) and during a screening ultrasound in 24 asymptomatic patients (29%). Fifty-four (65%) children with a positive ultrasound underwent cholecystectomy; 13 of these were initially asymptomatic patients who had subsequent development of clinical symptoms. Of the patients with cholecystectomy, 93% had histopathologic evidence of cholecystitis. Perioperative complications were rare, and there were no episodes of postoperative acute chest syndrome. Children who underwent elective surgery had an average 12-days-shorter overall hospital stay than those who underwent emergent surgery (4 vs 16 days, P &amp;amp;amp;amp;amp;amp;amp;amp;lt;.001). Elective laparoscopic cholecystectomy may be safely performed in children with SCD. Surgery should be strongly considered at the time of gallstone diagnosis before symptoms or complications develop. Histopathologic chronic cholecystitis does not correlate with clinical symptoms.

Journal of Pediatric Hematology/Oncology, 2013

A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair yo... more A formal Mentorship Program within the Children's Oncology Group (COG) was established to pair young investigators (mentees) with established COG members (mentors). Despite the American Academy of Pediatrics policy statement promoting mentorship programs, there are no publications describing and evaluating national mentorship programs in pediatric subspecialties. In this study, a series of internal program evaluations were performed using surveys of both mentors and mentees. Responses were deidentified and analyzed to determine the utility of the program by both participant satisfaction and selfreported academic productivity. Results indicated that mentees were generally satisfied with the program. Mentor-mentee pairs that met at least quarterly demonstrated greater academic productivity than pairings that met less frequently. This formal mentorship program appeared to have subjective and objective utility for the development of academic pediatric subspecialists. FIGURE 4. Relationship of the frequency of mentor-mentee interactions with reported predictors and productivity outcome measures. P-values shown are for Kruskal-Wallis analysis of the entire data set for each figure. Correlation of meeting frequency (and P-values for Spearman nonparametric correlation) with (A) the mentee's perceived degree of "fit" with their mentor (P = 0.0094), (B) the mentee's perceived match of program expectations with the mentor's (P = 0.0027), (C) the mentee's perceived match of time expectations with the mentor's (P = 0.0092), and (D) the mentee's reported productivity (P = 0.0059).