bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamics of asparaginases in antibody-negative pediatric patients with higher risk acute lymphoblastic leukemia (ALL): A report from CCG-1961
Authors: Arce F. J. , Seibel N. , Gaynon P. S. , Tiwari P. N. , Avramis I. A. , Ettinger L. J. , Sather H. N. , Franklin J. , Fu C. , Siegel S. E. , Avramis V. I. 
Published: March 2020

9027 Background: Asparaginase (ASNase) induces apoptosis in ALL lymphoblasts by depleting cells of extracellular asparagine (ASN) and possibly glutamine (GLN). On CCG-1961 [Seibel NL et al. Blood 2003; 102(11): 224a (abstract #787)], all patients (pts) received 9 doses of native E.coli-ASNase in induction (IND). Pts with rapid early response (marrow blasts < 25% on Day 7, RER) were randomized to standard intensity therapy and received native ASNase thereafter or to stronger intensity therapy and received PEG-ASNase post induction. All pts with slow early response (marrow blasts ≥ 25% on Day 7, SER) received PEG-ASNase after induction. Pts with clinical allergy to E.coli-ASNase were switched to Erwinase. Methods: Anti-ASNase Antibody (Ab) titers were assayed at the end of IND, prior to Delayed Intensification #1 and prior to starting Maintenance. Amino acid levels were measured in 430 sera from 187 patients with measurable ASNase activity. Results: Population pharmacokinetics (PK) and pharmacodynamics (PD) of the ASNase formulations demonstrated half-lives of native ASNase (6000 IU/m2): 30 hours, PEG-ASNase (2500 IU/m2): 156 hours, and Erwinase (6000 IU/m2): 18 hours. Subsequent exposures to either formulation resulted in increased activity with moderate prolongation of the elimination half-lives. One-hundred forty-two sera from 70 patients with ASNase activity between 0.03 and 1.11 IU/ml, had a mean ± SDEV ASNase activity, ASN levels, and GLN levels of 0.21 ± 0.23 IU/ml, 14.6 ± 17.7 μM, and 300.4 ± 233.8 μM, respectively; with median values of 0.11 IU/ml (range: 0.03–1.114 IU/ml), 4.7 μM (range: 0.38 - 81.34 μΜ), and 270.2 μM (range: 5.3 - 1189.1 μM), respectively. TTEST analyses linked higher ASNase activity with lower ASN levels and greater % ASN deamination. Higher ASNase activity did not assure greater GLN depletion. Conclusions: A sigmoid relationship between ASNase levels and % ASN deamination showed that activity of 0.41 ± 0.24 IU/ml (mean ± SDEV) provided 93% ± 13% ASN deamination. Therefore, >90% ASN deamination required ASNase >0.4 IU/ml. Kaplan-Meier analyses are pending. [Table: see text]
Treatment of EBV-associated T cell post-transplant lymphoproliferative disorder with CNS involvement in a pediatric solid-organ transplant patient
Authors: Harker-Murray P. D. , Dayton V. , Neglia J. , Tolar J. 
Published: March 2020

9040 Background: Post-transplant lymphoproliferative disorder (PTLD) is a known complication of immunosuppression following solid organ and stem cell transplantation. It ranges from benign lymphoid hyperplasia to fulminant systemic disease with high mortality. Most cases are B lineage and associated with Epstein-Barr virus (EBV+). T cell PTLD is rare and usually EBV negative. To date only 5 cases of EBV+ T cell PTLD have been reported in pediatric patients and none have had documented involvement of the central nervous system (CNS). Methods: We provide clinical, histologic, immunophenotypic and molecular details of a case of fulminant EBV+ T cell PTLD with CNS involvement and compare our data to the clinical presentations, biology and outcomes of the other reported cases of pediatric T cell PTLD (these include 5 EBV+ CNS− cases, 3 EBV− CNS+ cases, and 4 EBV− CNS− cases with dissemination or marrow involvement). Results: A 4.5 year old male developed EBV+ T cell PTLD with CNS involvement 3 years following a cadaveric renal transplantation. His fulminant presentation included fever, hypotension, splenomegaly, pancytopenia, coagulopathy, and bilateral pleural effusions. He had lymphocytosis in his CSF and his MRI showed brain white matter changes consistent with leukoencephalopathy. T lineage was confirmed by the presence of T cell markers CD3, 5, 7, 45 and TCRγ. The presence of EBV was demonstrated by in situ hybridization for EBER. His treatment followed the Children’s Oncology Group protocol A5971 for disseminated lymphoblastic lymphoma that employs a standard NHL/BFM-95 regimen with cyclophosphamide and anthracycline intensification during the induction and delayed intensification phases with a treatment duration of 2 years. He has received no irradiation. After 16 months, he has no measurable disease. Conclusions: EBV+ T cell PTLD is extremely rare in pediatrics and has resulted in mortality in 12 of 17 reported cases. This is the first report of EBV+ T cell PTLD with CNS involvement in a pediatric patient. Although no standardized treatment exists, the fulminant presentation, T lineage disease, and CNS involvement warranted aggressive systemic and intrathecal chemotherapy. No significant financial relationships to disclose.
Comparison of doxorubicin cardiotoxicity in pediatric patients when given with dexrazoxane versus a continuous infusion
Authors: Herzog C. E. , Huh W. , Jaffe N. , Durand J. 
Published: March 2020

9044 Background: Despite the effectiveness of doxorubicin (D) in sarcomas, its use is limited by cardiotoxicity. Both delivery by continuous infusion (CI) and use of the cardioprotectant dexrazoxane (Z) have been used to reduce cardiotoxicity. Since 1998 patients with Ewing’s sarcoma seen at MDACC have been treated with a total of 540 mg/m2 D given with Z (ZD). During this period patients with osteosarcoma have been treated with 360–540 mg/m2 D given as a 48-hour infusion (CID). Methods: To compare the cardiotoxicity of ZD versus CID, we did a retrospective review of patients seen on the pediatric service at MDACC since 1998. Patients included needed to have had 1) planned therapy of at least 360 mg/m2 D, given either as ZD or CID; 2) measurement of ejection fraction (EF) prior to any D; and 3) routine monitoring of cardiotoxicity with EF. Patients were recorded as having cardiotoxicity for any EF<50% or clinical symptoms. Groups were compared by 2-sided t-test and Fisher’s Exact test. Results: A total of 64 patients were treated with ZD or DCI, 52 of which are evaluable. Comparison of ZD to CID showed no significant difference in age or male:female ratio. Total D dose was higher in ZD. Cardiotoxicity was higher in DCI as determined by number of patients with cardiotoxicity and EF on worst Echo. Conclusions: Despite the higher total dose of D, patients treated with ZD had less cardiotoxicity. Whether this is due to giving a cardioprotectant or other factors, such as, higher degree of electrolyte abnormalities or greater degree of anemia in patients treated with CID needs to be investigated. [Table: see text] No significant financial relationships to disclose.
Outcomes of a two-drug chemotherapy regimen for retinoblastoma
Authors: Zage P. E. , Weinstein J. , Mets M. B. , Lasky J. B. , Goldman S. 
Published: March 2020

9064 Background: Retinoblastoma is the most common intraocular tumor of childhood in the U.S. and has an overall survival rate of over 90%. The optimal treatment regimen for intraocular retinoblastoma has not yet been established. Current treatment regimens for retinoblastoma involve combinations of chemotherapy with focal therapy. We report here the results of an institutional retinoblastoma treatment trial to determine the vision- and globe-salvage rates and associated toxicity of a regimen combining carboplatin and etoposide with focal therapy. Methods: 29 patients diagnosed with either bilateral retinoblastoma or unilateral retinoblastoma in infants under 12 months of age were treated prospectively with carboplatin and etoposide plus focal therapy between 1992 and 2004 at Children’s Memorial Hospital in Chicago. External beam radiation therapy (EBRT) and enucleation were utilized as needed. Results: The regression rate after 6 cycles of chemotherapy was 85.4%. 7 eyes received EBRT and 22 eyes were enucleated. The overall vision salvage rate without EBRT was 50%, with a vision salvage rate of eyes with Reese-Ellsworth (R-E) groups I-IV tumors of 82.6%. The vision salvage rate of eyes with R-E group V tumors was 20%. The vision salvage rate for eyes with Murphree groups A and B was 77.3%, but only 26.9% for groups C and D. The 10-year estimated EBRT/enucleation-free survival rate was 47%. There were no treatment related mortalities and minimal long-term side effects, with one case of secondary malignancy. Conclusions: The combination of carboplatin and etoposide with focal therapy is a well-tolerated regimen that avoids EBRT and has acceptable vision salvage rates for R-E groups I-IV and Murphree groups A and B retinoblastoma. Patients with R-E group V and Murphree groups C and D retinoblastoma do less well with chemotherapy and require more intensive or novel approaches to therapy. No significant financial relationships to disclose.
Do patients with initially resected metastatic GIST benefit from ‘adjuvant‘ imatinib (IM) treatment? Results of the prospective BFR14 French Sarcoma Group randomized phase III trial
Authors: Bui B. N. , Le Cesne A. , Ray-Coquard I. , Duffaud F. , Rios M. , Adenis A. , Bonpas E. , Perol D. , Berthaud P. , Blay J. 
Published: March 2020

9501 Background: Metastatic GIST patients (pts) without residual disease after surgical resection are considered as at very high risk of relapse (VHR) but the impact of imatinib (IM) treatment while in CR (‘adjuvant‘ IM) is still debated. Preliminary data for such patients included in the modified BFR14 (continuation vs discontinuation of IM after 3 years of treatment) are presented. Methods: Characteristics and outcome of patients with VHR at inclusion and treated with IM were analyzed. Pts initially allocated to the discontinuation of BFR14 after 1 year of IM were excluded from this analysis. Results: Out of 265 pts with advanced disease, 96 metastatic, completely resected, GIST pts (52 males and 44 females) were included in the trial with a median age of 61 years (range 28 to 87). Primary resected sites were gastric and small bowel in 40% and 42% of cases respectively. Site of dissemination in synchronously resected (R0/R1 resections) metastases was liver only (45%), peritoneum only (15%) and liver plus peritoneum (22%). The median duration of ‘adjuvant‘ IM in the whole population of 96 pts was 13 months (range 0 to 34.3). At time of analysis (december 2005), 34 pts have progressed and 13 pts died of their disease. The median PFS was 25 months (CI 95%: 20.3 ; 34.4) and the 2 year-OS was 80.7% (CI 95%: 68.6 ; 92.8). Conclusions: These results confirm the poor prognosis of VHR GIST pts and justify IM treatment of initially resected metastatic GIST like other metastatic diseases. Optimal duration of IM has to be validated in a prospective way and these pts are considered in BFR 14 trial Updated results will be presented at the meeting. This work is supported by research funding from Novartis Pharma. [Table: see text]
A SARC multicenter phase III study of gemcitabine (G) vs. gemcitabine and docetaxel (G+D) in patients (pts) with metastatic soft tissue sarcomas (STS)
Authors: Maki R. G. , Hensley M. L. , Wathen J. K. , Patel S. R. , Priebat D. A. , Okuno S. , Reinke D. , Thall P. F. , Benjamin R. S. , Baker L. H. 
Published: March 2020

9514 Background: We sought to compare the response of metastatic STS to G vs. G+D in a phase III study using a novel Bayesian adaptive randomization strategy. Methods: Entry criteria included non-GIST STS diagnosis, age > 10, measurable disease, ≤ 3 prior regimens, normal organ function, and Grade (Gr) ≤ 1 neuropathy. Pts were stratified by histology (leiomyosarcoma [LMS] vs. other), and history of prior pelvic radiation (PPR) or not, yielding 4 diagnostic subgroups. Therapy was G 1200 mg/m2 (over 120 min, d1+d8) or G 900 mg/m2 (over 90 min, d1+d8) and docetaxel (100 mg/m2 d8) q21d; all pts received (peg)-filgrastim starting d9. 25% dose reductions were employed for PPR or toxicity. The primary endpoint was tumor response (CR, PR, or 24+ weeks stable), using a double-blind Bayesian adaptive randomization procedure to incrementally assign more pts to the superior treatment arm, while accounting for possible treatment-subgroup interactions. Although this study is not based on a 1:1 randomized phase III design, enrolling ∼120 pts would show a difference between a response rate (RR) of 10% for G and 30% with G+D with a power of 0.8 and two-sided alpha of 0.05. Results: 122 pts were randomized; 119 pts had evaluable outcomes. Median number of prior regimens was 1; median number of cycles was 4 (range 1–26). 49 pts were adaptively randomized to G and 73 to G+D, indicating superiority of G+D. Of 119 evaluable pts, 27% (G) and 32% (G+D) showed response as defined. The odds of pts with LMS receiving G+D instead of G increased from 1:1 at the start of the study to ∼6:1 at its completion. RR was 10% (G) vs. 16% (G+D) (p=0.15, Fisher exact test). Consistent with the RR outcomes, progression free survival (PFS) was 6.2 m (G+D, K-M 95%CI 3.6–8.8) vs. 2.6 m (G, 95%CI 2.0–3.2). Overall survival (OS) was 18.0 m (G+D, K-M 95%CI 11.7–24.1) vs. 11.2 m (G, 95%CI 6.8–15.5). Pts receiving G+D had a higher rate of discontinuation due to toxicity than those receiving G (p<0.01, log rank). Conclusions: We observed substantial clinical activity in this pre-treated STS population. G+D yields superior PFS and OS to G, but at the price of increased toxicity. Adaptive randomization is an effective method that substantively reduces the number of pts receiving inferior therapy. [Table: see text]
The Type2 EWS-Fli1 protein causes a greater up-regulation of elements of the human stromelysin 3 promoter compared with EWS-Fli1 Type 1 and Fli1
Authors: Ubhi B. S. 
Published: March 2020

9538 Background: The role of EWS-Fli1 in the pathogenesis of Ewing’s sarcoma has been extensively investigated. This translocation is found in 85% of Ewing’s tumours. The translocation brings together two genes, EWS and Fli1. EWS is thought to have homology with RNA polymerase whilst Fli1 is a member of the ETS family of transcription factors. The EWS-Fli1 translocation was previously thought to result in an increase in Fli1 activity at target gene promoters including human stromelysin 1. Mutants of the human stromelysin promoter were therefore constructed and cloned into the pGL-3 luciferase reporter vector system and co-transfected with either EWS-Fli1 (type 1 or 2) and/or Fli1 expression vectors. We had previously detemined that EWS-Fli1 appeared to have greater activity at the 5’ end of the stromelysin promoter compared with Fli1.This system was therefore used to investigate the activity of EWS Fli1 type1, Ews-Fli1 type 2 and Fli1 on a 5’ element of the human stromelysin 1 promoter (containing the 5’ 335bp of the promoter). Methods: 1μg of the reporter vector strom-3’Δ5 (containing the 5’ 335bp of the human stromelysin 1 promoter) was co-transfected into NIH3T3 cells with 1μg of the expression vectors ES-TPF10 (EWS-Fli1 Type1),ES-RDP20 (EWS-Fli1 type 2) or Fli1-DH6 (Fli1). The cells were incubated at 37oC in 5% CO2 for 24 hours before being lysed and assayed for luciferase activity. Conclusions: Ews-Fli1 (type 1 and 2) caused a higher level of stimulation of this promoter element compared with Fli1. Interestingly, the type 2 translocation caused a significantly higher level of expression of this promoter element compared with type 1, a finding which may reflect the disease pattern observed clinically. [Table: see text] No significant financial relationships to disclose.
The contribution of epigenetic and genetic changes to predict gastrointestinal stromal tumors (GIST) behavior
Authors: Braggio E. , Guimaraes D. P. , Bacchi C. E. , Lopes L. F. , Small I. A. , Valadão M. , Portella M. J. , Romano S. , Zalcberg I. R. , Ferreira C. G. 
Published: March 2020

9542 Background: To search for markers for better prognostic evaluation in patients (pts) with GIST was our goal. Loss of E-cadherin expression and/or function by hypermethylation has been correlated with increase in the invasive potential of human tumors. Recently, loss of p16INK4a expression was considered as an independent prognostic factor in pts with GIST. Methods: We investigated the methylation (MT) status for p16Ink4a and E-cadherin by the MT -specific PCR, c-KIT mutation by SSCP-sequencing, p16INK4a and cKIT expressions and KI-67 index by IHC, in 81 pts with completely ressected GIST between Jan 1990 and April 2003. Clinical data and follow-up information were obtained from medical records.A cutoff at 20% and 5% positivity was used for p16INK4a and KI-67, respectively. Univariate analysis of disease-free survival (DFS) and overall survival (OS) were performed by Kaplan Meier method with the log-rank test. Results: Median age was 55 (9–78); Male/female 42/58%; primary tumor sites were stomach (46.9%), small bowell (37.0%), colorectal (8.6%) and peritoneal (6.2%). Median tumor size was 8cm (1.2–35.0). The median follow-up was 24 months. Pts were stratified into low- (24.7%), intermediate- (37.0%) and high- (38.3%) risk pts based on tumor size and mitotic index. There was a significant correlation between risk classification and disease free survival (DFS) (p=0.023) and overall survival (OS) (p=0.010). The p16Ink4a and E-cadherin MT were observed in 19.4% and 63.3% pts, respectively. We observed loss of p16INK4a expression in 64.9% of GISTs. Overall, 78.4% had KIT mutation in exon 11 or 9. There was non-significant correlations between epigenetic alterations, cKIT mutation, p16INK4a expression, KI-67 index and survival. By analysing the three groups separately we found a significant correlation between E-cadherin MT with DFS (p<0.047) only in the intermediate risk group. Conclusion: Our results suggest that E-cadherin MT may be a helpful prognostic factor particularly in the intermediate risk group of GISTs. In contrast with previous results from the literature p16INK4a alterations had no prognostic impact in our samples. No significant financial relationships to disclose.
Malignant hemangiopericytoma: A study of long-term outcomes
Authors: Yadav S. K. , Dwernychuk L. , Yadav A. S. , Alvi R. , Ahmad I. , Ahmed S. , Haider K. , Sami A. 
Published: March 2020

9560 Background: Malignant hemangiopericytoma (MH) is a rare disease with limited data on long term clinical outcomes. We presented a poster at ASCO 2005 annual meeting, outlining the long term follow up of 14 patients. We reviewed the data from 10 additional patients from our affiliated center and present here a combined analysis. Methods: Clinical characteristics, pathologic and treatment data of 24 patients diagnosed with MH between 1972 and 1995 was reviewed. All cases were histologically proven. Survival was determined by using Kaplan-Meier curve. Results: The median age was 52 yrs. (range 28 - 74). Male: female ratio was 1: 2.4. Patients presented with involvement of following primary sites: cranial/meningeal 8 (33.34%), extremities 4 (16.7%), uterus 3 (12.5%), metastatic 2 (8.3%), retroperitoneal 2 (8.3%), pelvis 2 (8.3%), sinonasal, middle ear and thyroid 1 each (4.2% each). 20 patients had definitive surgical resection at initial presentation. 4 patients received post operative radiation therapy (RT). No patient received adjuvant chemotherapy. 7 out of 8 patients who recurred died of disease. One patient who was alive 5 years after recurrence got stereotactic RT to localized recurrence. At disease recurrence, 2 patients received chemotherapy and RT, while 5 were treated with surgery and/or RT. 4 out of 8 patients with cranial/meningeal disease at diagnosis recurred. Two of them recurred after 6 years. Only one of the 4 recurred patients had post operative adjuvant RT. Median recurrence free survival was 5.25 years. Median survival after recurrence was 3.28 years. Fourteen year cause specific survival was 55%. Conclusions: Combined analysis of 24 patients shows that complete surgical resection is the main treatment with 55% of patients living at 14 years (median is not reached). Compared to our prior report, female preponderance was less marked. Radiation may play some part in adjuvant setting, but its role is not clearly defined. Role of systemic treatment is not clear. In our series 40% recurred after definitive treatment. Recurrences can occur several years after the initial diagnosis and definitive treatment. There is a need to develop effective adjuvant systemic treatments. No significant financial relationships to disclose.
Chemo-response biomarker discovery via expression profiling using soft-tissue sarcoma xenografts
Authors: Bruheim S. , Xi Y. , Ju J. , Fodstad O. 
Published: March 2020

9569 Background: Soft-tissue sarcoma (STS) constitute a heterogeneous group of tumours of mesenchymal origin. Whereas the mainstay of treatment has been surgery and radiation, these tumours are generally considered as quite chemoresistant. However, it is well known that subgroups of patients benefit from chemotherapy. Markers that could predict drug response would therefore be beneficial for the management of this malignancy. We have previously established panel of 17 unique human soft tissue xenografts, representing 7 different histological subgroups and assessed their responsiveness to doxorubicin, ifosfamide, etoposide, and cisplatin. We wanted to utilize these xenografts as a model system to discover for novel candidate marker genes for STS chemo-response. Methods: GE Uniset Human 20K microarrays were used to obtain gene expression profiles from the each xenografts. One-way ANOVA test with a Benjamini-Hochberg multiple test correction allowing a false discovery rate of 5% was used to identify genes with significantly differential expression. Results: Doxorubicin, ifosfamide, etoposide and cisplatin were efficient in 6/17, 10/17, 1/17 and 7/17 xenografts respectively. However, in the expression profiles obtained none of the genes showed significantly correlation with chemo-responsiveness to any of the drugs. Two of the xenografts, TAX 1 and TAX 2, both originate from a malignant fibrous histiocytoma (MFH) in the same patient, but show strikingly different sensitivity to ifosfamide (TAX1 resistant, TAX2 sensitive). When triplicate hybridizations of TAX1 and 2 were compared, 294 genes met the above criteria. In addition we identified a subset of 122 genes that were flagged absent in one of the specimens, present in the other. Among genes with an already described role in mediating drug resistance are GST-pi and glutathione peroxidase. Taken together, these results indicate that discovery of general response markers in STSs may be difficult due to the heterogeneity of the different subgroups constituting this malignancy. Conclusions: Gene expression profiling of the TAX 1 and TAX 2 xenografts revealed a number of interesting candidate marker genes for ifosfamide sensitivity of MFH. This list of genes will be further refined by validation in clinical samples. No significant financial relationships to disclose.