bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomised, placebo-controlled, trial comparing low dose versus standard dose Lenograstim (L) following myeloablative chemotherapy (HDT) and peripheral blood progenitor cell rescue (PBPCR) for lymphoma
Authors: Nolan L. , Chilton S. , Lorigan P. , Else R. , Smith P. , Sweetenham J. W. , Johnson P. W. 
Published: March 2020

7624 Background: This trial was performed to determine whether low-dose or standard dose L would influence recovery of haematopoiesis following HDT and PBPCR. Methods: 61 patients (pts) with non-Hodgkin lymphoma (40) or Hodgkin’s disease (21) undergoing HDT were randomised. Pts had normal peripheral blood counts prior to HDT (Hb ≥100g/L, total white cell count ≥ 3.0, neutrophils (N) ≥ 1.0 and platelets ≥ 50, and had a minimum 2.5 million CD34+ cells/kg PBPC previously collected following mobilisation with Cyclophosphamide 3g/m2 and G-CSF. All received HDT with BCNU 300mg/m2 d-7, Etoposide 200mg/m2 od d-5-d-2, Cytosine arabinoside 200mg/m2 bd d-5-d-2 and Melphalan 140mg/m2 d-1 before return of PBPC on D0. Pts were allocated standard dose L 263mcg daily (20 pts), low dose L 105mcg daily (21 pts) or placebo injections (20 pts). These commenced on day +5 following PBPCR and continued until N≥0.5. Pts received standard supportive care including prophylactic Fluconazole and Acyclovir, but not routine antibacterial prophylaxis, until haemopoietic recovery. Results: L at any dose resulted in a significantly shorter median time to N recovery ≥0.1 (10.0 vs 11.0 days, P=0.02) and ≥0.5 (11.0 vs 14.0 days, p=0.0003) compared to placebo. The only significant difference between standard- and low-dose L was in hospital stay (21.0 vs 22.0 days, p=0.04), however L at any dose showed a significant reduction over placebo (22.0 vs 23.0 days, p=0.01). Conclusions: Short course low dose L is as effective as standard dose in reducing neutrophil engraftment time following HDT and PBSCR. L at any dose reduces hospital stay when compared to placebo. This approach should be considered for those patients in whom growth factor support is indicated. Long-term follow-up data will be presented. [Table: see text] No significant financial relationships to disclose.
Polymorphisms in candidate genes in patients with congestive heart failure (CHF) after childhood cancer: A Report from the Childhood Cancer Survivor Study (CCSS)
Authors: Aplenc R. , Blanco J. , Leisenring W. , Davies S. , Relling M. , Robison L. , Sklar C. , Stovall M. , Bhatia S. 
Published: March 2020

9004 Background: In cancer survivors, CHF associated with the use of anthracyclines is an important clinical complication. Risk factors for anthracycline associated cardiac toxicity, including cumulative dose, gender, and age, have been described. However, these risk factors do not fully explain the observed clinical variability. Notably, the potential role of genetic risk factors has not been studied. A recent “unifying hypothesis” postulates that the early cardiac damage is mediated mostly by oxidative stress while the more chronic type of toxicity is induced by anthracycline alcohol metabolites synthesized by carbonyl reductases (CBRs). Therefore we hypothesized that genetic polymorphisms in genes encoding for enzymes involved in oxidative stress pathways, and the metabolism of anthracyclines may impact on the risk of anthracycline-related cardiotoxicity. Methods: We conducted a nested case-control study within a cohort of 5,739 patients enrolled in the CCSS. Forty-seven cases with CHF and 195 matched controls (matched for demographics, follow-up and treatment) were genotyped for 10 genetic polymorphisms in 7 genes: catalase (CAT), GSTP, GSTT, GSTM, superoxide dismutase (SOD 1), NQO1, and CBR3. Results: In the subjects who received anthracyclines, multivariable analyses of CHF risk, adjusted for gender, smoking history, recurrence, and family history of heart disease, showed the GSTP +313A>G polymorphism was a significant risk factor, HR = 5.0, p = 0.01 for the A/G genotype vs. A/A; HR = 3.3, p = 0.19 for the G/G genotype vs. A/A. In addition, a suggested association between CBR3 V244M polymorphism and the risk of CHF after treatment with anthracyclines, HR=10.2, p=0.06 for G/G vs. A/A; HR = 4.0, p=0.18 for G/A vs. A/A was seen in an identical multivariable analysis. Conclusions: These data suggest that specific polymorphic genetic variants on a panel of candidate genes relevant to the anthracycline pharmacodynamics may modify the risk of CHF in childhood cancer survivors. Future studies to further refine the role of these novel genetic risk factors affecting a large population are warranted. No significant financial relationships to disclose.
Gender affects survival from medulloblastoma only as a function of age: A SEER registry study
Authors: Curran E. K. , Le G. M. , Propp J. M. , Cobb K. L. , Fisher P. G. 
Published: March 2020

9005 Background: Males have a higher incidence of medulloblastoma (MB) than females, but studies examining whether gender affects survival are conflicting and limited. We aimed to determine the effect of gender on outcome in MB, via rigorous analysis of a large data set, comprised solely of MB patients. Methods: 1,226 subjects–763 males and 463 females–were identified from 1973 to 2002, using the Surveillance Epidemiology End Results (SEER-9) registry. MB was strictly defined, using histology and site codes, to exclude non-cerebellar embryonal tumors (primitive neuro-ectodermal tumors [PNETs]). Kaplan-Meier analysis and logrank tests were performed using SPSS 12.0. Because children <3 years (yr) of age are known to have worse survival, patients were stratified by age <3 yr at diagnosis (95 male, 82 female) and ≥3 yr (668 male, 381 female). Results: There was no significant difference in overall survival between males and females (logrank p= 0.22; median survival: males 90 months [mo], females 152 mo). Among subjects ≥3 yr, females had significantly greater survival than males (logrank p=.02; median survival: males 93 mo, females 211 mo). In children <3 yr, there was a trend toward worse survival in females (median survival: males 27 mo, females 13 mo), although this was not significant (logrank p=0.24). Females <3 yr comprised a significantly greater proportion of patients with medulloblastoma, compared to individuals ≥3 yr (chi-squared test p=.01). Conclusions: Females with MB have a survival advantage only in subjects ≥3 yr. In children <3 yr, females no longer possess this survival advantage and possibly have a worse outcome. The effect of gender on survival and incidence in MB warrants additional biologic investigation, and may differ in very young children with MB. No significant financial relationships to disclose.
Temozolomide phase II study in children with relapsing refractory high-risk neuroblastoma
Authors: Rubie H. , Chishlom J. , Defachelles A. , Morland B. , Munzer C. , Valteau Couanet D. , Hargrave D. , Bergeron C. , Coze C. , Djafari L. , Vassal G. 
Published: March 2020

9012 Background: To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population. Methods: A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m2 on 5 consecutive days and repeated every 28 days) was undertaken in children with a refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Evidence of activity was defined by radiologic or MIBG scan evidence of sustained reduction in lesion size or activity whenever it occurs. Methodology included a two-step study using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if 2 to 4 responses had been observed in the first cohort. All data were centrally reviewed by a panel. Results: Among 34 registered patients over a 14 month period in 14 centres, twenty five are finally evaluable and received 94 cycles of chemotherapy. Disease status was metastatic NB (n=23) either refractory (n=9) or in relapse (n=14). Grade ¾ thrombocytopenia was the most frequent toxic event (16% of the cycles). Myelosuppression resulted in significant treatment delays and dose reductions (24% and 21% of cycles respectively). Out of 25 patients, response (CR, VGPR or PR) was observed in 5 (RR=20 ± 8%) with a median duration of 6 months. Furthermore a mixed response or an objective effect was observed in respectively 2 and 3 additional patients. Conclusions: Temozolomide is effective in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug No significant financial relationships to disclose.
Phase I study of concurrent motexafin gadolinium (MGd) with radiation therapy for children with newly diagnosed brain stem gliomas (BSG): A Children’s Oncology Group study
Authors: Bradley K. , Mehta M. , Adamson P. , Ames M. , Jakacki R. , Vezina G. , Ingle A. , Ivy P. , Blaney S. , Pollack I. 
Published: March 2020

9014 Background: MGd, a radiosensitizer that selectively accumulates in tumors, generates reactive oxygen species intracellularly. In preclinical experiments, MGd enhances RT-induced apoptosis. Methods: A multi-institutional Phase I dose escalation and pharmacokinetic (PK) study was performed in children with newly diagnosed BSG to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of MGd administered i.v. 2 to 5 hours prior to involved field radiotherapy (RT) (1.8 Gy/day, total 54 Gy). Cohort 1 received MGd, 1.7 mg/kg/dose M-F × 3 wks and cohort 2 received the same dose M, W and F × 6 wks. The 6 subsequent cohorts of 3 to 6 pts received MGd M-F × 6 weeks at doses of 1.9, 3.4, 4.4, 5.5, 7.1 and 9.2 mg/kg/dose. Serum for PK analysis, and MRI scans (MGd is detectable by MR), were obtained for analysis of drug accumulation and responses. Results: 44 pts (42 fully evaluable for toxicity) with a median age of 6 years (range 2–20) were enrolled. At the 9.2 mg/kg/dose, 2/2 pts experienced DLT. During subsequent expansion of the 7.1 and 5.5 mg/kg/dose cohorts, DLTs, including transaminitis, hypertension and urticaria, were observed in 2/5 and 2/6 pts. At the MTD of 4.4 mg/kg/dose, 1/6 pts had reversible grade 3 serum transaminase elevations. PK analysis showed biphasic elimination with a terminal t 1/2 of 6.4 h. At the MTD, serum MGd concentrations were >250 ng/ml for 24 h. Serum clearance and steady-state volume of distribution were 0.0243 L/h/kg and 0.162 L/kg. MRI for intra-tumoral MGd distribution is ongoing. One patient had a CR and 4 had a PR. The estimated median survival is 10.3 months (95% confidence interval: 8.1 months-11.5 months). Conclusions: The recommended phase II dose of MGd for children with BSG is 4.4 mg/kg/d administered M-F × 6 weeks with involved field RT. A COG phase II trial is planned. [Table: see text]
A phase I study of bortezomib (PS-341) in pediatric patients with relapsed or refractory leukemia: A Children’s Oncology Group study
Authors: Horton T. M. , Thompson P. A. , Bomgaars L. R. , Adamson P. C. , Krailo M. , Ingle A. , Blaney S. M. 
Published: March 2020

9021 Background: Bortezomib is a 26S proteasome inhibitor that is effective as a single agent for the treatment of multiple myeloma in adults. Bortezomib at a dose of 1.2 mg/m2 is well tolerated as a single agent in pediatric patients with solid tumors. This phase 1 study examined the tolerability and efficacy of bortezomib in pediatric patients with relapsed/refractory leukemia. Methods: Cohorts of 3–6 patients received bortezomib administered twice weekly (days 1, 4, 8 and 11) for two weeks every 21 days. Pharmacokinetics and NF-κB activation status were examined in peripheral blood mononuclear cells (PBMC) at 6, 12, and 24 hours following the first dose of bortezomib, and from bone marrow leukemic cells before treatment and on days 8 and 18 of the first treatment cycle. Results: Twelve patients (4 female, 8 male) (ALL=9, AML=3), median age 11y (range 1–18y), were enrolled at the 1.3 mg/m2 (6 enrolled, 3 evaluable) or 1.7 mg/m2 (6 enrolled, 2 evaluable) dose levels. Patients not fully evaluable for toxicity experienced disease progression prior to completing the first 21-day cycle of therapy. Two DLTs occurred at the 1.7 mg/m2 dose level. One patient had altered mental status and the other patient had febrile neutropenia associated with Grade 3 hypotension, Grade 4 renal insufficiency and hypoxia, followed by death on day 9 of cycle 1. No CRs or PRs were observed in the 10 patients evaluable for response. One patient had SD for 2 cycles. PK analysis (n= 5) revealed a Cl of 0.62 L/min/m2, Vd of 13 L/m2, and a terminal T1/2 of 12.6 h. NF-κB activation was inhibited in the leukemic blasts of 2 patients examined to date. Conclusions: Bortezomib was tolerated at 1.3 mg/m2 in children with relapsed/refractory leukemia. Although bortezomib appeared to inhibit NF-κB activation, it was ineffective as a single agent for pediatric leukemia treatment. No significant financial relationships to disclose.
Increase of creatine kinase value (CK) correlates with muscoloskeletal complaints (MSC) in GIST patients during imatinib therapy
Authors: Allione P. , Grignani G. , Aliberti S. , Rota Scalabrini D. , Carnevale Schianca F. , Capaldi A. , Vormola R. , Caravelli D. , Galla A. , Aglietta M. 
Published: March 2020

9509 Background: MSC-pain, muscle cramps, myalgias, arthralgias-are commonly associated with imatinib therapy, affecting 25% to 50% of patients. The cause is still unknown. MSC is usually mild to moderate and manageable without reduction of imatinib dose. Calcium and magnesium supplements have occasionally provided some relief. It is rather difficult to quantify MSC and patients who deserve interruption or analgesia on the base of symptoms alone. Since CK values are commonly elevated during imatinib therapy, we evaluate CK as a surrogate marker of MSC. Methods: Since 2002, 40 patients (pts) affected by advanced GIST were treated with imatinib 400 mg/day until progressive disease when dosage would be increased to 800 mg/day. Toxicity (CTC 2.0) and blood chemical values were prospectively collected on a monthly basis. Results: G1–2 MSC was observed in 22 pts (55%). We had to stop therapy in one patient only for one week because of uncontrolled MSC. CK was abnormal in 23 pts (57%). 13 pts (32%) had CK values up to twice upper normal value (UNV); 8 pts (20%) above thrice the UNV and 2 pts (5%) above 5 times the UNV. Among 10 pts having MSC G2, seven had CK above thrice UNV. The 2 pts experiencing MSC G3 had also CK above 5 times UNV. Conclusions: CK increase reflects MSC in a great majority of the patients who experienced this rather common imatinib side effect. To consider CK into standard clinical chemistry work up of patients on imatinib allows clinicians to add an objective measure of MSC. No significant financial relationships to disclose.
A SARC phase II multicenter trial of imatinib mesylate (IM) in patients with aggressive fibromatosis
Authors: Chugh R. , Maki R. G. , Thomas D. G. , Reinke D. , Wathen J. K. , Patel S. , Priebat D. A. , Meyers P. A. , Benjamin R. S. , Baker L. H. 
Published: March 2020

9515 Background: Aggressive fibromatosis (desmoid tumors, AF) are uncommon, locally aggressive, connective tissue neoplasms. Existing literature on systemic treatment of AF is sparse and consists mostly of case reports and small case-series. Based on previous observation of regression of AF treated with IM and tumoral expression of IM targets, SARC (Sarcoma Alliance for Research through Collaboration) included the treatment of AF onto a multi-institution phase II trial of IM in sarcoma. Here we report early clinical and laboratory results of the AF group. Methods: Eligible patients had histologically proven AF, unresectable or difficult to resect without considerable functional impairment. Patients were treated with IM 300 mg po BID (BSA≥1.5m2). The primary endpoint was complete (CR) or partial response(PR) at two months or stable disease (SD) or better at four months. Tumor DNA was extracted from available formalin fixed paraffin embedded tissue specimens and analyzed via allelic PCR and genomic DNA sequence analysis for specific point mutations in PDGFRα exons 12/14/18, PDGFRβ exons 12/18, KIT exons 9/11/13/17, and bRAF. Results: 51 patients were enrolled from 10/02 to 12/05 at 5 institutions, with 45 patients currently evaluable. The median age is 37 (range 14–67), and median number of prior therapies is 1 (range 0–3). 36 patients (80%) reached the primary endpoint of CR/PR at 2 months or SD or better at 4 months. The median time to treatment failure is 6.8 months (95% C.I. 5.8–17.1). Thus far, the maximum change in the largest dimension of the tumor ranged from a 21% increase to a 45% decrease. In 22 available tumor specimens, deletions within PDGFRαE12 and E18 were noted in 1 and 3 patients, respectively, while a wildtype genotype was found in other regions. Conclusions: IM has activity in AF, the mechanism of which remains unclear. While this is the largest reported phase II trial of AF, further improvement in evaluating clinical efficacy in this disease is clearly necessary. We plan an analysis of the maximum change in largest tumor dimension for each patient, which will be particularly beneficial in AF as responses often occur late. We have not as yet identified a laboratory predictor of clinical benefit. Further investigation of other potential targets in fresh tissue is warranted. [Table: see text]
Long-term follow-up of a phase II randomized trial in advanced gastrointestinal stromal tumor (GIST) patients (pts) treated with imatinib mesylate
Authors: Blanke C. D. , Demetri G. D. , Von Mehren M. , Heinrich M. C. , Eisenberg B. L. , Fletcher J. , Corless C. L. , Wehrle E. , Sandau K. B. , Joensuu H. 
Published: March 2020

9528 Background: Imatinib achieves tumor control in most pts with advanced GIST, but the durability of remissions has not been well described. We now present an updated long-term analysis of a randomized phase II trial first presented in 2001, with a median follow-up of 52 months. Methods: 147 pts with unresectable or metastatic malignant GIST were randomized to treatment with daily dosing of imatinib, 400 or 600 mg po. Results: Two pts (1%) achieved a complete response, 98 (67%) achieved a partial response (PR), and 23 (16%) exhibited stable disease (SD) as their best response. Median time-to-response was 13 weeks (95% CI; 12–23 weeks), but one quarter of pts responded after 23 weeks. No significant response differences were seen between the two dose levels tested. The median duration of response was 27 months, and median overall survival was 58 months. Pts with SD or PR had similar 4-year survival rates (64% versus 62%). KIT and/or PDGFRA mutational analyses were obtained in 87% of patients, and the mutational status was highly significant in predicting outcome. GISTs harboring KIT mutations in exon 11, exon 9, and with no detectable mutations in KIT or PDGFRA demonstrated PR rates of 87%, 48%, and 0%, respectively. The median survival for pts with exon 11 KIT mutations has not yet been reached, and it was 45 months for those with exon 9 mutations. Conclusions: While late progression can be seen in GIST pts treated with imatinib, the majority of pts derive benefit. Survival in those achieving SD parallels those with PRs. Late responses are often seen in pts with initial SD, and responses in general are of lasting duration. In particular, pts with KIT mutations in exon 11 (the most common exon affected) have very high response rates and favorable long term survival. [Table: see text]
Six drugs induction chemotherapy for patients with localised Ewing sarcoma (ES): A pilot study
Authors: Palmerini E. , Bertoni F. , Mercuri M. , Barbieri E. , Longhi A. , Picci P. , Bacci G. , Ferrari S. 
Published: March 2020

9537 Background: Vincristine (V), doxorubicin (A), cyclophosphamide (C), ifosfamide (I), actinomycin-D (Ac) and etoposide (E) are the standard drugs active against ES. Feasibility and efficacy of a six drugs induction treatment were investigated in a monoinstitutional study. Methods: Between March 1998 and May 1999, nonmetastatic ES aged ≤ 50 years were enrolled. Induction treatment: VAC (V 2 mg, A 80 mg/m2, C 1200 mg/m2, weeks 0 and 6), IVAc (I 9 g/m2, V 2 mg, Ac 2 mg, week 3), IE (I 9 g/m2, E 450 mg/m2, week 9). Local treatment, surgery whenever possible, was planned on week 12. Maintenance treatment: alternating courses of VAC-IVAc-IE (three times). In surgically treated patients, chemoinduced necrosis was evaluated and graded: grade III (complete necrosis), II (persistence of microfoci of viable tumor cells) and I (persistence of macrofoci of tumor cells). Results: 34 patients were enrolled; median age was 19 years (6–50); 22 were males and 12 females. Site: extremity 22 (65%), axial location 12 (35%). Despite a large use of G-CSF (94% of cycles), grade IV leukopenia was common (60% of cycles). Nevertheless, febrile neutropenia was observed in only 10.6% of cycles. Grade IV thrombocytopenia occurred in 12.5% of cycles. Platelet and red blood cell transfusions were required in 4% and 11% of cycles, respectively. No toxic deaths were recorded. Local treatment: surgery in 24 patients (70%), followed by post operative radiation (RT) in 6 of them; RT in 10 patients (30%). Chemoinduced necrosis was grade III in 29% of patients, grade II in 34% and grade I in 37%. With a median follow-up of 80 months (1–69) 5 years overall survival (OS) was 62%. 5 years Event free survival (EFS) was 56%. 5 years EFS according to site was: extremity 68%, axial location 33% (p < 0.02); according to local treatment was: surgery 61% (with RT 67%), RT 30% (p = 0.027); according to chemoinduced necrosis: grade III 86%, II 50%, I 55% (p = 0.26). Conclusions: The treatment is feasible. Surgery was possible in 70% of patients with a high cure rate for patients with a grade III chemoinduced necrosis. No significant financial relationships to disclose.
Regression of chemotherapy-refractory metastatic tumor from CD117-negative prostate sarcoma with imatinib mesylate plus thalidomide
Authors: Kok V. C. , Yeh K. , Chang W. 
Published: March 2020

9557 Background: Chemoresistant relapsing prostate sarcoma has no standard treatment and the prognosis is extremely poor. Imatinib mesylate may target on tyrosine kinases of platelet-derived growth factor receptor (PDGFR) which has been shown to be important in tumor growth of certain types of soft tissue sarcoma. Thalidomide, itself a potent immunomodulatory agent has exhibited clinical activity in several malignant neoplasms which have been linked to abnormal angiogenesis and tumor vasculature. Case Report: A 38-year-old man who underwent radical cystoprostatectomy in June 2004 for a stage III high-grade soft tissue sarcoma of spindle and round cell type of prostate staged pT2b(8cm) pN0(0/26) M0, received adjuvant radiotherapy up to 6,660 cGy/37Fx postoperatively. Immunohistochemistry study showed vimentin+, CD34+, CD117−, desmin+, SMActind- and S-100−. Distant relapse in lungs was noted in April 2005. Shortly later massive pleural effusion developed. Three cycles of salvage chemotherapy with MAID were given. Tumor assessment disclosed Progressive Disease status and metastatic tumors were chemoresistant. Imatinib mesylate 400 mg once a day plus thalidomide with increment dose to 200 mg/day was chosen as biologic treatment for his devastating condition after an informed consent was obtained. PDGFR immunohistochemistry staining of the paraffin block and gene sequencing are planned. Results: Marked tumor regression reaching very good partial remission and resolution of pleural effusion without recurrence. Dramatic improvement in terms of performance status and cancer-associated symptoms are obvious. Except for skin changes and mild periorbital edema from imatinib, no other significant adverse reactions were noted. Postulated mechanism of action may suggest PDGFR tyrosine kinase inhibition as well as antiangiogenesis. Conclusions: We documented a case of undifferentiated sarcoma of prostate with pulmonary metastases which were refractory to MAID chemotherapy but subsequently regressed on a combination of double biologic agents, imatinib mesylate plus thalidomide. No significant financial relationships to disclose.