bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of ALK activation in the development and maintenance of the neoplastic phenotype in neuroblastoma
Authors: Regairaz M. , Munier F. , Sartelet H. , Marty V. , Castaing M. , Michiels S. , Fabre M. , Roesel J. , Vassal G. 
Published: August 2020

10008 Background: Activating mutations of the Anaplastic Lymphoma Kinase (ALK) receptor could be responsible for most familial neuroblastoma cases and for up to 15% of somatic cases. The objective of the present study was to further investigate the role of ALK activation in neuroblastoma. Methods: Tissue microarrays were constructed containing 101 primary tumors and 56 paired normal tissues. Sections were immunostained with anti-ALK or anti-P-ALK antibodies, and with antibodies directed against the ALK ligands: PTN (Pleiotrophin) or MDK (Midkine). The Wilcoxon signed rank test was applied for comparison of paired data. Associations with prognostic factors were analyzed using t-tests. Effects of the ALK inhibitor TAE684 (Novartis) on cell proliferation and signaling was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts. Results: ALK was expressed in about 100% of tumors and normal tissues, while phospho-ALK was detected in 5% of normal tissues and 50% of tumors. Sequencing of the kinase domain of ALK showed that its phosphorylation was largely independent of mutations and we found that MDK and PTN ligands were expressed in 66% and 50% of tumors, respectively. Interestingly, ALK, P-ALK, and MDK were expressed at higher levels in tumors as compared with paired normal tissues (p < 0.0001), while PTN showed an inverse tendency, being more expressed in normal tissues (p = 0.07). In tumors, P-ALK was associated with good-prognosis factors, including favorable stages (p = 0.01), absence of MYCN amplification (p = 0.05) and a younger age at diagnosis (p = 0.03). Inhibition of cell proliferation by TAE684 was detectible in all neuroblastoma cell lines, regardless of ALK status. However, TAE684 failed to demonstrate antitumor activity in advanced stage neuroblastoma xenografts expressing either a wild-type or a mutated ALK. Interestingly, ALK pathway activation (P-STAT3, P-AKT) was weak or barely detectible in these xenografts. Conclusions: ALK activation occurs during neuroblastoma oncogenesis, along with a concomitant switch between the expressions of PTN and MDK. However, ALK may not be a relevant therapeutic target since in vivo inhibition showed no antitumor activity. [Table: see text]
Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial
Authors: Widemann B. C. , Fox E. , Adamson P. C. , Baruchel S. , Kim A. , Ingle A. M. , Bender J. Glade , Stempak D. , Balis F. M. , Blaney S. M. 
Published: August 2020

10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m2/dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m2) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m2, and the dose was re-escalated to 150 mg/m2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m2. At 200 mg/m2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC0–24h was similar at 150 mg/m2 (28±24 μg · h/mL, n = 9) and 200 mg/m2 (28±17 μg · h/mL, n = 4). Tmax was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m2, similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.
Elevated expression of VEGFR-2 and VEGFA in desmoplastic small round cell tumor (DSRCT) and activity of bevacizumab and irinotecan in a xenograft model of DSRCT
Authors: Magnan H. D. , Chou T. , LaQuaglia M. P. , Gerald W. , Ladanyi M. , Merchant M. S. 
Published: August 2020

10016 Background: Desmoplastic small round cell tumor (DSRCT) is an aggressive tumor with poor response to multimodality therapies. Given the vascular nature of many DSRCT, we sought to determine if VEGF targeting could be effective in a preclinical model of DSRCT. Methods: RNA was extracted from frozen tumor samples (DSRCT, alveolar soft part sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, and Ewing sarcoma) and a human DSRCT cell line, JN-DSRCT. Microarray profiling utilized Affymetrix U133A/B or Affymetrix U133 Plus 2.0 chips. DSRCT xenografts were established by intramuscular injection of 20 million JN-DSRCT cells into the lower extremity of SCID/bg mice. A primary tumor developed within 8 - 12 weeks with concomitant development of abdominal metastases. Mice were treated during primary tumor growth with bevacizumab (5ug/kg IP weekly), irinotecan (2.5mg/kg IP ×10 days q3 weeks), or a combination of both. Results: Microarray data demonstrated an average of 4.5 times higher RNA expression of VEGFR-2 (KDR) in DSRCT tumor samples as compared to the other translocation-associated sarcomas (p = 3.6 E-12). VEGFR-2 was highly expressed in the JN-DSRCT line as compared to other sarcoma lines. VEGFA was also highly overexpressed in the DSRCT line and tumor samples when compared to the other translocation-associated sarcomas (2.5 times, p = 1.1E-10). Xenografts treated with bevacizumab had slowed growth over 100 days compared to control groups (volume of 0.52 mm3 vs 1.52, p = 0.002). Marked long term regressions were evident following treatment with the combination of irinotecan plus bevacizumab compared with irinotecan alone (0.12mm3 vs 0.44 at 100 days, p < 0.0001). Conclusions: VEGFR-2 and VEGFA are overexpressed in DSRCT. DSRCT xenografts were highly responsive to bevacizumab or bevacizumab plus irinotecan. Taken together, the expression data and the sustained response of DSRCT xenografts to bevacizumab suggest that VEGF-dependent angiogenesis is important for DSRCT tumor biology and represents an attractive target for therapy. These studies suggest that irinotecan and bevacizumab should be considered for inclusion in clinical trials for the treatment of DSRCT. No significant financial relationships to disclose.
Are all stage III Wilms tumors the same? Data from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)
Authors: Spreafico F. , Piva L. , D'Angelo P. , Terenziani M. , Collini P. , Gandola L. , Bianchi M. , Tamburini A. , Provenzi M. , Fossati Bellani F. 
Published: August 2020

10030 Background: Criteria to classifying Wilms tumor (WT) as stage III are much heterogeneous, including factors referring both to tumor biology and surgical skills. Methods: We analyzed survival results in patients aged less than 18 years with stage III WT enrolled in the AIEOP CNR92 and TW2003 clinical trials (10/1991–10/2008). Main therapy differences across the trials were the timing of abdominal radiotherapy (RT) (anticipated to 2nd week from nephrectomy) and doxorubicin cumulative dose reduction from 360 mg/m2 to 240 in TW2003. Results: Of 553 in-study patients, 106 (19%) were classified as stage III according to NWTS4 criteria (59 patients in CNR92, 47 in TW2003; median age 49 months). Reasons for stage III as follows: lymph nodes (LN) 40 cases (alone 28 cases, combined with other factors 12); cava vein tumor thrombus 7, peritoneum involvement 8, post-operative gross or microscopic tumor remains 24, pre-operative rupture 9, surgical rupture 17. For 29 patients (27%) information on regional LN were missing. 36 patients received primary 4-week vincristine/dactinomycin regimen, while the others had up-front nephrectomy. Adjuvant therapy consisted of 8-months vincristine/dactinomycin/doxorubicin + flank 1440 cGy RT (whole abdominal 15 Gy in case of diffuse peritoneal contamination). 7 patients had intensified chemotherapy/RT for diffuse anaplasia. Interval between nephrectomy and RT was 75 days in CNR92 (median) and 33 in TW2003. Overall 16 tumor failure occurred (2 in anaplastic tumors): abdominal relapse 8 (combined to other extra-abdominal site 3), lung 5, tumor progression 2, metacronous tumor 1. After median follow-up of 49 months 5-year RFS and OS were 83% ±4 and 90% ±3 for the whole cohort of children, respectively. Noteworthy the doxorubicin dose reduction in TW2003 did not jeopardize survival (82% 4-year RFS for CNR92, 84% TW2003). Overall, RFS was 75% ±7 in patients with at least LN involvement compared to 89% ±4 in patients classified as stage III for the remaining criteria, including those without LN sampling (Logrank p.09). Conclusions: The sensible doxorubicin dose reduction did not jeopardize survival. 1440 cGy flank RT warranted satisfactory local tumor control. The worse outcome reported in LN-positive patients deserves further attention. No significant financial relationships to disclose.
Differences in length of stay among hospitalized children with acute lymphoblastic leukemia
Authors: Tai E. , Richardson L. , Townsend J. , Steele B. 
Published: August 2020

10044 Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy among children in the United States. While age, race, and clinical complications have been associated with longer length of stay (LOS) among children with cancer, it is unknown what factors are related to LOS among children with ALL. We examined differences in LOS among hospitalized children with ALL. Methods: We used 2000, 2003, and 2006 data from the Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database (KID) which contains pediatric discharges from community, non-rehabilitation hospitals. We used negative binomial regression to determine factors related to LOS. Results: We found the following factors related to greater LOS among hospitalized children with ALL: Non-Hispanic blacks vs. non-Hispanic whites (Rate Ratio (RR) = 1.06, CI:1.03–1.10), Hispanics vs. non-Hispanic whites (RR = 1.07, CI:1.04–1.10), age < 1 year vs. age 1–5 years (RR = 1.93, CI:1.83–2.04), female vs. male (RR = 1.05, CI:1.03–1.07), lowest quartile of household income in patient's zip code vs. highest quartile (RR = 1.09, CI:1.06–1.12), Medicaid vs. private insurance (RR = 1.11, CI:1.09–1.14), children's hospital vs. non-children's (RR = 1.11, CI:1.08–1.14), Western region of United States vs. Northeast region (RR = 1.14, CI:1.11–1.17), emergency room admission vs. routine admission (RR = 1.23, CI:1.20–1.26), blood transfusion (RR = 1.64, CI:1.61–1.67), bone marrow transplant (RR = 7.64, CI:7.11–8.20), and neutropenia (RR = 1.22, CI:1.19–1.24). Conclusions: Race/ethnicity, age, sex, household income, insurance status, admission source, hospital type and region, transfusion, bone marrow transplant, and neutropenia were significantly associated with longer LOS. These factors may help identify children with ALL at risk for complications. Prophylactic treatment for clinical complications may reduce LOS. No significant financial relationships to disclose.
Result of adolescent acute lymphoblastic leukemia protocol (MCP 841) from a developing country
Authors: Mukhopadhyay A. , Gupta P. , Mukhopadhyay S. , Dey S. , Basak J. , Pandey R. 
Published: August 2020

10046 Background: Acute Lymphatic Leukemia is a curable disease in the range of 80 - 90% in developed countries by aggressive protocol like BFM, St. Judes’ but result is much less in adolescence age group (60–70%). In developing countries like ours, patients can't tolerate that aggressive protocol because of socio-economic and nutritional factors. The less aggressive protocol like MCP841 is suitable in developing countries like ours. The aim of our study was to see outcome of adolescent ALL patient with protocol MCP 841 and tolerability of the protocol in Indian-Asian population. Methods: We treated 75 children with age range 13 - 18 years (median age of 15 yrs) with MCP 841 Protocol at Netaji Subhash Chandra Bose Cancer Research Institute, Kolkata, India, a tertiary cancer center from Eastern India during the period of April 1999 to Dec 2007. There was female preponderance in the study. Fever 48 (64.0%), lymphadenopathy 35 (46.7%), and haepatosplenomegaly 28 (37.3%) were the major clinical presentation. Eight (10.7%) patients were present with hyper leukocytosis. T-ALL phenotype was the largest group though the incidence of the C-ALL was quite high 23 (30.7%). Results: Remission induction was seen in 65 (86.7%) of the patients. In a follow-up period of 24 - 88 months (with an average of 54 months) the disease-free survival ( DFS) was 42 (56%) patients with an overall survival of 46 (61.34%) patients. The isolated bone marrow relapse was seen in majority of the cases 28 (37.34%) and the major relapse was in maintenance and first 6 months of completion of therapy. The major cause of morbidity was infection 53 (70.7%) followed metabolic complications 16 (21.34%), pancreatitis 3 (4.0%), hemorrhage 10 (13.3%), neurologic 2 (2.7%), and hepatitis 1 (1.3%). The major cause of the mortality was infection 18% (24.0% patients) followed progressive disease 9 (12.0%) and hemorrhage 2 (2.7%). As compared to our all pediatric ALL group the outcome is much less and complications are much more. Conclusions: The data of acute lymphatic leukemia in adolescent is not satisfactory as compared to other pediatric patients. They also tolerate chemotheraphy badly. Therefore there is need for modified protocol for this age group. No significant financial relationships to disclose.
Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral center in India
Authors: Ghadyalpatil N. , Banawali S. , Kurkure P. , Arora B. , Bansal S. , Amare P. , Choughule A. , Soy L. , Singh R. 
Published: August 2020

10047 Background: Chronic myeloid leukemia (CML) is a rare disease in children and there is limited data of safety and efficacy of imatinib mesylate (IM) in this age group. Methods: We analyzed the outcomes of 48 consecutive children (September 1998 to December 2008) in chronic phase (CP) or accelerated phase (AP) CML not eligible for Allo-SCT and were treated with IM [Glivec (Novartis), through patient assistance programme GIPAP or Veenat (NATCO), generic brand for GIPAP ineligible patients] within 12 months of diagnosis. The dose of IM was 260 mg/m2(maximum 400 mg) per day. Results: The median age at the time of diagnosis was 12 years (range 3–18 years). Of 48 patients, (34 males and 14 females) 46 were in CP and 2 in AP. Forty-three patients (89.5 %) achieved complete cytogenetic response (CCR) at median time of 10 months (range 3–31 months). Five patients (10 %) had hematological response but did not have CCR, of which 2 progressed to AP and 1 had hematological relapse. One patient had secondary IM resistance and had progressive disease even on dose escalation. Two patients in AP at diagnosis achieved CCR at 5 and 7 months and continue to be in CCR. Thirty-one out of 35 patients on Glivec and 12 out of 13 patients on Veenat achieved CCR. At a median follow up 29 months, the event free survival and overall survival was 74.1% and 100 % respectively. IM was well tolerated with grade III and IV neutropenia and thrombocytopenia seen in 2 and 7 patients respectively. Significant non hematological toxicities were uncommon except for hypopigmentation which was seen in more than half the cohort. Conclusions: Results from this largest single center study indicate that outcome of children with CML receiving IM is similar to adults. This data will be especially useful for financially challenged patients in developing countries where Allo-SCT is still not an affordable option while generic brand of IM seems to be feasible alternative. No significant financial relationships to disclose.
RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC)
Authors: Robert N. J. , Dieras V. , Glaspy J. , Brufsky A. , Bondarenko I. , Lipatov O. , Perez E. , Yardley D. , Zhou X. , Phan S. 
Published: August 2020

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]
The economic implications of rasburicase treatment in pediatric tumor lysis syndrome patients
Authors: O'Day K. , Eaddy M. , Seal B. , Tangirala K. M. 
Published: August 2020

10050 Background: Rasburicase is a recombinant urate-oxidase enzyme used to reduce high levels of plasma uric acid (UA) resulting from tumor lysis syndrome (TLS) in pediatric patients. Rasburicase reduces UA levels within 4 hours of administration, minimizing risk of serious complications from TLS. Although the efficacy of rasburicase has been demonstrated in clinical trials, there are few studies that have evaluated the economic implications of using rasburicase rather than allopurinol, the current standard of care. Methods: Pediatric patients administered rasburicase or allopurinol within 2 days of hospital admission were eligible for study inclusion. Patients were excluded if they were ≥ 18 years of age or received hemodialysis on admission. Patients receiving allopurinol or combination therapy were then propensity score matched to rasburicase patients based on gender, race, hospital type, provider type, payer type, admission source, use of electrolyte modification therapy, critical care admission, and comorbid diagnoses. Differences in healthcare costs, length of stay, and duration of subsequent critical care were assessed using gamma distributed generalized linear models with a log link function. Results: There were 63 allopurinol and 63 rasburicase patients matched in the analysis. The mean age of the sample was 7.4 years, with 27% being female. There were no statistical differences in matched covariates across the cohorts. Rasburicase patients incurred an average of $30,470 per hospitalization compared to $35,165 for allopurinol patients (p = 0.427). Mean length of stay was not statistically different across the cohorts, averaging 14 days. Duration of critical care was significantly lower for rasburicase (1.4 days) when compared to allopurinol (2.5 days, p = 0.0001). Conclusions: Treatment with rasburicase is associated with similar costs and a lower duration of critical care when compared to allopurinol therapy. [Table: see text]
Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC)
Authors: Conlin A. K. , Hudis C. A. , Bach A. , Moynahan M. , Lake D. , Forero-Torres A. , Wright G. , Hackney M. , Clawson A. , Seidman A. D. 
Published: August 2020

1006 Background: Nanoparticle albumin-bound paclitaxel (nab-P) 260 mg/m2 is superior to paclitaxel 175 mg/m2 (P) every 3 weeks (Gradishar et al., J Clin Oncol. 2005). Weekly uninterrupted P is more effective than q3wk P in MBC (Seidman et al., J Clin Oncol. 2008). Bevacizumab (bev) nearly doubles response rate and time to progression (TTP) when added to P as 1st line therapy for MBC (Miller et al., N Engl J Med. 2007). Methods: This open-label, phase II study randomized patients (pts) to nab-P at 260 mg/m2 q3wk (arm A) versus 260 mg/m2 q2wk with filgrastim (arm B) versus 130 mg/m2 weekly uninterrupted, all with bev (15 mg/kg q3wk arm A, 10 mg/kg q2wk arms B and C). Pts were required to have measurable, HER-2-negative MBC and no prior chemotherapy for MBC. The primary endpoints were response rate and toxicity. Results: Accrual is complete, with 25% of pts still on study as of December 1, 2008. Of 208 pts randomized, 202 (72 arm A, 54 arm B, 76 arm C) were treated, with balanced demographics and baseline characteristics. The median age was 56 (range 29–85). 89% had visceral disease and 61% had prior neo-adjuvant or adjuvant chemotherapy. No significant differences in confirmed complete and partial response rates were noted (A: 42%, B: 42%, C: 41%). TTP was longer in arm C (9.2 months) versus both arms B (6.4 months) and A (7.7 months), overall p = 0.028. As per protocol-specified stopping rule, arm B was closed early due to unacceptable safety profile with significantly more grade ≥ 2 fatigue (B:57%, A: 39%, C:39%, p = 0.048) and bone pain (B: 19%, A: 10%, C:4%, p = 0.024). Neurotoxicity grade ≥ 2 was equivalent across all 3 arms (50%); febrile neutropenia occurred in <2% of pts in all arms. Arm C had significantly less arthralgia, myalgia, and nausea compared with arms A and B. Conclusions: Significant antitumor activity was observed in all arms. Weekly nab-P with bev (Arm C) resulted in a significantly longer TTP. Weekly nab-P with bev (Arm C) appears to have the highest therapeutic index, however sensory neuropathy is limiting, suggesting a 3 week on/1 week off schedule could be preferable and should be studied comparatively. [Table: see text]