bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can pediatric and adolescent patients with recurrent tumors benefit from a precision medicine program? The European MAPPYACTS experience.
Authors: Berlanga Pablo , Pierron Gaëlle , Lacroix Ludovic , Adam de Beaumais Tiphaine , Bernard Virginie , Cotteret Sophie , Andre Nicolas , Corradini Nadege , Thebaud Estelle , Abbou Samuel , Casanova Michela , Owens Cormac , Michiels Stefan , Delattre Olivier , Vassal Gilles , Schleiermacher Gudrun , Geoerger Birgit 
Published: May 2019

10018 Background: The international prospective precision medicine trial MAPPYACTS (NCT02613962) aims to define the molecular profile in recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. Methods: Patients < 18 years-old at the time of initial diagnosis underwent on-purpose tumor biopsy/surgery of their recurrent/refractory malignancy for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years. 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients did not undergo intervention procedure (10 screening failures, 1 consent withdrawal). Molecular profiling was performed on samples in 433 patients and was contributive for 390 patients. For 271/390 patients (70%), there was at least one genetic alteration that could represent a potential therapeutic target and 8% had alterations considered as “ready for use” for treatment at relapse. Among them, 19 (7%) died before the CMTB. With follow-up censored in January 2019, 72 patients (27%) were treated with at least one matched targeted agent, 57 of them in a clinical trial, mostly the proof-of concept AcSé-ESMART trial (NCT02813135). Of the 166 patients (61%) that did not receive the matched treatment recommended by CMTB (80 still on follow-up), main reasons were: response/stable disease under previous therapy (50), another treatment (48), rapid disease progression/death (30) and legal representative refusal (12). Conclusions: MAPPYACTS profiling allowed tailored targeted treatment, mainly through early clinical trials, in patients with recurrent pediatric cancer. Since most detected molecular findings are within the investigational or hypothetical evidence level, therapeutic proof-of-concept trials that are exploring targeted therapies in molecularly enriched patient populations are crucial to improve knowledge and potentially outcome. Clinical trial information: NCT02613962.
Impact of protein supplementation on lean muscle mass in adult survivors of childhood cancer engaged in resistance training.
Authors: Krull Matthew R , Howell Carrie R. , Partin, MS Robyn , Carney Ginger , Mulrooney Daniel A. , Robison Leslie L. , Hudson Melissa M. , Ness Kirsten K. 
Published: May 2019

10027 Background: Muscle weakness, low lean muscle mass and poor physical performance are prevalent among adult survivors of childhood cancer. We evaluated the effects of resistance training with and without protein supplementation on lean muscle mass, and muscle strength among childhood cancer survivors. Methods: This double-blind placebo-controlled trial enrolled survivors aged ≥18 to < 45 years. Participants were randomized to resistance training with daily protein supplement (21g protein/day, 90kcal) (RT+S) or resistance training with placebo (sucrose, 90kcal) (RT+P). Both groups received educational materials, access to a local fitness center and a tailored resistance training program with tapered supervision. Lean muscle mass and muscle strength were assessed at baseline and 24 weeks, using dual x-ray absorptiometry and dynamometer testing respectively. Mean changes were compared within and between groups. Results: Of 93 participants randomized, 57 completed the 24-week intervention (24 in RT+S, 33 in RT+P). The mean age was 33.1 (SD 7.0), 67% were white and 47% female. The RT+S group had a significant increase in lean body mass (1.05 kg [SD 2.34], p = 0.04), while the RT+P group did not (0.13 kg [SD 2.19], p = 0.74). Mean change in handgrip strength also improved in the RT+S group (1.98 [SD 4.30], p = 0.03); change approached significance in the RT+P group (1.49 [SD 4.60], p = 0.07). All survivors significantly improved their strength over time (Table) as measured by one max repetition test at baseline and follow-up. Conclusions: Preliminary findings indicate that a supervised resistance training program among adult survivors of childhood cancer that includes protein supplementation is feasible and may increase total lean body mass and muscle strength. Clinical trial information: NCT02501460. [Table: see text]
IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC).
Authors: Schmid Peter , Adams Sylvia , Rugo Hope S. , Schneeweiss Andreas , Barrios Carlos H. , Iwata Hiroji , Dieras Veronique , Henschel Volkmar , Molinero Luciana , Chui Stephen Y. , Husain Amreen , Winer Eric P. , Loi Sherene , Emens Leisha A. 
Published: May 2019

1003 Background: IMpassion130 evaluated atezo (anti–PD-L1) + nP vs placebo + nP in 1L mTNBC. The primary PFS analysis found that atezo + nP significantly improved PFS in intent-to-treat (ITT) and PD-L1+ pts vs placebo + nP, with efficacy driven by the PD-L1+ population. At that time, the 1st interim OS analysis was conducted (Schmid, NEJM 2018). Here we report the 2nd interim OS analysis. Methods: Eligible pts had histologically documented locally advanced or mTNBC, ECOG PS 0-1 and tumor tissue for PD-L1 testing. Pts were randomized 1:1 to IV atezo 840 mg or placebo on d1 and d15 + nP 100 mg/m2 on d1, d8 and d15 of each 28-d cycle until progression (stratification factors: prior taxanes, liver metastases, PD-L1 on tumor-infiltrating immune cells [IC]). RECIST 1.1 PFS (in ITT and PD-L1+ pts) and OS (tested in ITT and, if significant, PD-L1+ pts) were co-primary endpoints. Results: OS data are shown (Table). As of data cutoff (Jan 2, 2019), 9% of pts in the atezo + nP arm and 3% in the placebo + nP arm were still on treatment. Statistical significance was not demonstrated in ITT pts, but a 7.0-month improvement in median OS was observed in PD-L1+ pts with atezo + nP (25.0 mo) vs placebo + nP (18.0 mo; HR, 0.71 [95% CI: 0.54, 0.93]). A 4.5-mo safety update (Schneeweiss, ASCO 2019, submitted) showed that atezo + nP remained tolerable. Conclusions: The 2nd IMpassion130 interim OS analysis was consistent with the 1st analysis, confirming clinically meaningful OS benefit with atezo + nP in previously untreated PD-L1+ mTNBC. Clinical trial information: NCT02425891. [Table: see text]
A novel association between GSTM1 null variant and anthracycline-induced cardiac dysfunction (ACD) in childhood cancer survivors (CCS): A COG ALTE03N1 report.
Authors: Singh Purnima , Wang Xuexia , Hageman Lindsey , Chen Yanjun , Magdy Tarek , Landier Wendy , Ginsberg Jill P. , Neglia Joseph Philip , Sklar Charles A. , Castellino Sharon M. , Dreyer ZoAnn Eckert , Hudson Melissa M. , Robison Leslie L. , Blanco Javier G. , Relling Mary V. , Burridge Paul , Bhatia Smita 
Published: May 2019

10030 Background: ACD is a leading cause of mortality in CCS. Previous studies have identified genomic variants that moderate the ACD risk. An agnostic evaluation of differential gene expression between those with and without ACD has not been explored, and could provide insights into the mechanism of cardiotoxicity. Methods: Gene expression profiles in leukocyte RNA from anthracycline-exposed non-Hispanic white (NHW) CCS (20 with ACD [cases]; 20 without ACD [controls]) used Illumina HumanHT-12 v4.0 Expression Beadchips. Gene expression profiles in h uman iPSC-derived cardiomyocytes (hiPSC-CMs – Day 30) from 6 childhood cancer patients (3 each with and without CD) treated with 1μM doxorubicin or vehicle for 24 h, used RNA-seq. Genotyping in leukocyte DNA from anthracycline-exposed NHW CCS (65 cases; 76 controls) to determine if the differentially-expressed genes mapped to genetic variants that modified ACD risk, used conditional logistic regression analysis adjusted for sex, age at cancer diagnosis, chest radiation and anthracycline dose. Patient characteristics are in Table. Results: Gene-expression in survivors:Glutathione S transferase mu 1 ( GSTM1) was differentially-expressed; RT q-PCR showed significant downregulation of GSTM1 in cases (0.67±0.57 vs. 1.33±1.33, p=0.049). hiPSC-CMs gene expression: GSTM1 was downregulated in patients with ACD (logFC = -1.4). Genotyping: Using PCR for GSTM1 null, we observed a significant association between CD risk and GSTM1 null genotype (OR=3.0; 95%CI, 1.4-6.2, p=0.003). Conclusions: We report an association between GSTM1 null genotype and ACD, previously unreported likely because GWAS studies did not examined gene deletions. GSTM1 is involved in detoxification of anthracyclines. This finding could facilitate identification of childhood cancer survivors at increased risk of ACD. [Table: see text]
Gene expression signature associated with in vitro dexamethasone resistance and post-induction minimal residual disease in pediatric T-cell acute lymphoblastic leukemia.
Authors: Meyer Lauren K. , Delgado-Martin Cristina , Roy Ritu , Huang Benjamin J. , Vincent Tiffaney , Olshen Adam , Wood Brent L. , Liu Yu , Zhang Jinghui , Mullighan Charles Grenfell , Horton Terzah M. , Loh Mignon L. , Devidas Meenakshi , Raetz Elizabeth A. , Hayashi Robert J. , Winter Stuart , Dunsmore Kimberly P. , Hunger Stephen , Teachey David T. , Hermiston Michelle L. 
Published: May 2019

10033 Background: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, which has largely precluded the use of genetic mutations for risk stratification. We hypothesized that despite this heterogeneity, diverse T-ALLs may have functional similarities that underlie patterns of chemotherapy sensitivity. Methods: We used flow cytometry to evaluate in vitro dexamethasone (DEX) sensitivity and baseline expression of signal transduction effectors and BCL2-family proteins in 68 fresh diagnostic T-ALL samples from patients enrolled on the Children’s Oncology Group (COG) trial AALL1231. We also performed RNA-sequencing (RNA-seq) on 40 AALL1231 samples and used hierarchical clustering and linear regression to analyze these and published T-ALL RNA-seq data from COG AALL0434. Comparisons between groups were made using t-tests and Fisher’s exact tests. Results: Of the proteins analyzed, only high BCL2 expression was significantly associated with increased in vitro DEX resistance (p = 0.002). Hierarchical clustering of the AALL1231 RNA-seq data identified two distinct clusters. Cluster 1 was associated with significantly higher BCL2 transcript expression (p = 0.0002) and in vitro DEX resistance (p = 0.04) relative to cluster 2. We defined a gene set consisting of the top 210 differentially expressed genes between these clusters and applied this gene set to the COG AALL0434 cohort. In this analysis, the early T-cell precursor (ETP) and near-ETP samples clustered together (p < 0.0001) in cluster 1 along with 39 of 146 non-ETP samples. Not only did these cluster 1 non-ETP samples have significantly higher BCL2 transcript expression relative to the non-ETP samples in cluster 2 (p < 0.0001), but 54% of these non-ETP samples were minimal residual disease (MRD) positive (≥0.01%) at the end of induction, as opposed to only 16% of the non-ETP samples in cluster 2 (p < 0.0001). Conclusions: Gene expression profiling identifies non-ETP T-ALLs that cluster with ETP/near-ETP T-ALLs and have significantly higher BCL2 expression and increased rates of post-induction MRD.
Vincristine, irinotecan, and temozolomide as a salvage regimen for relapsed or refractory sarcoma in children and young adults.
Authors: Park Byung-Kiu , Ju Hee Young , Park Meerim , Park Hyeon Jin 
Published: May 2019

10040 Background: No standard salvage regimen is available for recurrent or refractory sarcoma. Only a few studies using vincristine (V), irinotecan (I), and temozolomide (T) for rhabdomyosarcoma or Ewing sarcoma have been conducted mostly in pediatric age. We investigated the efficacy and toxicity of VIT regimen for several relapsed or refractory sarcomas in children and young adults. Methods: We retrospectively reviewed the relapsed or refractory sarcoma patients who were treated at the Center for Pediatric Cancer of the National Cancer Center, Korea between 2012 and 2018. VIT regimen given every 3 week schedule was as follows; V, 1.5mg/m2 i.v. on day 1, I, 50mg/m2 i.v. on days 1-5, and T, 100mg/m2 p.o. on days 1-5. Cefixime prophylaxis at 4mg/kg/day p.o. was administered to reduce irinotecan-induced diarrhea. Results: Total 26 patients (12 males) were treated with VIT during the study period. Patients were diagnosed with rhabdomyosarcoma ( n= 8), osteosarcoma ( n= 7), Ewing sarcoma ( n= 3), synovial sarcoma ( n= 3), alveolar soft part sarcoma ( n= 2), and mixed rhabdomyosarcoma and liposarcoma, hemangiopericytoma and desmoplastic small round cell tumor, one for each. Median age at the start of VIT was 18.5 years (range 2.0-39.9). VIT was delivered as the 2nd to 7th line of treatment, with the 4th line most common (9/26, 34.6%). Number of administered courses were 1-18, with two courses most common (6/26, 23.1%). Of the 25 evaluable patients, we had 2 partial response (PR), 13 stable disease (SD), and 11 progressive disease (PD) with an overall control rate (CR + PR + SD) of 60.0% as assessed by RECIST 1.1. According to diagnoses, we observed 4SD and 4PD for rhabdomyosarcoma; 1PR, 2SD and 4PD for osteosarcoma; 1PR, 1SD and 1 non-evaluable for Ewing sarcoma; 2SD and 1PD for synovial sarcoma; 2SD for alveolar soft part sarcoma. With a median follow-up of 24 months, 5 patients were alive without disease; 9 were alive with disease; 12 died of PD. Progression-free survival rate at one year was 33.8%, and overall survival rate was 79.3% at one year and 45.5% at 2 years. Of the 26 patients, two patients had grade 4 neutropenia; two had grade 3 colitis and another two had grade 3 neutropenic fever; 8 had grade 2 diarrhea. Grade 4 non-hematologic toxicity or treatment-related mortality was not observed. Conclusions: VIT was effective especially for disease control and relatively safe in our cohort of sarcoma patients.
What is the best therapy for grossly resected synovial sarcoma? Experience of the CWS Study Group.
Authors: Scheer Monika , Vokuhl Christian , Stegmaier Sabine , Muenter Marc W. , von Kalle Thekla , Serwa Paulina , Sparber-Sauer Monika , Kazanowska Bernarda , Niggli Felix , Ladenstein Ruth Lydia , Ljungman Gustaf , Jahnukainen Kirsi , Bauer Sebastian , Fuchs Joerg , Bielack Stefan S. , Koscielniak Ewa , Klingebiel Thomas 
Published: May 2019

10042 Background: Adjuvant therapy in patients with localized grossly resected synovial sarcoma (SS) still is a matter of debate. This analysis was performed to contribute to the clarification. Methods: SS patients of all ages with initially gross tumor resection registered in the prospective international CWS-trials 1981–2013 were evaluated. CWS-protocols currently recommend chemotherapy for all SS patients. Results: 185 patients with median age of 13.9 years (range 0.1–56.9) and median follow-up of 7.2 years (0.2-31.1) had 5-year event-free (EFS) and overall survival (OS) of 82.9%±5.7 (95%CI) and 92.5%±3.9, respectively. All but six patients received adjuvant chemotherapy. Best surgical treatment consisted of R0-resection in 107 and R1-resection in 70; no information in 7. 135 (73%) were irradiated. In the univariate analysis factors associated with EFS are tumor size and the application of chemotherapy; factors associated with OS are tumor site, size and invasiveness. In the multivariate analysis independent factors for adverse EFS are large tumor size and the application of chemotherapy, for OS tumor site and size. In the group of 58 patients with tumors < 3cm one patient suffered metastatic recurrence (2%), in those 59 patients with tumors 3-5cm 3 suffered metastatic recurrence (5%). In 42 patients with tumors 5-10cm, 4 metastatic and 2 combined recurrences were reported (14%), and in those 13 patients with tumors > 10cm 4 suffered metastatic and 1 combined relapse (38%). Conclusions: Patients with grossly resected SS treated according to the CWS recommendations have an excellent prognosis. A subgroup with very low metastatic potential probably does not need chemotherapy. Whether tumor size and surgery are sufficient criteria has still to be proven by long term results. Biological studies are needed.
Late toxicities, especially second malignancies, with GWAS analysis in hepatoblastoma cases treated in the Japanese study group for pediatric liver tumor protocol-2.
Authors: Hiyama Eiso , Watanabe Kenichiro , Mori Makiko , Ida Kohmei , Hishiki Tomoro , Yano Michihiro , Tanaka Yukichi , Yoshimura Kenichi , Hiyama Keiko 
Published: May 2019

10043 Background: This study focused on late toxicities, especially second malignancies (SMNs), experienced by patients with hepatoblastoma (HB) treated with CITA (cisplatin and pirarubicin) in the Japanese Study Group for Pediatric Liver Tumor protocol-2 (JPLT-2). Methods: In the JPLT-2, 361 children with HB were eligible for inclusion. We evaluated late effects including ototoxicity, cardiotoxicity and SMN in these patients. PRETEXT I/II patients were typically treated by initial resection at diagnosis followed by CITA. Otherwise, patients received preoperative CITA, followed by surgery and postoperative chemotherapy. Non-responders to CITA received ITEC (ifosfamide, pirarubicin, etoposide, and carboplatin) or intensified chemotherapeutic regimens. In 267 patients whose germline DNA samples were available, genotyping analysis was performed using the Illumina Human Omni Express Exome-8 v.1.3 BeadChip. Associations between single nucleotide polymorphisms (SNPs) and toxicities were assessed using logistic regression analysis. Results: Among the patients (n = 300) who survived more than 5 years, ototoxicity was detected in 61 and cardiotoxicity in 18. The presence of ototoxicity was associated with a significantly higher dose of cisplatin, and the Brock grade of ototoxicity was correlated with the total dose of cisplatin (P < 0.01). SMNs occurred in 13 patients (9 leukemia, 1 myelodysplastic disease, 1 lymphoma, 1 Ewing sarcoma and 1 thyroid tumor). The total dose of pirarubicin in SMN cases was significantly higher than those without SMNs (P = 0.035). The mean age at onset of HB was 13 months in the patients with SMNs and 23.3 months in the other patient (P = 0.12). However, two-way analysis of variance showed that SMN occurrence was significantly correlated with the age of HB onset and the total dose of pirarubicin (P < 0.0001). We identified ten inherited SNPs, including six SNPs associated with ototoxicity such as ACYP2, two SNPs associated with cardiotoxicity and two candidate SNPs associated with SMNs. Conclusions: The total dose of cisplatin was significantly associated with ototoxicity development. A low incidence of cardiotoxicity but high rates of SMTs, which were correlated with a high dose of pirarubicin and younger age at diagnosis, were found in this study. We also identified SNPs associated with SMNs in HB. Our study provides strong evidence that germline mutation may modify the effect of chemotherapy for childhood cancers on late toxicities, especially during early childhood. Clinical trial information: UMIN000001116.
ONC201 in previously-irradiated pediatric H3 K27M-mutant glioma.
Authors: Gardner Sharon L. , Allen Jeffrey C. , Zaky Wafik Tharwat , Odia Yazmin , Daghistani Doured , Khatib Ziad , Koschmann Carl Johannes , Aguilera Dolly , MacDonald Tobey J. , Chi Andrew S. , Tarapore Rohinton , Merdinger Krystal , Oster Wolfgang , Allen Joshua E. , Khatua Soumen 
Published: May 2019

10046 Background: ONC201 is the first DRD2 antagonist for clinical oncology. The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This multicenter, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) determined the RP2D of ONC201 in pediatric H3 K27M-mutant glioma patients as a single agent. ONC201 was orally administered once a week and scaled by body weight. Dose escalation was performed by a 3 + 3 design beginning with one 125mg capsule less than the adult RP2D equivalent. Three patients were treated at the starting dose and 19 were treated at the adult RP2D equivalent. Results: The primary endpoint was achieved by establishing the safety of the adult RP2D scaled by body weight to pediatric patients. Twenty-two patients with a median age of 9 (range 3-18) years old who received at least prior radiation have been treated with ONC201: 15 with diffuse intrinsic pontine glioma (DIPG) (4 recurrent; 11 not recurrent) and 7 with non-DIPG H3 K27M-mutant glioma (all not recurrent). As of February 5, 2019, patients have received a median of 18 ONC201 doses (range 3-41) without instance of dose-limiting toxicity. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL) and exposure was similar across body weights. Nine of 22 patients remain on therapy, 13 have discontinued due to progression, and 4 off-study patients are alive with a median follow up of 5.8 months. Five of the 11 (45%) DIPG patients who initiated ONC201 following radiation, but prior to recurrence, remain on therapy (median 7.4 months; range 4.4-9.6): median PFS is 4.4 months from initiation of ONC201 and 9.7 months from diagnosis; 7 of 11 (64%) patients are alive with median follow up of 11.8 months from diagnosis. Conclusions: ONC201 was well tolerated and achieved therapeutic exposure in pediatric H3 K27M-mutant glioma patients at the adult RP2D scaled by body weight. Further investigation of first-line ONC201 to treat H3 K27M-mutant glioma and/or DIPG is ongoing. Clinical trial information: NCT03416530.