bluuebunny/crossref_metadata_2025_split huggingface dataset:
Temsirolimus combined with etoposide and cyclophosphamide for relapsed/refractory acute lymphoblastic leukemia: Therapeutic advances in Childhood Leukemia Consortium (TACL 2014-001) trial.
Authors: Rheingold Susan R. , Silverman Lewis B. , Whitlock James A. , Sposto Richard , Schafer Eric S. , Schultz Kirk R. , Hutchinson Raymond J. , Gaynon Paul S. , Bateman Caroline , Cooper Todd Michael , Laetsch Theodore Willis , Sulis Maria Luisa , Wayne Alan S. , Tasian Sarah K. 
Published: May 2020

10512 Background: PI3K/mTOR signaling, a critical pathway in cell proliferation, metabolism, and apoptosis, is often dysregulated in acute lymphoblastic leukemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus combined with etoposide and cyclophosphamide was performed in children with relapsed/refractory (r/r) ALL. Methods: Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily days 1-5. The starting dose level (DL) of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). MRD was performed centrally. PI3K pathway inhibition was measured by phosphoflow cytometry (PFC) analysis of peripheral blood (PB) from treated patients (pts). Results: Sixteen heavily pretreated r/r ALL pts ages 2-19 years with marrow blasts > 25% were enrolled; 15 were evaluable [10 B-ALL/5 T-ALL]. One dose-limiting toxicity (DLT) of grade (Gr) 4 pleural and pericardial effusions with pneumonitis/lung infection leading to Gr 5 cardiorespiratory arrest occurred in a pt treated at DL3. No further DLTs were seen in the DL3 expansion and DL4 cohorts. Gr 3/4 non-hematologic toxicities occurring in ≥ 3 pts included febrile neutropenia, elevated ALT, hypokalemia, mucositis, and tumor lysis syndrome and were independent of dose. Of 15 evaluable pts, 4 (27%; 2 B-ALL/2 T-ALL) had a complete response (CR) after cycle 1, comprised of 1 pt at each DL. Three had MRD < 0.01%. Three pts (20%; 2 B-ALL/1 T-ALL) had partial response (PR). Overall response rate (CR+PR = ORR) was 47%. Pharmacodynamic PFC studies compared phosphoprotein levels pre (day 0) and post treatment (days 3-5) in 9 consenting pts with available PB. All tested pts showed basal activation of PI3K pathway signaling. Dose-dependent inhibition of mTOR targets phosphorylated (p) S6 and/or p4EBP1 was observed in 9/9 and 6/9 pts, respectively, following temsirolimus and chemotherapy treatment. Various patterns of compensatory upregulation of pPI3K, pmTOR, pAkt, and/or pERK was observed. Conclusions: Temsirolimus at 25 mg/m2 combined with salvage etoposide and cyclophosphamide has an acceptable safety profile in high-risk pediatric patients with r/r ALL. Responses were observed at all DLs. mTOR target inhibition was achieved and appeared to correlate with dose level. Future testing of other PI3K/mTOR pathway inhibitors in combination with chemotherapy may be warranted with a goal of further increasing response in r/r ALL. Clinical trial information: NCT01614197.
Dexrazoxane and heart function among long-term childhood cancer survivors: A Children’s Oncology Group study.
Authors: Chow Eric Jessen , Aggarwal Sanjeev , Doody David R , Aplenc Richard , Armenian Saro , Baker Kevin Scott , Bhatia Smita , Blythe Nancy , Colan Steven , Constine Louis S. , Freyer David Robert , Kopp Lisa M. , Laverdiere Caroline , Leisenring Wendy M. , Sasaki Nao , Vrooman Lynda M. , Asselin Barbara , Schwartz Cindy L. , Lipshultz Steven E. 
Published: May 2020

10513 Background: Dexrazoxane (DRZ) has cardioprotective effects among doxorubicin (DOX) treated childhood cancer survivors up to 5 years after therapy. However, longer-term data are lacking. Methods: P9404, P9425, P9426, and DFCI 95-01 were randomized trials of acute lymphoblastic leukemia and Hodgkin lymphoma, where patients were randomly assigned to DOX±DRZ. P9754 enrolled osteosarcoma patients who all received DOX+DRZ. In all studies, DRZ was given as an intravenous bolus before DOX (10:1mg ratio). DOX doses ranged from 100-600 mg/m2 across these 5 trials. A subset of COG institutions prospectively assessed cardiac function in long-term survivors from these trials, plus a matched group of osteosarcoma survivors treated with DOX alone. Echocardiograms (left ventricular [LV] Biplane ejection fraction [EF], shortening fraction [SF]) and blood biomarkers (b-type natriuretic peptides [BNP], N-terminal [NT] proBNP) were all analyzed centrally, with DRZ status masked. Lower LV function was defined as EF<50% or SF<30%. T-test, rank-sum, and multivariate regression adjusted for sex, cancer diagnosis age, current age, DOX dose, and chest radiotherapy were used to examine differences and associations by DRZ status. Results: Among 173 participants assessed (52% DRZ+; 54% male; mean DOX 294±96 mg/m2) 17.6±2.4y since cancer diagnosis, DRZ+ participants were slightly younger (27.8 vs 29.6y, p=0.02), but baseline characteristics otherwise did not differ significantly by DRZ status. DRZ status was associated with higher FS (34.7±3.6% vs 33.4±4.3%, p=0.04) and EF (63.4±5.4% vs 61.4±5.5%, p=0.01), and lower BNP (median 10.4 pg/mL [IQR 6.0-18.0] vs 13.0 [IQR 6.0-28.2], p=0.03) and NT-proBNP (median 30.8 pg/mL [IQR 18.9-58.2] vs 47.1 [IQR 23.0-83.1], p<0.01). In stratified analyses, the cardioprotective effects associated with DRZ tended to be more pronounced in females (vs males) and those who received DOX ≥300 mg/m2 (vs <300mg/m2). Results from multivariate models were similar: DRZ was associated with higher SF (1.4% [95% CI 0.2, 2.6]) and EF (2.7% [95% CI 0.8, 4.6]), and reduced BNP (-4.0 pg/mL [95% CI -7.6, -0.4]) and NT-proBNP (-20.7 pg/mL [95% CI -33.5, -7.9]). Overall, DRZ was associated with a reduced risk of having lower LV function (odds ratio 0.27 [95% CI 0.08-0.96]). Conclusions: After >17y, childhood cancer survivors treated with DOX+DRZ had better LV systolic function and less myocardial wall stress compared with those treated with DOX alone. DRZ may preferentially benefit females and those treated with greater DOX doses.
Individual prediction of non-adherence to oral mercaptopurine (6MP) in children with acute lymphoblastic leukemia (ALL): Results from COG AALL03N1 study.
Authors: Hoppmann Anna Lynn , Chen Yanjun , Landier Wendy , Hageman Lindsey , Relling Mary V. , Wong F. Lennie , Bhatia Smita 
Published: May 2020

10530 Background: Poor adherence to 6MP (measured electronically [MEMS]) increases relapse risk in children with ALL (Bhatia et al. JAMA Oncol 2015). Adherence is difficult to assess clinically and non-adherers are more likely to over-report 6MP intake (Landier et al. Blood 2017). Key sociodemographic/clinical factors (Bhatia et al. JCO 2012) and red cell methyl-mercaptopurine (MMP, a 6MP metabolite) levels (Hoppmann et al. ASCO 2017) are associated with non-adherence and could potentially identify non-adherers. Methods: We developed a prediction model for 6MP non-adherence (MEMS adherence rate < 90%), using receiver operating characteristic (ROC) analyses in 407 children with ALL receiving 6MP (mean age 7.7±4.4y; 68% males; 35% Caucasians, 34% Hispanics, 16% African Americans, 15% Asians). The cohort was divided into a training set (n = 250) and test set (n = 157) using stratified random sampling (stratified by race/ethnicity, gender, age and 6MP non-adherence). We used logistic regression with backward variable elimination, guided by change in area under ROC (AUC), to create a prediction model in the training set, using only clinical and sociodemographic variables (Clinical Model). We then generated a model that added 6MP dose-intensity (6MPDI)-adjusted red cell MMP levels to the Clinical Model (Final Model). All models were validated in the test set. Results: Predictors retained in the Training Clinical Model included: age, race/ethnicity, absolute neutrophil count, 6MPDI, family structure, and taking 6MP at the same vs varied time of day (AUC = 0.79; 95%CI 0.72-0.85). The Training Final Model (adding 6MPDI-adjusted MMP to the Clinical Model) yielded an AUC = 0.79 (95%CI 0.72-0.86). The Test Final Model (AUC = 0.79, 95%CI 0.69-0.88) showed significantly superior discrimination compared to the Test Clinical Model (AUC = 0.74, 95%CI 0.63-0.85; P = 0.002). Using a binary classifier with predicted probability of non-adherence ≥0.5, the Test Final Model had an accuracy of 79%, and positive and negative predictive values of 71% and 80%, respectively. Conclusions: We created, validated, and compared 2 risk-prediction models for 6MP non-adherence in children undergoing maintenance chemotherapy. While inclusion of red cell MMP levels provided superior discrimination in identifying non-adherent patients, the Clinical Model (without MMP levels) performed adequately well, and could be used in the clinical setting.
A phase I/II study of eribulin mesilate (ERI) plus irinotecan (IRI) in children with refractory or recurrent solid tumors.
Authors: Casanova Michela , Kramm Christof , Reinhardt Dirk , Locatelli Franco , D'Adamo David R. , Scott Rachael , Jia Yan , Aluri Jagadeesh , Favre Claudio , Bautista Francisco , Hladun Alvaro Raquel , Sastre Urgelles Ana , Kontny Udo 
Published: May 2020

10535 Background: ERI is an inhibitor of microtubule dynamics. IRI is used to treat pediatric sarcomas. In the pediatric preclinical testing program, ERI was well tolerated and had promising activity compared with vincristine (a common chemotherapeutic for pediatric cancers) for various solid tumors ( in vivo xenograft panels). Methods: Children with relapsed/refractory solid tumors (excluding active central nervous system tumors) were enrolled. Prior treatment with IRI was allowed. Dose escalation was conducted for 2 schedules with the primary objective (phase 1) of determining the maximum tolerated dose and the recommended phase 2 dose: (A) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 20 or 40 mg/m2 IV infusion (Days 1–5 of 21-day cycle); (B) ERI 1.4 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle) + IRI 100 or 125 mg/m2 IV infusion (Days 1 + 8 of 21-day cycle). Safety and pharmacokinetic parameters were assessed. Results: 13 patients (pts) were enrolled (median age: 9 years [range: 3–17]); 4 pts had rhabdomyosarcoma (RMS), 2 had non-RMS soft tissue sarcoma, 2 had Ewing sarcoma, 2 had hepatoblastoma, 2 had nephroblastoma, and 1 had neuroblastoma. Overall, 7 pts previously received IRI. No dose-limiting toxicities (DLTs) were reported for either schedule. At data cut-off (July 14, 2019), 4 pts (with Ewing sarcoma, neuroblastoma, RMS, or hepatoblastoma) continued treatment (A, n = 2; B, n = 2) and 9 pts discontinued treatment (primarily for radiographic progression, n = 7 [A, n = 4; B, n = 3]). All pts experienced ≥1 treatment-emergent adverse event (TEAE); the most common any grade TEAE was neutropenia (n = 10; A, n = 5; B, n = 5). 11 pts had grade ≥3 TEAEs (A, n = 6; B, n = 5); the most frequent grade ≥3 TEAE was neutropenia (n = 9; A, n = 5; B, n = 4). No pt withdrew ERI or IRI due to an AE; 3 pts had dose reductions for ERI (A, n = 1; B, n = 2) and 3 pts had dose interruption of ERI (A, n = 2; B, n = 1) due to AEs. No pt had dose reductions for IRI, and 3 pts had dose interruption of IRI (A, n = 2; B, n = 1) due to AEs. 3 deaths occurred; 2 deaths were the result of tumor progression (A, n = 1; B, n = 1), and the cause of 1 was unknown (B). 1 pt with neuroblastoma treated according to schedule A had a partial response. Systemic exposures of ERI, IRI, and SN-38 (IRI active metabolite) were similar between schedules and doses. Conclusions: No DLTs were observed. Toxicity was manageable. Administration of IRI treatment on Days 1–5 is widely used in pediatric cancers; enrollment for phase 2 is ongoing with treatment Schedule A (ERI 1.4 mg/m2 Days 1 + 8 of 21-day cycle; IRI 40 mg/m2 Days 1–5 of 21-day cycle). Clinical trial information: NCT03245450.
Deep learning for improved prediction of late-onset cardiomyopathy among childhood cancer survivors: A report from the St. Jude Lifetime Cohort (SJLIFE).
Authors: Gunturkun Fatma , Davis Robert L , Armstrong Gregory T. , Jefferies John L. , Ness Kirsten K. , Green Daniel M. , Lucas John Thomas , Srivastava Deokumar , Hudson Melissa M. , Robison Leslie L. , Mulrooney Daniel A. , Soliman Elsayed Z , Karabayir Ibrahim , Akbilgic Oguz 
Published: May 2020

10545 Background: Early identification of survivors at high risk for treatment-induced cardiomyopathy may allow for prevention and/or early intervention. We utilized deep learning methods using COG guideline-recommended baseline electrocardiography (ECG) to improve prediction of future cardiomyopathy. Methods: SJLIFE is a cohort of 5-year clinically assessed childhood cancer survivors including baseline ECG measurements. Development of cardiomyopathy was identified from clinical and echocardiographic measurement using CTCAE criteria (grade 3-4). We applied deep learning approaches to ECG, treatment exposure and demographic data obtained at baseline SJLIFE assessment. We trained a cascaded model combining a 12-layer 1D convolutional neural network to extract features from waveform ECG signals with a 2-layer dense neural network to embed features from other phenotypic data in tabular format to determine if use of deep learning with ECG data could improve prediction of cardiomyopathy. Results: Among 1,218 subjects (median age 31.7 years, range 18.4-66.4) without cardiomyopathy at baseline evaluation, 616 (51%) were male, 1,041 (85%) white, 157 (13%) African American and 792 (65%) were survivors of lymphoma/leukemia. Follow-up averaged 5 (0.5 to 9) years from baseline examination. Mean chest radiation dose was 1350 cGy (range 0 to 6,200 cGy) and mean cumulative anthracycline dose was 191 mg/m2 (range o to 734 mg/m2). A total of 114 (9.4%) survivors developed cardiomyopathy after baseline. A cascaded deep learning model built on a training set (N = 974 participants) classified cardiomyopathy in the test set (N = 244 participants) using both clinical and ECG data with a sensitivity of 70%, specificity of 73%, and AUC of 0.74 (95% CI 0.63-0.85), compared to a model using clinical data alone (sensitivity 61%, specificity 62%, and AUC 0.67, 95% CI 0.56-0.79). In subgroup analyses, models predicting cardiomyopathy within 0-4 years following baseline had a sensitivity, specificity, and AUC of 77%, 78%, and 0.78 (0.65-0.91), respectively. When predicting cardiomyopathy 5-9 years following baseline, model performance dropped to a sensitivity, specificity, and AUC of 70%, 70%, and 0.68 (0.50-0.87), respectively. Conclusions: Deep learning using ECG at baseline evaluation significantly improved prediction of cardiomyopathy in childhood cancer survivors at high risk for cardiomyopathy. Future directions will incorporate deep learning approaches to echocardiography to further improve prediction.
HAGHL genetic variants increase first fracture risk (FFR) in female childhood cancer survivors: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort Study (SJLIFE).
Authors: Im Cindy , Li Nan , Moon Wonjong , Morton Lindsay M. , Leisenring Wendy M. , Howell Rebecca M. , Oeffinger Kevin C. , Sklar Charles A. , Wilson Carmen Louise , Sapkota Yadav , Ness Kirsten K. , Hudson Melissa M. , Robison Leslie L. , Bhatia Smita , Armstrong Gregory T. , Yasui Yutaka 
Published: May 2020

10554 Background: Recent genome-wide association studies (GWAS) have reported substantial sex differences in the genetic architectures of bone-related phenotypes. We investigated sex-specific genetic determinants of FFR in survivors of childhood cancer. Methods: We performed sex-combined and sex-stratified GWAS for FFR using Cox regression models fitted on follow-up age in 2,453 long-term (≥5 years) survivors in CCSS with ~5.4 million imputed SNPs (minor allele frequency, MAF≥5%), with self-reported FFR defined by first fracture at any site after diagnosis. Replication analyses were conducted in an independent sample of 1,417 SJLIFE survivors with whole-genome sequencing and clinician-assessed FFR. All models were adjusted for relevant genetic (e.g., ancestry) and clinical (e.g., height, weight, treatment) factors. Results: Sex-combined and male-specific analyses yielded no associations with P < 10−7. Among female CCSS survivors (N = 1,289, 33% ≥1 fractures), we discovered 7 genome-wide significant (P < 5x10−8) SNP-FFR associations with strong evidence of sex effect heterogeneity (P < 7x10−6) across 2 independent loci with no known associations with bone phenotypes. We replicated these associations in SJLIFE (P≤0.05) for 3 coding SNPs in the HAGHL gene (16p13.3), among which rs1406815 showed the strongest association (MAF = 20%, meta-analysis HR = 1.43, P = 8.2x10−9; N = 1,935 women, 35% ≥1 fractures). We observed increased HAGHL SNP effects on FFR that corresponded with increasing head/neck (HN) radiation therapy (RT) dose (Table). Public omics data show replicated SNPs are associated with differential HAGHL expression in sex gland and musculoskeletal tissues (GTEx) and in osteoblasts treated with dexamethasone or prostaglandins (GRASP), suggesting sex-/therapy-specific biological pathways involving HAGHL SNPs for fracture are plausible. Conclusions: Novel associations between HAGHL genetic variants and FFR potentially reveal new sex- and therapy-specific biological mechanisms underlying bone-related health conditions in survivors of childhood cancer. [Table: see text]
Is it safe and worthwhile? A multi-site randomized clinical trial of FAmily CEntered (FACE) pediatric advance care planning for adolescents with cancer and their families.
Authors: Baker Justin N. , Thompkins Jessica , Needle Jennifer , Cheng Yao , Friebert Sarah , Lyon Maureen E 
Published: May 2020

10557 Background: Many clinicians express concern that pediatric ACP (pACP) is too distressful for families. We describe the effect of FAmily CEntered pACP for Teens with Cancer (FACE-TC) on families’ self-reported experience. Methods: A 4-site, intent-to-treat, longitudinal, randomized clinical trial recruited adolescent/family dyads from hospital-based cancer-specialty clinics from 2016-2019. Adolescent/family dyads were screened/assented/consented/enrolled and randomized at a 2:1 ratio to either FACE-TC or Treatment as Usual control. FACE-TC is three weekly, 60-minute sessions with a certified facilitator (ACP survey; Next Steps: Respecting Choices Interview; Five Wishes advance directive). Satisfaction Questionnaire measured 7 positive (useful, helpful, load off my mind, satisfied, something I needed to do, courageous, worthwhile) and 6 emotional reactions (scared, hurtful, harmful, too much to handle, angry, sad). It was administered by a trained/blinded research assistant immediately following the Respecting Choices interview or 3 weeks post-baseline for controls. Results: Family participants were: primarily mothers (75%); mean age 46 years; 83% female; 82% white. Household income was ≤100% Federal poverty level for 26%; 58% had less than a Bachelor’s degree. Attendance was 92% for three FACE sessions. FACE families (N = 116) compared to controls were more likely to report the study was “worthwhile” (97% vs. 86%, 0 = 0.0245); “useful” (97% vs. 83%, p = 0.0102); “helpful” (96% vs. 79%, p = 0.0079); and “something I needed to do” (84% vs. 55%, p = 0.0006). FACE families (Mean 28.1, SD 3.3) reported higher positive subscale scores than control families (Mean 24.9, SD 4.4) (β = 2.98, p = 0.0001). No significant differences were found for age, gender, race, household income, or adolescent on active treatment. There were no differences between FACE or control dyads on the 6 emotional reactions subscale score. Conclusions: Among a geographically, economically diverse families, FACE pACP was safe and worthwhile. Clinicians can be assured that a structured facilitated pACP intervention, although emotionally intense, did not unduly distress families who found the experience overwhelmingly worthwhile. Results fill the gap about how to successfully engage families in pACP with their adolescent child. Clinical trial information: NCT02693665.
NivoCUP: An open-label phase II study on the efficacy of nivolumab in cancer of unknown primary.
Authors: Tanizaki Junko , Yonemori Kan , Akiyoshi Kohei , Minami Hironobu , Ueda Hiroki , Takiguchi Yuichi , Kondoh Chihiro Nakayama , Segawa Yoshihiko , Takahashi Shin , Iwamoto Yasuo , Kidera Yasuhiro , Fukuoka Kazuya , Nakamura Yasushi , Chiba Yasutaka , Nishio Kazuto , Nakagawa Kazuhiko , Hayashi Hidetoshi 
Published: May 2020

106 Background: CUP has a poor prognosis with a median survival of less than 12 months. Given the recent approval of immune checkpoint inhibitors in several cancer types, we performed a multicenter phase II study of nivolumab in CUP patients (pts). Methods: The main population of this study is CUP pts who were previously treated with more than one line of systemic chemotherapy. Previously untreated CUP pts were also enrolled for exploratory analysis. Pathological examination (including IHC), CT, FDG-PET, gastroscopy and colonoscopy and medical examination were mandatory for diagnosis of CUP before enrollment. CUP pts belonging to favorable prognosis groups were excluded from the trial. Nivolumab (240 mg/body) was delivered as an intravenous infusion every 2 weeks for up to 52 cycles until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 by an Independent Endpoint Review Committee in previously treated pts. The secondary objectives include investigator-assessed ORR, progression-free survival (PFS), overall survival (OS), safety and the association between the efficacy of nivolumab and PD-L1 expression. Results: A total of 56 CUP pts, 45 previously treated and 11 previously untreated pts, were enrolled in this trial. The median age was 65.5 years, 22 pts were male. Median follow-up was 8.05 mo (range, 0.1 to 20.7 mo). Of 45 previously treated pts, 2 and 9 had an investigator-assessed complete response and partial response (ORR 24.4%, 95% CI: 12.9-39.5%), with a median PFS (mPFS) and OS (mOS) of 5.4 mo (95% CI: 2.6-6.9) and 15.1 mo (95% CI: 8.3-NR), respectively. Among 11 previously untreated pts, 1 pt had partial response (ORR 9.1%, 95% CI: 0.2-41.3%). The mPFS was 3.9 mo and the mOS was not reached in untreated pts (95% CI: 1.1-5.6, and 95% CI: 2.6-NR, respectively). Nivolumab demonstrated a mPFS of 5.1mo (95% CI: 2.7-5.6) and a mOS of 15.9 mo (95% CI: 8.4-NR) in an overall population. Immune-related adverse events occurred in 57% of overall pts with 5% of grade 3 or higher, and the most common were rash (27%), hypothyroidism (16%), and diarrhea/colitis (16%). No treatment related death was observed. Conclusions: In pts with previously treated and untreated CUP, nivolumab demonstrated durable antitumor activity with a manageable safety. Clinical trial information: UMIN000030649.