bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of exercise on muscle immune response and mitochondrial damage and their relationship with cancer-related fatigue: A URCC NCORP study.
Authors: Peoples Anita Roselyn , Peppone Luke Joseph , Lin Po-Ju , Cole Calvin , Heckler Charles E. , Janelsins Michelle Christine , Rousey Steven , Onitilo Adedayo A. , Melnik Marianne , Mustian Karen Michelle 
Published: September 2018

10119 Background: Chemotherapy (CT) via inflammation and oxidative stress can cause muscle inflammatory injury, mitochondrial damage, and cancer-related fatigue (CRF). Following muscle and mitochondrial damage, various cytoplasmic and mitochondrial components are released into circulation. HLA-DQB1 gene encodes a protein involved in the activation of immune response, and is not expressed in normal muscle cells but is up-regulated under highly inflammatory states. Mitochondrial gene MT-CO2 encodes subunit 2 of complex IV, which plays a critical role in energy metabolism and mitochondrial function. We investigated the (i) influence of an exercise intervention, Exercise for Cancer Patients (EXCAP), on gene expression levels of muscle immune response and mitochondrial damage and (ii) the relationships of these genes with CRF. Methods: In this nationwide, multicenter, phase III RCT conducted through the URCC NCORP Research Base, cancer patients (N = 350; mean age = 55.7) were randomized to 2 groups: (i) CT and (ii) CT plus a 6-week individualized, home-based, aerobic and resistance exercise program (EXCAP). Gene expression and CRF were assessed pre- and post-intervention from whole blood by qPCR and from patient-report by MFSI, respectively. Results: T-tests revealed significant upregulation of peripheral HLA-DQB1 and MT-CO2 mRNA following CT in controls (both p < 0.00001) while there was less up-regulation in exercisers (both p≤0.005). ANCOVA showed a trend for significant differences between controls and exercisers for HLA-DQB1 (9.2% vs 5.4%; p = 0.059) and MT-CO2 (16.3% vs 12.7%; p = 0.061). Pearson correlations revealed that increases in HLA-DQB1 (r = 0.21; p = 0.051) and MT-CO2 (r = 0.19; p = 0.025) were significantly associated with concurrent increase in CRF in controls, but not in exercisers. Conclusions: CT alters muscle immune response and mitochondrial gene expression causing muscle and mitochondrial damage, which may be mediators for CRF. EXCAP is a promising intervention that may reduce both muscle and mitochondrial damage via its positive effects on HLA-DQB1 and MT-CO2. Funding: NCI UGCA189961, R25 CA102618. Clinical trial information: NCT00924651.
Phase 1 dose escalation of ZW25, a HER2-targeted bispecific antibody, in patients (pts) with HER2-expressing cancers.
Authors: Meric-Bernstam Funda , Beeram Muralidhar , Blum Mariela A. , Hausman Diana Felice , Infante Jeffrey R. , Patnaik Amita , Piha-Paul Sarina Anne , Rasco Drew W. , Rowse Gerry , Thimmarayappa Jamuna , Tolcher Anthony W. , Hamilton Erika Paige 
Published: September 2018

1035 Background: The HER2 receptor is expressed across a range of cancers (ca) although expression and heterogeneity vary greatly within and between tumors. FDA approved HER2-targeted therapies (tx) have shown clinical benefit only in HER2 high (IHC3+ or IHC2+/FISH+) breast and gastric ca. ZW25, built on the Azymetric™ platform which utilizes unique Fc mutations to create IgG1-like bispecific antibodies, binds to the same extracellular domains of HER2 as trastuzumab (T) and pertuzumab (P) with increased binding and internalization compared to T alone. In preclinical studies ZW25 was well tolerated and active in models of HER2 low to high ca. Methods: Eligible pts (HER2 IHC 1-3+, progression after standard of care (SOC) tx, normal LVEF) were enrolled in a 3+3 dose escalation study of ZW25 (5, 10 or 15 mg/kg) IV weekly in 4 week cycles. Assessments included adverse events (AEs), LVEF, tumor response and PK. Results: 9 pts have received ZW25 at 5 (n = 3) or 10 mg/kg (n = 6); 15 mg/kg is ongoing. All pts were HER2 high (breast = 4; gastric/GEJ = 4; adnexal = 1). Prior tx included T in all pts; P and T-DM1 in 4 and lapatinib (L) in 3 of 4 breast pts. The most common AEs (all Gr 1/2) were infusion reaction (IR) (5/9), diarrhea (4/9), and fatigue (3/9), with no DLTs and one related Gr 3 AE of hypophosphatemia. The IRs occurred only with 1st dose and did not recur with prophylactic tx (primarily acetaminophen and diphenhydramine; steroids included for 2 pts). At 5 mg/kg, peak drug levels after C1D1 = ~100 ug/ml, accumulating ~50% higher by dose 4. Best response in 8 pts (1 too early): 2 PR (both breast ca with prior T, P, T-DM1, and L; 10 mg/kg, 55% and 33% target lesion decrease, respectively, after 2 cycles), 1 SD (breast ca, 5 mg/kg, ongoing after 4 cycles), and 5 PD. 5 pts currently active; includes 1 gastric pt (10 mg/kg) with PD (new nodal lesions) and clinical benefit with decrease in target lesions and CEA (33 to 1.5 ng/ml). Conclusions: ZW25 has been well tolerated with promising anti-tumor activity in pts with HER2-expressing ca progressing after SOC therapy. These early signs of activity support the therapeutic potential for bispecific antibodies using the Azymetric platform. Development of ZW25 is ongoing, including in lower HER2-expressing ca. Clinical trial information: NCT02892123.
Phase II study of gemcitabine (G), trastuzumab (H), and pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) after prior pertuzumab-based therapy.
Authors: Iyengar Neil M. , Smyth Lillian Mary , Lake Diana , Gucalp Ayca , Singh Jasmeet Chadha , Traina Tiffany A. , DeFusco Patricia Anne , Dickler Maura N. , Fornier Monica N. , Goldfarb Shari Beth , Jhaveri Komal L. , Modi Shanu , Troso-Sandoval Tiffany A. , Jack Kellie , Ulaner Gary , Jochelson Maxine S. , Baselga Jose , Norton Larry , Hudis Clifford A. , Dang Chau T. 
Published: September 2018

1037 Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of G with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of 1-27-17, 41 of 45 pts are enrolled; 34 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 26/34 (76%) are progression free (1 CR, 8 PR, 17 SD); 8 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% in evaluable pts (95% CI 60% to 88%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation. Clinical trial information: NCT02252887.
Safety and efficacy of the BCL2 inhibitor venetoclax in estrogen receptor (ER) and BCL2-positive metastatic breast cancer: The mBEP study.
Authors: Lindeman Geoffrey John , Lok Sheau Wen , Bergin Alice Ruth , Whittle James Richard , Shackleton Kylie , Sherman Peter , Dawson Sarah-Jane , Desai Jayesh , Liew Danny , Mann Bruce , Murugasu Anand , Roberts Andrew Warwick , Rosenthal Mark , Visvader Jane 
Published: September 2018

1044 Background: The anti-apoptotic protein BCL2 is overexpressed in ~85% of ER+ breast cancer (BC). Venetoclax (ABT-199), a BCL2 inhibitor approved for CLL (400 mg/day), synergizes with tamoxifen in preclinical patient derived xenograft models by increasing apoptosis. In the first study to evaluate venetoclax in solid tumors, we tested the safety and efficacy of this combination in ER+BCL2+ metastatic BC. Methods: A ‘3+3 design’ dose escalation phase 1b study enrolled women with ER+ ( > 1%), BCL2+ ( > 10%, mod-high) and HER2 non-amplified metastatic BC. Patients received escalating doses of venetoclax 200, 400, 600 or 800 mg/day with tamoxifen 20 mg/day. The primary objective was to determine dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) over 4 weeks. There was no limit to the number of prior lines of therapy. Results: Fifteen patients were enrolled (mean age 62 years, range 44-78; previous tamoxifen, 10 pts). Mean lines of prior therapy for metastatic BC was 2.5 (median 2, range 0-6) and included tamoxifen (6 pts). ESR1 mutations were present in ctDNA of 4 patients. Treatment was well tolerated, with no DLT observed. MTD was not reached; 6 patients received the maximal planned dose (800 mg). The most common adverse event (AE) was lymphopenia (67% Grade 1-2; 13% Grade 3; No Grade 4), followed by nausea (46%, Grade 1-2), which was readily managed. Of 13 women with measurable disease (RECIST v1.1), 4 (31%) had a partial response and 5 (38%) had stable disease (clinical benefit rate, 69%). For patients with a partial response, tumor regression was rapid (evident at first restaging) and occurred in the 400-800 mg dose levels. Two patients with non-measurable bone-only disease had clinically stable disease (1 ongoing > 64 weeks). The median duration of response has not yet been reached (range, 12 to > 64 weeks). Conclusions: We demonstrated the safety of tamoxifen and venetoclax in ER+BCL2+ metastatic BC, with preliminary evidence of clinically relevant activity. A dose expansion study including serial biopsy, ctDNA and PET scans is ongoing at the 800 mg/day recommended phase 2 dose. Sponsor: Royal Melbourne Hospital Clinical trial information: ISRCTN98335443 , ACTRN12615000702516.
Age-associated vulnerability to treatment-related late cardiotoxicity: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Bates James Edward , Liu Qi , Yasui Yutaka , Howell Rebecca M. , Mulrooney Daniel A. , Dhakal Sughosh , Leisenring Wendy M. , Indelicato Daniel J. , Gibson Todd M. , Armstrong Gregory T. , Oeffinger Kevin C. , Constine Louis S. 
Published: September 2018

10501 Background: Cardiovascular disease (CVD) is the most common non-cancer cause of death in long-term survivors of pediatric cancer. We investigated the role of age at diagnosis in modifying treatment-related late CVD risk in the CCSS population. Methods: We evaluated CTCAE grade 3 – 5 CVD events occurring ≥5 years after diagnosis in 23,465 5-year survivors of pediatric cancer diagnosed 1970-1999. We estimated the rates of developing any CVD, including coronary artery disease (CAD) or heart failure (HF). Modifications of treatment effects by age at diagnosis were analyzed using piecewise exponential models adjusting for current age, race, and smoking. Results: At a median age of 28.4 years (range 5.6 –58.3) and follow up of 20.2 years (5 – 39.3), 239 CAD and 359 HF events occurred. The cumulative incidence of CVD, CAD, and HF were 4.8% (95% CI: 4.3-5.3), 2.4% (95% CI: 2.2-2.9), and 2.5% (95% CI: 2.2-2.9) by 30 years from diagnosis. Mean cardiac radiotherapy (CRT) doses of ≥10 Gy were associated with a progressively increasing risk of CVD (10 - < 20 Gy: RR 3.6, 95% CI 2.1 – 6.2, p < 0.01; 20 - < 30 Gy: RR 4.4, 95% CI 2.7 – 7.2, p < 0.01; ≥30 Gy: RR 7.5, 95% CI 4.9 – 11.5, p < 0.01) relative to those receiving no CRT. In those receiving a low mean CRT dose (0.1 - < 10 Gy), younger children had higher rates of CVD (0 – 4 years: RR = 2.2, 95% CI = 1.0 – 4.6, p = 0.04; > 4 - ≤13 years: RR = 2.1, 95% CI = 1.1 – 4.1, p = 0.03) compared to those > 13 years, an effect not seen at higher doses. Among survivors exposed to anthracycline doses ≥250 mg/m2, those age 0 – 4 at diagnosis had increased risk of both CAD (RR = 4.9, 95% CI 1.5 – 16.3, p = 0.01) and HF (RR = 3.0, 95% CI 1.6 – 5.0, p < 0.01). Cisplatin exposure ≥300 mg/m2 was associated with increased risk of any CVD (RR = 1.8, CI = 1.2 – 2.6, p < 0.01), primarily attributable to increased risk of HF (RR = 2.3, 95% CI = 1.5 - 3.5, p < 0.01). Conclusions: Among long-term survivors of pediatric cancer, increasing CRT dose is associated with increased risk for CVD in a dose-response relationship. Young children are at higher risk for CVD after low-dose CRT or high-dose anthracycline exposure. Cisplatin exposure significantly increases risk for CVD. These findings should inform future treatment and surveillance protocols.
Intensive multi-modality therapy for extra-ocular retinoblastoma (RB): A Children's Oncology Group (COG) trial (ARET0321).
Authors: Dunkel Ira J. , Krailo Mark D. , Chantada Guillermo L. , Banerjee Anuradha , Abouelnaga Sherif , Buchsbaum Jeffrey , Merchant Thomas E. , Granger Meaghan , Jubran Rima Fuad , Kellick Michael , Weinstein Joanna , Abramson David H. , Rodriguez-Galindo Carlos , Chintagumpala Murali M. 
Published: September 2018

10506 Background: Metastatic RB is associated with a poor prognosis. Previous small series suggested that intensified systemic chemotherapy with or without radiation therapy (RT) may improve outcomes in this population. COG opened this prospective, multi-institutional, international trial to study the effectiveness of this approach. Methods: Patients with regional extra-ocular RB (stage 2 or 3) were treated with 4 cycles of intensive conventional chemotherapy (vincristine 0.05 mg/kg/day, cisplatin 3.5 mg/kg/day, cyclophosphamide 65 mg/kg x 2 days, etoposide 4 mg/kg x 2 days) followed by involved-field RT (4500 cGy). Two strata of patients with metastatic RB [stage 4a: distant metastases not involving the central nervous system involvement (CNS); and stage 4b (CNS metastases)/trilateral RB)] were treated with 4 cycles of the same chemotherapy. Patients with ≥ partial response then received 1 cycle of high-dose carboplatin (Calvert formula with AUC = 7/day, maximum 16.7 mg/kg/day) on days -8 to -6, thiotepa (10 mg/kg/day), & etoposide (8.3 mg/kg/day) on days -5 to -3 with autologous hematopoietic stem cell rescue on day 0. Patients with metastatic RB who did not achieve an adequate response to chemotherapy also received RT. Results: Sixty subjects (20 in each stratum) were enrolled; 57 were eligible and included in the analyses (based on data current to June 30, 2016). Toxicity was significant as expected and there were 2 therapy related deaths. Event-free survival (EFS) at 36 months was 87.7% (90% CI 65.4 to 96.0%) for subjects with stage 2 or 3 disease, 79.3% (90% CI 54.2 to 91.6%) for subjects with stage 4a disease and 8.0% (90% CI 1.0 to 25.1%) for subjects with stage 4b/trilateral disease. The observed results significantly improved the EFS in each stratum compared with historical results used for planning the study. Conclusions: This is the first prospective, multi-institutional, international study to show that intensive multi-modality therapy is highly effective for patients with regional extra-ocular RB and metastatic RB not involving the CNS. More effective therapy is required for patients with CNS RB. Clinical trial information: NCT00554788.
The INFORM personalized medicine study for high-risk pediatric cancer patients.
Authors: Worst Barbara Christine , Pfaff Elke , Van Tilburg Cornelis M. , Balasubramanian Gnana Prakash , Fiesel Petra , Pajtler Kristian W. , Freitag Angelika , Witt Ruth , Kulozik Andreas E. , von Deimling Andreas , Eggert Angelika , Dirksen Uta , Lichter Peter , Capper David , Pfister Stefan M. , Jones David T. W. , Witt Olaf 
Published: September 2018

10509 Background: Relapses from high-risk tumors pose a major clinical challenge in pediatric oncology. The German INFORM registry (INdividualized therapy FOr Relapsed Malignancies in children) addresses this problem using integrated next-generation sequencing to rapidly identify patient-specific therapeutic targets. Methods: Whole-exome, low-coverage whole-genome and RNA sequencing is complemented with microarray-based DNA methylation profiling. Identified alterations are discussed and prioritized according to biological significance and potential druggability in a weekly molecular tumor board. Results: To date, 214 tumor samples of high-risk pediatric cancer patients have been profiled from 47 German centers, with 39% being sarcomas, 30% brain tumors, 13% neuroblastoma and 18% hematological or other malignancies. Turnaround time from tissue arrival to molecular results was 21 calendar days on average. In 14/214 patients (7%) we identified an underlying germline predisposition syndrome. In several cases there were discrepancies between the original histological diagnosis and our molecular findings, especially in brain tumors. We detected one or more potentially druggable alterations in 147/214 (69%) cases. Tyrosine kinases, the PI3K/mTOR pathway, MAPK pathway, and cell-cycle as well as transcriptional regulators were commonly affected. Based on these findings, targeted therapeutics were incorporated into the therapy regime in one-third of patients, with anecdotal reports of marked responses, including a patient with a pleomorphic sarcoma, where we detected a previously undescribed RAF-fusion, showing a partial remission upon RAF-inhibition. Conclusions: In summary, real-time comprehensive profiling of pediatric tumors provides valuable diagnostic information and identifies potential therapeutic targets. In parallel, the implementation of a systematic program for reverse-translational evaluation is ongoing. Recently, this nationwide effort has expanded to include patients from other countries. We will also recruit patients to the complementary eSMART and INFORM2 biomarker-driven, phase I/II combination trial series, to provide unprecedented access to targeted therapies in Europe.
Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).
Authors: Bhojwani Deepa , Sposto Richard , Shah Nirali , Rodriguez Vilmarie , O'Brien Maureen Megan , McNeer Jennifer Lynn , Loh Mignon L. , Rheingold Susan R. 
Published: September 2018

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.
Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: A Children’s Oncology Group report.
Authors: Getz Kelly D. , Alonzo Todd Allen , Sung Lillian , Meshinchi Soheil , Gerbing Robert B , Raimondi Susana , Hirsch Betsy A , Kahwash Samir B , Choi John , Kolb E. Anders , Gamis Alan S. , Aplenc Richard 
Published: September 2018

10515 Background: For pediatric patients with low risk (LR) acute myeloid leukemia (AML), the Children’s Oncology Group (COG) trial AAML1031 used a 4-course chemotherapy backbone consisting of two induction courses of cytarabine/daunorubicin/etoposide, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. The prior COG trial, AAML0531, included the same four courses plus a fifth course of high dose cytarabine. Removal of course 5 from AAML1031 was based in part on prior studies that suggested no benefit from a fifth course. Methods: We compared overall survival (OS), disease free survival (DFS), and relapse risk (RR) for LR patients receiving four versus five chemotherapy courses in a pooled analysis of comparable patients treated on AAML0531 and AAML1031. LR was defined as the presence of inv(16)/t(16;16) or t(8;21) cytogenetic features, NPM1 or CEBPA mutations, or MRD < 0.1% post-Induction I in those with no high risk features. AAML0531 patients assigned to gemotuzumab were excluded. Follow-up for outcomes began at the start of course 4. Cox (OS and EFS) and risk (RR) regressions were used to estimate unadjusted hazard ratios (HR) comparing outcomes for patients who received only four versus five chemotherapy courses. Start of a fifth chemotherapy course was assessed as a time-varying exposure in all analyses to avoid exposure misclassification. Results: A total of 921 LR patients (225 from AAML0531, 696 from AAML1031) were included; 191 (21%) received a fifth course. There were no significant differences in distributions of sex, age, race, or ethnicity between patients treated with four or five courses. Median times to absolute neutrophil count and platelet count recovery after course 4 were also comparable. Patients who received only four courses had significantly lower OS (HR = 1.83, 95% CI: 1.22-2.74, p = 0.003), DSF (HR = 1.49, 95% CI: 1.13-1.97, p = 0.005), and higher RR (HR = 1.42, 95% CI: 1.08-1.88, p = 0.013) compared to those who received five courses. Conclusions: Removal of a fifth cytarabine-containing course appears to result in worse OS, DFS, and RR in pediatric patients with LR AML. Multivariable analyses to further refine the estimates are ongoing.