bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adapting molecular inversion probe (MIP) technology for allele quantification in childhood leukemia
Authors: Schiffman J. D. , Welch K. M. , Davis R. , Dahl G. V. , Lacayo N. J. , Faham M. , Ford J. M. , Ji H. 
Published: March 2020

9530 Background: Leukemia accounts for ∼40% of newly diagnosed pediatric malignancies, and relapsed leukemia is the leading cause of death in childhood cancer. Genomic instability events contribute to neoplastic development and have been used to classify and risk stratify non-leukemic adult and pediatric tumors. Analyzing leukemic blasts for gene copy changes with advanced molecular techniques could prove useful in further risk stratifying and developing new treatment strategies for pediatric leukemia. Methods: Molecular Inversion Probes (MIPs) analyze genetic target sequences in parallel with high specificity and sensitivity at the highest genomic resolution, and were originally designed for single nucleotide genotyping. The MIP assay was adapted to analyze both gene copy number and loss of heterozygosity (LOH) events in pediatric leukemia samples (pre-B ALL, T-ALL, AML). DNA was extracted (100 ng) from paired bone marrow (diagnosis) and peripheral blood (remission) samples (n = 40). The MIP assay was run with a customized Affymetrix 20K Cancer Panel (representing oncogenes, tumor suppressor, DNA repair, cell growth, and metabolism genes). Gene copy number changes were identified by comparing probe signal intensity between leukemia samples and normal cell-lines. LOH events were determined by identifying genotype changes between matched leukemic and remission samples. Results: Each sample had unique patterns of multiple gene copy changes and LOH events distributed across all chromosomes. Additionally, samples were found to have overlapping copy number changes and LOH regardless of leukemia type. AML samples had fewer LOH events and could be separated by unsupervised clustering from the other leukemia samples. Conclusions: MIPs represent novel genotyping technology that can be adapted for gene copy analysis of childhood leukemia. Unique and distinguishing signatures of allelic imbalance can be determined between ALL and AML clinical samples using MIP technology. The unexpected overlap of LOH and deleted genes may represent a common molecular mechanism that requires further investigation. No significant financial relationships to disclose.
Age, tumor grade, and mitosis-karyorrhexis index (MKI) are independently predictive of outcome in neuroblastoma (NB)
Authors: London W. B. , Shimada H. , d'Amore E. , Peuchmar M. , Hero B. , Faldum A. , Machin D. , Mosseri V. , Iehara T. , Pearson A. , Cohn S. L. 
Published: March 2020

9558 Background: NB is a rare pediatric malignancy (USA incidence 1:100,000), and treatment is tailored according to risk. NB patients (pts) in the Children's Oncology Group are stratified to low, intermediate or high risk according to age at diagnosis, stage of disease, MYCN status, histopathology, and tumor cell ploidy. The International NB Pathologic Classification (INPC) uses age at diagnosis to classify tumors as Favorable or Unfavorable histology. This results in duplication of the prognostic contribution of age when both age and INPC, with other factors, are used to assign risk groups or build multivariable models of prognostic factors. To eliminate the confounding contribution of age and INPC, and determine if tumor pathology is predictive of outcome independent of age, we performed multivariable modeling using the underlying pathologic components of INPC. Methods: Using the largest cohort of NB pts ever assembled (n=11,054; 1980–2002; international), 1,860 pts with known age, INPC, diagnosis, tumor grade of differentiation, MKI, and outcome were identified. Half were selected at random (reserving the other half for validation) for analysis. A Cox multivariable model was used to perform survival tree regression to identify factors statistically significantly (p<0.05) prognostic of event-free (relapse, progression, secondary malignancy, death) survival (EFS). Factors tested were age, diagnosis, grade, and MKI. Results: Age (<547 v. ≥547 days) was the most significant factor (p<0.0001). Within pts <547 days, no factors were significantly prognostic. Within pts ≥547 days, stroma-poor NB and nodular (composite) ganglioNB was associated with significantly lower EFS than intermixed ganglioNB and ganglioneuroma, maturing (p<0.0001). Pts were further stratified within the latter diagnoses by MKI (Low/Intermediate v. High) (p=0.0016). These results were validated in the other half of the cohort. Conclusions: Histologic features of NB tumors are predictive of outcome. To remove confounding of the prognostic contribution of age, the underlying histologic features of the tumor (diagnosis, MKI, grade) should be used instead of INPC class to assign pts to risk groups or identify prognostic factors with multivariable models. No significant financial relationships to disclose.
Safety, pharmacokinetics, and efficacy of palonosetron in pediatric patients: A multicenter, stratified, double-blind, phase 3, randomized study
Authors: Kadota R. , Shen V. , Messinger Y. 
Published: March 2020

9570 Background: A single intravenous (IV) dose of palonosetron (PALO) 0.25 mg is used in the prevention of acute chemotherapy-induced nausea and vomiting (CINV) after highly (HEC) and moderately emetogenic chemotherapy (MEC) and in the prevention of delayed CINV after MEC. Since younger age is a risk factor that increases the likelihood of CINV, we conducted this study to explore the safety, pharmacokinetics (PK) and efficacy of PALO in pediatric patients receiving MEC (32% of patients) or HEC (68%). Methods: Sixty pediatric patients in 2 age strata, ages 2–11 and 12–17 years, were randomized to receive a single IV dose of PALO 3 mcg/kg (max total dose = 0.25 mg) or 10 mcg/kg (max total dose = 0.75 mg), with no concomitant antiemetics prior to MEC or HEC. The same doses were used in 12 additional younger patients (age range: 28 days - 23 months) treated in an open-label fashion. Safety, assessed as incidence of adverse events (AEs), was the primary between-group analysis endpoint. Plasma concentrations, PK parameters and efficacy (up to 24 hours after chemotherapy) were assessed descriptively for both PALO doses in each age group. Results: Only 3 AEs, 2 (pyrexia and pruritus) in the 3 mcg/kg dose group (5.7%) and 1 (pain) in the 10 mcg/kg group (2.7%), were judged possibly related to study medication by the investigators, and none of them were severe or led to study discontinuation. No cardiac safety issues were identified; vital signs and laboratory data did not raise any safety concerns for the administration of either dose of PALO. Systemic exposure (AUC) to PALO increased with increasing dose across all age groups (AUC0–8: 22.17–33.25 ng*h/mL at 3 mcg/kg dose; 49.85–75.1 ng*h/mL at 10 mcg/kg dose). Clearance and volume of distribution increased in correlation with age-related growth in body weight. T1/2 ranged from 21–37 hours across groups, slightly shorter than adult T1/2 of 40 hours. Complete Response (no emesis no rescue, 0–24 hours) rates showed overlapping Confidence Intervals in the two dose groups (37.1% [22.0%-55.1%] at 3 mcg/kg, n=35; and 54.1% [37.1%-70.2%] at 10 mcg/kg, n=37). Conclusions: PALO, dosed according to patient's weight at 3 and 10 mcg/kg, was effective and well tolerated in the pediatric population. No significant financial relationships to disclose.
Anglo-Celtic IV: First results of a UK National Cancer Research Network randomized phase III pharmacogenetic trial of weekly compared to 3 weekly paclitaxel in patients with locally advanced or metastatic breast cancer (ABC)
Authors: Verrill M. W. , Lee J. , Cameron D. A. , Agrawal R. , Coleman R. E. , McAdam K. , Wardley A. , Bowman A. , Ferrigan L. , Yellowlees A. 
Published: March 2020

LBA1005 Background: Phase II studies of weekly paclitaxel (P) confirm this to be a well tolerated regimen in ABC with potentially superior efficacy to standard q3w schedules. This was tested in the phase III CALGB 9840 trial, which used a “patient resource conserving” design, combining randomised patients with imported control data from a previous CALGB study of predominantly 2nd line treatment. This and the higher total dose of P in the weekly arm, left many unsure if there really was superior activity for the weekly schedule. Methods: The primary efficacy objective was to detect a 2 month improvement (6 to 8 months, HR = 1.33) in time to progression (TTP) by the giving the same total dose of P weekly (wP) vs. 3 weekly (3wP). 560 randomised patients were required to give 90% power to detect this difference at the 0.05 significance level. A single analysis was planned six months after study closure. Secondary endpoints include overall survival, toxicity and quality of life. The primary translational endpoint is a pharmacogenetic (PG) study of the effect of MDR and CYP single nucleotide polymorphisms. Between Sept. 2002 and July 2006, 569 patients were randomized to receive either wP 90 mg/m2 for 12 weeks or 3wP 175 mg/m2 for 6 cycles. Patients were stratified for measurable disease, prior treatment for ABC and Trastuzumab use. Results: The investigator reported response rates were 27% (3wP) and 42% (wP), p=0.002. Median TTP was 22.0 weeks for 3wP (95% CI 19.7–24.6) and 23.9 weeks for wP (95% CI 20.7–26.7), HR=0.92, p=0.06. Both schedules were well tolerated. PG samples from 325 patients are being matched to the unblinded efficacy data. Conclusions: This phase III trial shows that, for a matched total dose, wP produces a higher response rate than 3wP. This confirms the result from CALGB 9840. The mismatch in treatment duration in this trial may explain why TTP with wP was superior in CALGB 9840 while in the current study we have failed to detect superiority despite a higher response rate. Combining the trial results supports the hypothesis that total dose and schedule of P are important. Our results support the widespread adoption of wP as the standard schedule. No significant financial relationships to disclose.
Randomized phase III study of 5-fluorouracil (5-FU) alone versus combination of irinotecan and cisplatin (CP) versus S-1 alone in advanced gastric cancer (JCOG9912)
Authors: Boku N. , Yamamoto S. , Shirao K. , Doi T. , Sawaki A. , Koizumi W. , Saito H. , Yamaguchi K. , Kimura A. , Ohtsu A. 
Published: March 2020

LBA4513 Backgrounds: We conducted a 3-arm phase III study to investigate superiority of CP and non-inferiority of S-1 to 5-FU for advanced gastric cancer in the primary endpoint of overall survival (OS) and secondary endpoints of response rate (RR), time to treatment failure (TTF), non-hospitalized survival (NHS) and toxicities. Methods: Treatments with 5-FU (800mg/m2/d, ci, d1–5, q4w), CP (irinotecan, 70mg/m2, div, d1&15 and cisplatin, 80mg/m2, div, d1, q4w) and S-1 (40mg/m2, b.i.d., d1- 28, q6w) were continued until disease progression or unacceptable toxicities. Tumors were evaluated every two months. With 230 patients (pts) per arm, this study had 80% power to demonstrate 10% superiority of CP and non-inferiority with 5% margin (hazard ratio, HR=1.16) of S-1 and 0.05 study-wise 1-sided alpha. Results: 704 pts having unresectable or recurrent gastric adenocarcinoma with/without target lesions (TL) were randomized between Nov 2000 and Jan 2006. Final analysis was performed in Feb 2007 when 601 pts (85%) were dead. The results of OS are shown in Table . Median TTF/NHS were 2.3M/7.2M for 5-FU, 3.7M/9.5M for CP, and 4.0M/9.2M for S-1. Incidences (%) of grade 4 neutropenia, grade ≥3 febrile neutropenia, infection with neutropenia, anorexia, diarrhea within 6M, and treatment related death (5- FU/CP/S-1) were 0/37/0, 0/9/0, 0/8/0, 13/33/12, 0/9/8, and 0/1.3/0.4. In the subset having TL, RRs of 5-FU/CP/S-1 (n=175/181/175) were 9%/38%/28%, and their median survival times (MST) were 9.0M/12.1M/10.5M and HRs to 5-FU were 0.78 (95%CI, 0.63–0.98) for CP and 0.85 (0.68–1.06) for S-1. In the subset not having TL, the MSTs of 5-FU/CP/S-1 (n=59/55/59) were 13.5M/14.4M/18.1M and HRs were 1.02 (0.68–1.55) for CP and 0.82 (0.55–1.24) for S-1. Conclusions: S-1 showed a significant non-inferiority to 5-FU. Although CP did not show statistically significant superiority to 5-FU in all pts, it may have a benefit for some subgroups such as pts with measurable metastatic diseases. [Table: see text] [Table: see text]
Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC)→paclitaxel (T) vs. AC→T with trastuzumab (H)
Authors: Rastogi P. , Jeong J. , Geyer C. E. , Costantino J. P. , Romond E. H. , Ewer M. S. , Keefe D. L. , Levine T. , Swain S. M. , Wolmark N. 
Published: March 2020

LBA513 Background: Trastuzumab (H) has been shown to improve survival in HER2 positive, node-positive breast cancer patients when combined with paclitaxel following AC (Romond NEJM 2005:353;1673–1684). Cardiac dysfunction is the major toxicity associated with this regimen. Methods: NSABP B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node- positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on MUGA scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by a panel of cardiologists to determine whether criteria were met for a cardiac event (CE), defined as NYHA class III or IV CHF or possible/probable cardiac death. Among patients with normal post-AC LVEF who began post-AC treatment, 10 of 872 (1.3%) control patients subsequently had confirmed CEs (9 CHFs and 1 cardiac death) compared with 35 of 932 (3.9%) trastuzumab-treated patients (35 CHFs and no cardiac deaths). The difference in cumulative incidence at 5 years was 2.7%. Risk factors for CHF were age 50 (5.2–5.3%), requirement for hypertension medication (7.7%), and post AC-LVEF values of 50–54% (13.0%). Conclusion: Administering trastuzumab with paclitaxel after AC increases incidence of CHF. Risk factors for increased risk of cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy. No significant financial relationships to disclose.
A randomized phase III study of gemcitabine (GEM) versus pegylated liposomal doxorubicin (PLD) in progressive/recurrent ovarian cancer (OC)
Authors: Ferrandina G. , Lorusso D. , Pignata S. , Breda E. , Savarese A. , Nardi M. , Scaltriti L. , Ludovisi M. , Scambia G. 
Published: March 2020

LBA5506 Background: This multi-center Phase III study was designed to compare the efficacy and safety of PLD vs GEM in ovarian cancer (OC) patients relapsing within 12 months from platinum/paclitaxel treatment. Methods: Recurrent OC patients failing only one line of platinum/paclitaxel regimen with a platinum-free interval (PFI) ≤12 months, and with measurable or evaluable disease were eligible. Patients were randomized to receive PLD 40 mg/m2 d1 over 1 hr q 4 wk versus GEM 1,000 mg/m2 d1,8,15 over 30 min q 4 wk. The primary endpoint was time to progression (TTP), with overall survival (OS), overall response rate (ORR), safety/toxicity, and quality of life (QoL) as secondary endpoints. A total of 147 patients was calculated to be required (alpha=0.05, beta=0.80) in order to detect an increase in median TTP from 12 to 19 weeks in control (PLD) versus experimental (GEM) arm. Results: As of December 2006, 147 patients were enrolled; 74 and 73 patients were randomized to PLD versus GEM, respectively: overall, median age was 65 yrs (range 28–80); 69 (46.9%) patients had a PFI < 6 months, while 78 (53.1%) had a PFI between 6–12 months. response evaluation was possible in 129 cases: in PLD arm, the ORR was 15.9%, compared to an ORR=28.3% in GEM arm, p value=0.13). With a median follow up of 9 months, there was no difference in TTP between PLD and GEM arms (median TTP=16 versus 20 weeks, respectively; p value=0.44). Median OS was 56 weeks in PLD patients versus 50 weeks in GEM arm (p value=0.17). Total number of cycles was 301 in PLD arm, and 275 in GEM arm. Grade 3–4 leukopenia was documented in 8.7% of patients allocated to PLD versus 22.0% of patients administered GEM (p value=0.03); no difference in the distribution of severe anemia and thrombocytopenia was observed. There was no difference in non hematological toxicity. A total of 121 patients were considered for QoL data analysis: a trend to a better global QoL score was documented in PLD arm. (p value=0.015) Conclusions: PLD and GEM show similar activity in OC recurring within 12 months from primary treatment. No significant financial relationships to disclose.
Pemetrexed in advanced non-small cell lung cancer: A randomized trial of 500 mg/m2 vs 900 mg/m2 in 588 patients who progressed after platinum-containing chemotherapy
Authors: Cullen M. , Zatloukal P. , Sörenson S. , Novello S. , Fischer J. R. , Joy A. , Zereu M. , Peterson P. , Visseren-Grul C. , Iscoe N. 
Published: March 2020

LBA7727 Introduction: The mild toxicity profile of pemetrexed (P), seen in a phase III trial of P 500 mg/m2 vs docetaxel 75 mg/m2 in vitamin-supplemented patients (pts), suggests higher doses of P can be given in pts with previously treated advanced non-small cell lung cancer (NSCLC) without significant toxicity. We conducted a phase III trial to determine if a higher dose of P (900 mg/m2) could improve survival vs the standard P dose in pts with NSCLC. Methods: Pts with stage III/IV NSCLC, previously treated with platinum-based chemotherapy, were randomized to P 500 or 900 mg/m2 iv q3week. After the second planned interim analysis, the Data Safety Monitoring Board recommended discontinuation of enrollment due to low probability of demonstrating a survival advantage and a greater incidence of some toxicities on the P 900 arm. Patients were allowed to continue treatment at the P 500 dose. Results: 588 randomized pts were evaluated for efficacy and 581 pts, who received =1 dose, for safety. Safety data for pts who transitioned from P 900 to P 500 were analyzed separately. The treatment arms were balanced regarding baseline characteristics and prior treatment. Both arms had: ∼67% males, median age 62 yrs, 87% pts with an ECOG PS of 0 or 1, and 77% pts with stage IV disease. Key results are shown in the table . There was no statistical difference between arms for any efficacy measure. In general, the incidence of adverse events (AEs) was comparable or numerically higher in the P 900 arm. Some AEs (all grades) reported a >5% difference between the P 900 (N=240) and P 500 arms: fatigue (41.7% vs 32.8%), anemia (32.9% vs 22.1%), vomiting (20.0% vs 13.1%), stomatitis (17.9% vs 10.0%), diarrhea (15.4% vs 10.0%), and thrombocytopenia (11.3% vs 5.5%). Conclusion: P 900 offers no advantage over P 500 mg/m2 as second-line therapy for pts with advanced NSCLC. Certain toxicities were somewhat more pronounced in the P 900 group. No significant financial relationships to disclose. [Table: see text]
Clinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohorts.
Authors: Burgess Melissa Amber , Bolejack Vanessa , Schuetze Scott , Van Tine Brian Andrew , Attia Steven , Riedel Richard F. , Hu James S , Davis Lara Emily , Okuno Scott H. , Priebat Dennis A. , Movva Sujana , Reed Damon R. , D'Angelo Sandra P. , Lazar Alexander J. , Keung Emily Zhi-Yun , Reinke Denise K. , Baker Laurence H. , Maki Robert G. , Patel Shreyaskumar , Tawbi Hussein Abdul-Hassan 
Published: March 2020

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.