Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer.

Loss of the histone demethylase KDM5D (lysine-specific demethylase 5D) leads to in vitro resistance of prostate cancer cells to androgen deprivation therapy (ADT) with and without docetaxel. We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP-seq) of the LNCaP cell line (androgen-sensitive human prostate adenocarcinoma) with and without silenced KDM5D, MYBL2-binding sites were analyzed.

Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR.

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial.

Aim: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.

Methods: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest.

Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib.

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.

Incorporation of extracorporeal photopheresis into a reduced intensity conditioning regimen in myelodysplastic syndrome and aggressive lymphoma: results from ECOG 1402 and 1902.

Background: Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma).

A novel PrECOG (PrE0901) dose-escalation trial using eltrombopag: enhanced platelet recovery during consolidation therapy in acute myeloid leukemia.

High-dose cytarabine (HiDAC) consolidation for acute myeloid leukemia (AML) induces transient profound myelosuppression and potential morbidity/mortality. PrE0901 was a phase I multi-center trial evaluating the safety/toxicity of eltrombopag in AML patients receiving HiDAC consolidation. We used a standard 3 + 3 design employing a unique dose-escalation/de-escalation strategy.

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond.

Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.

Background: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.

Methods: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point.

Association between age and sex and mortality after adjuvant therapy for renal cancer.

Background: In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial.

Methods: The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial.

A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease.

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re-induction chemotherapy. They were randomized to the following regimens: carboplatin-topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S-MEC).

Meta-STEPP with random effects.

We recently developed a method called Meta-STEPP based on the fixed-effects meta-analytic approach to explore treatment effect heterogeneity across a continuous covariate for individual time-to-event data arising from multiple clinical trials. Meta-STEPP forms overlapping subpopulation windows (meta-windows) along a continuous covariate of interest, estimates the overall treatment effect in each meta-window using standard fixed-effects method, plots them against the continuous covariate, and tests for treatment-effect heterogeneity across the range of covariate values. Here, we extend this method using random-effects methods and find it to be more conservative than the fixed-effects method.

Tumor Microvessel Density as a Prognostic Marker in High-Risk Renal Cell Carcinoma Patients Treated on ECOG-ACRIN E2805.

Increased vascularity is a hallmark of renal cell carcinoma (RCC). Microvessel density (MVD) is one measurement of tumor angiogenesis; however, its utility as a biomarker of outcome is unknown. ECOG-ACRIN 2805 (E2805) enrolled 1,943 resected high-risk RCC patients randomized to adjuvant sunitinib, sorafenib, or placebo.

Subpopulation Treatment Effect Pattern Plot (STEPP) analysis for continuous, binary, and count outcomes.

Background: For the past few decades, randomized clinical trials have provided evidence for effective treatments by comparing several competing therapies. Their successes have led to numerous new therapies to combat many diseases. However, since their conclusions are based on the entire cohort in the trial, the treatment recommendation is for everyone, and may not be the best option for an individual.

Meta-STEPP: subpopulation treatment effect pattern plot for individual patient data meta-analysis.

We have developed a method, called Meta-STEPP (subpopulation treatment effect pattern plot for meta-analysis), to explore treatment effect heterogeneity across covariate values in the meta-analysis setting for time-to-event data when the covariate of interest is continuous. Meta-STEPP forms overlapping subpopulations from individual patient data containing similar numbers of events with increasing covariate values, estimates subpopulation treatment effects using standard fixed-effects meta-analysis methodology, displays the estimated subpopulation treatment effect as a function of the covariate values, and provides a statistical test to detect possibly complex treatment-covariate interactions. Simulation studies show that this test has adequate type-I error rate recovery as well as power when reasonable window sizes are chosen.

Younger adults with acute myeloid leukemia in remission for ≥ 3 years have a high likelihood of cure: The ECOG experience in over 1200 patients.

We examined 1229 younger patients with acute myeloid leukemia who achieved CR1 on Eastern Cooperative Oncology Group trials. We defined late relapse as occurring after ≥ 3 years of CR1. With median follow-up of 11.

Comparative meta-analysis of prognostic gene signatures for late-stage ovarian cancer.

Background: Ovarian cancer is the fifth most common cause of cancer deaths in women in the United States. Numerous gene signatures of patient prognosis have been proposed, but diverse data and methods make these difficult to compare or use in a clinically meaningful way. We sought to identify successful published prognostic gene signatures through systematic validation using public data.

E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer.

Purpose: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC).

Methods: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.

curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome.

This article introduces a manually curated data collection for gene expression meta-analysis of patients with ovarian cancer and software for reproducible preparation of similar databases. This resource provides uniformly prepared microarray data for 2970 patients from 23 studies with curated and documented clinical metadata. It allows users to efficiently identify studies and patient subgroups of interest for analysis and to perform meta-analysis immediately without the challenges posed by harmonizing heterogeneous microarray technologies, study designs, expression data processing methods and clinical data formats.

Clinical correlates of promoter hypermethylation of four target genes in head and neck cancer: a cooperative group correlative study.

Purpose: Promoter hypermethylation is a well-documented mechanism for tumor-specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16(INK4a) in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes.

Estimation of sequencing error rates in short reads.

Background: Short-read data from next-generation sequencing technologies are now being generated across a range of research projects. The fidelity of this data can be affected by several factors and it is important to have simple and reliable approaches for monitoring it at the level of individual experiments.

Results: We developed a fast, scalable and accurate approach to estimating error rates in short reads, which has the added advantage of not requiring a reference genome.

Unifying gene expression measures from multiple platforms using factor analysis.

In the Cancer Genome Atlas (TCGA) project, gene expression of the same set of samples is measured multiple times on different microarray platforms. There are two main advantages to combining these measurements. First, we have the opportunity to obtain a more precise and accurate estimate of expression levels than using the individual platforms alone.

Active surfaces for CO oxidation on palladium in the hyperactive state.

Hyperactivity was previously observed for CO oxidation over palladium, rhodium, and platinum surfaces under oxygen-rich conditions, characterized by reaction rates 2-3 orders higher than those observed under stoichiometric reaction conditions [Chen et al. Surf. Sci.