We identified prominent molecular features of BCR-ABL-positive adult ALL, which may be useful for developing novel therapeutic targets and prognostic markers in this disease.
Objective Identifying subgroups of intensive care unit (ICU) patients with similar clinical needs and trajectories may provide a framework for more efficient ICU care through the design of care platforms tailored around patients’ shared needs. However, objective methods for identifying these ICU patient subgroups are lacking. We used a machine learning approach to empirically identify ICU patient subgroups through clustering analysis and evaluate whether these groups might represent appropriate targets for care redesign efforts. Design We performed clustering analysis using data from patients’ hospital stays to retrospectively identify patient subgroups from a large, heterogeneous ICU population. Setting Kaiser Permanente Northern California (KPNC), a healthcare delivery system serving 3.9 million members. Patients ICU patients aged ≥ 18 years with an ICU admission between January 1, 2012 and December 31, 2012 at one of 21 KPNC hospitals. Interventions none. Measurements and Main Results We used clustering analysis to identify putative clusters among 5,000 patients randomly selected from 24,884 ICU patients. To assess cluster validity, we evaluated the distribution and frequency of patient characteristics, and the need for invasive therapies. We then applied a classifier built from the sample cohort to the remaining 19,884 patients to compare the derivation and validation clusters. Clustering analysis successfully identified six clinically-recognizable subgroups that differed significantly in all baseline characteristics and clinical trajectories, despite sharing common diagnoses. In the validation cohort, the proportion of patients assigned to each cluster was similar and demonstrated significant differences across clusters for all variables. Conclusions A machine learning approach revealed important differences between empirically-derived subgroups of ICU patients that are not typically revealed by admitting diagnosis or severity of illness alone. Similar data-driven approaches may provide a framework for future organizational innovations in ICU care tailored around patients’ shared needs.
Purpose: We investigated the gefitinib, 5-fluorouracil (5-FU), leucovorin and oxaliplatin (IFOX) regimen as first-line therapy in patients with metastatic colorectal cancer. Experimental Design: Eligible patients had stage IV colorectal adenocarcinoma, and had not received prior chemotherapy for metastatic disease. Each cycle consisted of 14 days. Cycle 1 consisted of oxaliplatin, leucovorin, and 5-FU (FOLFOX-4). All subsequent cycles consisted of FOLFOX-4 with gefitinib at 500 mg orally daily throughout the 14-day cycle. Results: Forty-five patients were enrolled and were assessable for toxicity. Forty-three patients were assessable for response.Thirty-one of the 43 patients (72%) had either a complete or partial response by the Response Evaluation Criteria in Solid Tumors. Median overall survival was 20.5 months. Median time to progression was 9.3 months. Commonly encountered grade 3 or 4 toxicities included diarrhea in 67% of patients and neutropenia in 60%. Grade 2 acneiform skin rash typical of gefitinib occurred in 60% of patients. Conclusions: IFOX is an active first-line regimen in patients with metastatic colorectal adenocarcinoma, showing higher response rates but also increased toxicities compared with FOLFOX-4 alone in a similar patient population.Over the last 10 years, incremental gains in response rates and the median survival for patients with metastatic colorectal cancer have been achieved with the introduction of active new chemotherapeutic and biologically targeted agents. Combinations of irinotecan or oxaliplatin with 5-fluorouracil (5-FU) and leucovorin for first-line therapy of metastatic colorectal cancer have shown improved response rates and median survival times over 5-FU and leucovorin alone (1, 2). In addition, infusional 5-FU has replaced bolus 5-FU as a platform for combination chemotherapy based on decreased toxicity and improved efficacy (3,4). In the initial study investigating the combination of oxaliplatin, 5-FU, and leucovorin (FOLFOX-4) for first-line therapy of metastatic colorectal cancer, there was a 50% objective response rate compared with 22% with infusional 5-FU/leucovorin alone (2). The FOLFOX-4 regimen was also associated with a longer time to progression (9.0 months versus 6.2 months) and a trend toward improved overall survival. Although a direct comparison of FOLFOX-4 and irinotecan, 5-FU, and leucovorin in previously untreated patients showed that FOLFOX-4 was superior, a subsequent comparison of FOL-FOX-6 and folinic acid, 5-FU, and irinotecan showed no significant difference in efficacy (5, 6). This confirmed that both irinotecan and oxaliplatin are active agents against colorectal cancer, and selection of an appropriate regimen could focus on their different toxicity profiles.The effort to further improve the efficacy and tolerability of treatment for metastatic colorectal cancer has led to the discovery of new agents targeting cell-signaling molecules such as epidermal growth factor receptor (EGFR). EGFR expression has been shown in 60% to 80% of ...
BCR/ABL is associated with an unfavorable prognosis in adults with acute lymphoblastic leukemia (ALL). We used DNA microarrays to identify gene expression profiles and molecular interaction networks related to BCR/ABL status and clinical outcome in a set of 54 adult ALL specimens from the MRC UKALL XII/ECOG E2993 intergroup study (21 p185BCR/ABL- and 16 p210BCR/ABL-positive and 17 BCR/ABL negative). In order to avoid biases associated with commonly used sample amplification procedures, we have implemented an indirect two-step labeling protocol based on signal amplification by use of dendrimer technology. Using a two-class, non-parametric t-test and a false discovery rate cutoff of 5%, we identified 271 genes (including GAB1, CIITA, XBP1, CD83, SERPINB9, PTP4A3, NOV, LOX, CTNND1, BAALC and RAB21) as differentially expressed in BCR/ABL positive ALL compared with BCR/ABL negative ALL. They separate these two classes of adult ALL with an overall accuracy of 93% and are enriched for three highly relevant biological functions: Cellular Growth and Proliferation (57 genes, p = 0.004–0.044), Cell Death (49 genes, p = 0.0007–0.049), and Hematological System Development and Function (40 genes, p = 0.00004–0.049). Network analysis demonstrated complex interaction patterns of these genes, and identified FYN and IL15 as the hubs of the top-scoring network. We confirmed these findings by both qRT-PCR analysis of the initial set of samples and by cross-platform validation in an independent cohort of 128 adult ALL specimens. In addition, within the BCR/ABL positive subgroup, we identified 14 clones found to be over-expressed (TSPAN16, ADAMTSL4) or under-expressed (PILRB, STS-1, SPRY1) in p185BCR-ABL- relative to p210BCR-ABL-ALL. In a nearest-centroid classification, these clones correctly predict the BCR/ABL subtype with a cross-validated prediction accuracy of 95%. No differential gene expression was detected among Rho family GTPases and their known interaction partners. Finally, we constructed a gene expression- and interaction-based outcome predictor consisting of 27 genes (including GRB2, GAB1, GLI1, IRS1, RUNX2 and SPP1), which strongly correlated with overall survival in BCR/ABL positive adult ALL (p=0.0001), independently of other clinical parameters such as age (p=0.25) and white blood cell count at presentation (p = 0.003). These findings may be useful for developing novel therapeutic targets and prognostic markers in adult ALL.
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