Publications
Department of Medicine faculty members published more than 3,600 peer-reviewed articles in 2024.
2017
2017
2017
2017
Droplet single-cell RNA-sequencing (dscRNA-seq) has enabled rapid, massively parallel profiling of transcriptomes. However, assessing differential expression across multiple individuals has been hampered by inefficient sample processing and technical batch effects. Here we describe a computational tool, demuxlet, that harnesses natural genetic variation to determine the sample identity of each droplet containing a single cell (singlet) and detect droplets containing two cells (doublets). These capabilities enable multiplexed dscRNA-seq experiments in which cells from unrelated individuals are pooled and captured at higher throughput than in standard workflows. Using simulated data, we show that 50 single-nucleotide polymorphisms (SNPs) per cell are sufficient to assign 97% of singlets and identify 92% of doublets in pools of up to 64 individuals. Given genotyping data for each of eight pooled samples, demuxlet correctly recovers the sample identity of >99% of singlets and identifies doublets at rates consistent with previous estimates. We apply demuxlet to assess cell-type-specific changes in gene expression in 8 pooled lupus patient samples treated with interferon (IFN)-β and perform eQTL analysis on 23 pooled samples.
View on PubMed2017
BACKGROUND
In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.
METHODS
In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
RESULTS
Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
CONCLUSIONS
In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
View on PubMed2017
2017
2017
2017
PURPOSE
Clinical pathways increase compliance with treatment guidelines, improve outcomes, and reduce costs. Guidelines recommend single fraction radiation therapy (SFRT) for palliation of uncomplicated bone metastases, but implementation is variable. We examined the effects of a pathway tool on SFRT rates in an academic radiation oncology practice.
METHODS AND MATERIALS
Using published literature, clinical guidelines, and expert input, we designed a clinical pathway for bone metastases radiation therapy displayed on a Web-based electronic interface. In March 2016, the pathway launched on a palliative radiation service at the Dana Farber/Brigham and Women's Cancer Center main campus and at affiliated community sites. Providers were surveyed pre- and postimplementation to assess expectations and elicit feedback. Rates of pathway utilization, compliance with SFRT recommendations, and reasons for noncompliance were assessed.
RESULTS
The final pathway includes 20 endpoints and several validated prognostic scoring systems. It was used in 38% of 723 bone metastases radiation prescriptions, with appropriate SFRT rates rising from 18% before implementation to 48% after launch (P < .01). Major reasons for rejecting recommendations included disagreement with life expectancy prognostication and patient convenience. The pathway increased physicians' confidence regarding compliance with treatment guidelines and made it easier to find well-supported treatment recommendations. Workflow disruptions and the inability to handle nuanced situations emerged as limitations.
CONCLUSIONS
Our experience demonstrates the utility of clinical pathway decision support for bone metastases radiation in complex academic settings. Next steps include increasing the pathway's ease of use, refining the pathway's prognostic abilities, and measuring cost savings related to the pathway.
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