To improve cancer therapy, it is critical to target metastasizing cells. Circulating tumor cells (CTCs) are rare cells found in the blood of patients with solid tumors and may play a key role in ...cancer dissemination. Uncovering CTC phenotypes offers a potential avenue to inform treatment. However, CTC transcriptional profiling is limited by leukocyte contamination; an approach to surmount this problem is single cell analysis. Here we demonstrate feasibility of performing high dimensional single CTC profiling, providing early insight into CTC heterogeneity and allowing comparisons to breast cancer cell lines widely used for drug discovery.
We purified CTCs using the MagSweeper, an immunomagnetic enrichment device that isolates live tumor cells from unfractionated blood. CTCs that met stringent criteria for further analysis were obtained from 70% (14/20) of primary and 70% (21/30) of metastatic breast cancer patients; none were captured from patients with non-epithelial cancer (n = 20) or healthy subjects (n = 25). Microfluidic-based single cell transcriptional profiling of 87 cancer-associated and reference genes showed heterogeneity among individual CTCs, separating them into two major subgroups, based on 31 highly expressed genes. In contrast, single cells from seven breast cancer cell lines were tightly clustered together by sample ID and ER status. CTC profiles were distinct from those of cancer cell lines, questioning the suitability of such lines for drug discovery efforts for late stage cancer therapy.
For the first time, we directly measured high dimensional gene expression in individual CTCs without the common practice of pooling such cells. Elevated transcript levels of genes associated with metastasis NPTN, S100A4, S100A9, and with epithelial mesenchymal transition: VIM, TGFß1, ZEB2, FOXC1, CXCR4, were striking compared to cell lines. Our findings demonstrate that profiling CTCs on a cell-by-cell basis is possible and may facilitate the application of 'liquid biopsies' to better model drug discovery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To assess the spectrum and reversibility of the cardiotoxicity observed in the adjuvant trastuzumab trials.
The design and efficacy of the major adjuvant trastuzumab trials was assessed, including ...the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group N9831, Herceptin Adjuvant, Breast Cancer International Research Group 006, and Finland Herceptin trials. The cardiotoxicity data were evaluated with a focus on the follow-up cardiac evaluations of women who were diagnosed with cardiotoxicity. Proposed mechanisms of trastuzumab-related cardiotoxicity were considered. The natural history of congestive heart failure (CHF) was reviewed with the goal of placing the trastuzumab experience in context.
Up to 4% of patients enrolled onto the adjuvant trastuzumab trials experienced severe CHF during treatment. In these trials, early stopping rules that identified an unacceptable level of cardiotoxicity were never reached. Despite this, a large number of patients on these trials experienced some form of cardiotoxicity that ultimately required discontinuation of trastuzumab. Approximately 14% of patients in the NSABP B-31 trial discontinued trastuzumab because of asymptomatic decreases in left ventricular ejection fraction (LVEF). Results of follow-up cardiac evaluations of patients diagnosed with any degree of cardiotoxicity in the NSABP B-31 trial document that a clinically significant proportion of patients have sustained decrements in their LVEF to less than 50%.
Adjuvant trastuzumab provides substantial benefits to patients with human epidermal growth factor receptor 2-positive breast cancer, however, competing immediate and long-term cardiovascular risks are a great concern. Continued cardiac follow-up of these women is of critical importance.
Objective
The objective was to compare first‐attempt intubation success using direct laryngoscopy augmented by laryngeal manipulation, ramped patient positioning, and use of a bougie (A‐DL) with ...unaided video laryngoscopy (VL) in adult emergency department (ED) intubations.
Methods
This study was a secondary analysis of a multicenter prospective observational database of ED intubations from the National Emergency Airway Registry (NEAR). We compared all VL procedures to seven exploratory permutations of A‐DL using multivariable regression models. We further stratified by blade shape into hyperangulated VL (HA‐VL) and standard‐geometry VL (SG‐VL). We report differences in first‐attempt intubation success and peri‐intubation adverse events with cluster‐adjusted odds ratios (ORs) with 95% confidence intervals (CIs). We report univariate comparisons in patient characteristics, difficult airway attributes, and intubation methods using descriptive statistics and OR with 95% CI.
Results
We analyzed 11,714 intubations performed from January 1, 2016, through December 31, 2017. Of these encounters, 6,938 underwent orotracheal intubation with either A‐DL or unaided VL on first attempt. A‐DL was used first in 3,936 (56.7%, 95% CI = 46.9 to 66.5) versus unaided VL in 3,002 (43.3%, 95% CI = 33.5 to 53.1). Of the A‐DL first intubations 1,787 (45.4%) employed ramped positioning alone, 1,472 (37.4%) had external laryngeal manipulation (ELM), and 365 (9.3%) used a bougie. Rapid sequence intubation (RSI) was the most common method used in 5,602 (80.8%, 95% CI = 77.0 to 84.5) cases. First‐attempt success was significantly higher with all VL (90.9%, 95% CI = 88.7 to 93.1) versus all A‐DL (81.1%, 95% CI = 78.7 to 83.5) despite the VL group having more patients with reduced mouth opening, neck immobility, and an initial impression of airway difficult. Multivariable regression analyses controlling for indication, method, operator specialty and year of training, center clustering, and all registry‐recorded difficult airway predictors revealed first‐attempt success was higher with all unaided VL compared with any A‐DL (adjusted OR AOR = 2.8, 95% CI = 2.4 to 3.3), DL with bougie (AOR = 2.7, 95% CI = 2.1 to 3.5), DL with ELM (AOR = 1.8, 95% CI = 1.5 to 2.2), DL with ramped positioning (AOR = 2.8, 95% CI = 2.3 to 3.3), or DL with ELM plus bougie (AOR = 2.8, 95% CI = 2.3 to 3.3). Subgroup analyses of HA‐VL and SG‐VL compared with any A‐DL yielded similar results (AOR = 3.2, 95% CI = 2.6 to 3.0; and AOR = 2.4, 95% CI = 1.9 to 3.0, respectively). The propensity score–adjusted odds for first‐attempt success with VL was also 2.8 (95% CI = 2.4 to 3.3). Fewer esophageal intubations were observed in the VL cohort (0.4% vs. 1.3%, AOR = 0.2, 95% CI = 0.1 to 0.5).
Conclusions
Video laryngoscopy used without any augmenting maneuver, device, or technique results in higher first‐attempt success than does DL that is augmented by use of a bougie, ELM, ramping, or combinations thereof.
The NCCN 2022 Annual Conference Carlson, Robert W; Koh, Wui-Jin
Journal of the National Comprehensive Cancer Network,
06/2022, Letnik:
20, Številka:
5.5
Journal Article
There is a lack of treatments providing survival benefit for patients with metastatic triple-negative breast cancer (mTNBC), with no standard of care. A randomized phase II trial showed significant ...benefit for gemcitabine, carboplatin, and iniparib (GCI) over gemcitabine and carboplatin (GC) in clinical benefit rate, response rate, progression-free survival (PFS), and overall survival (OS). Here, we formally compare the efficacy of these regimens in a phase III trial.
Patients with stage IV/locally recurrent TNBC who had received no more than two previous chemotherapy regimens for mTNBC were randomly allocated to gemcitabine 1,000 mg/m(2) and carboplatin area under the curve 2 (days 1 and 8) alone or GC plus iniparib 5.6 mg/kg (days 1, 4, 8, and 11) every 3 weeks. Random assignment was stratified by the number of prior chemotherapies. The coprimary end points were OS and PFS. Patients receiving GC could cross over to iniparib on progression.
Five hundred nineteen patients were randomly assigned (261 GCI; 258 GC). In the primary analysis, no statistically significant difference was observed for OS (hazard ratio HR = 0.88; 95% CI, 0.69 to 1.12; P = .28) nor PFS (HR = 0.79; 95% CI, 0.65 to 0.98; P = .027). An exploratory analysis showed that patients in the second-/third-line had improved OS (HR = 0.65; 95% CI, 0.46 to 0.91) and PFS (HR = 0.68; 95% CI, 0.50 to 0.92) with GCI. The safety profile for GCI was similar to GC.
The trial did not meet the prespecified criteria for the coprimary end points of PFS and OS in the ITT population. The potential benefit with iniparib observed in second-/third-line subgroup warrants further evaluation.
NCCN Evidence Blocks Carlson, Robert W; Jonasch, Eric
Journal of the National Comprehensive Cancer Network,
05/2016, Letnik:
14, Številka:
5 Suppl
Journal Article
Recenzirano
Odprti dostop
NCCN has developed a series of Evidence Blocks: graphics that provide ratings for each recommended treatment regimen in terms of efficacy, toxicity, quality and consistency of the supporting data, ...and affordability. The NCCN Evidence Blocks are currently available in 10 tumor types within the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). At a glance, patients and providers can understand how a given treatment was assessed by the NCCN Guidelines Panel and get a sense of how a given treatment may match individual needs and preferences. Robert W. Carlson, MD, CEO of NCCN, described the reasoning behind this new feature and how the tool is used, and Eric Jonasch, MD, Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center, and Vice Chair of the NCCN Kidney Cancer Panel, described its applicability in the management of metastatic renal cell carcinoma.
We demonstrate the versatility of a collection of insertions of the transposon Minos-mediated integration cassette (MiMIC), in Drosophila melanogaster. MiMIC contains a gene-trap cassette and the ...yellow+ marker flanked by two inverted bacteriophage ΦC31 integrase attP sites. MiMIC integrates almost at random in the genome to create sites for DNAmanipulation. The attP sites allow the replacement of the intervening sequence of the transposon with any other sequence through recombinase-mediated cassette exchange (RMCE). We can revert insertions that function as gene traps and cause mutant phenotypes to revert to wild type by RMCE and modify insertions to control GAL4 or QF overexpression systems or perform lineage analysis using the Flp recombinase system. Insertions in coding introns can be exchanged with protein-tag cassettes to create fusion proteins to follow protein expression and perform biochemical experiments. The applications of MiMIC vastly extend the D. melanogaster toolkit.
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