ED staff lack adequate exposure to critical pediatric patients to develop competence and confidence in resuscitation scenarios. Simulations of various designs have shown success at increasing health ...care staff performance and self-efficacy.
We developed a nurse-led, low-fidelity in situ simulation of a pediatric sepsis scenario. The primary goal was to improve staff adherence to resuscitation guidelines, as measured by the Clinical Performance Tool, a set of checklists designed to measure adherence to Pediatric Advanced Life Support algorithms by multidisciplinary teams during simulations. The secondary goal was to improve staff confidence, measured by the Confidence Scale, a 5-item Likert-type scale that can measure any psychomotor skill.
A total of 43 RNs participated in 12 simulations over a period of 3 months. Mean Clinical Performance score improved by 74%, from 5.3 to 9.2 (P < 0.001). Mean confidence score for RNs improved by 56%, from 2.48 (standard deviation SD 0.83) to 3.88 (SD 0.66) (P < 0.001). Several systems issues were identified and addressed by multidisciplinary teams, such as increasing respiratory therapist response to the emergency department and updating of the Broselow cart.
In situ low-fidelity simulations led by RNs contributed to significant improvement in adherence to resuscitation guidelines and in staff confidence. The simulation design had minimal impact on staffing and budget and enabled identification and correction of systems issues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MYCN activates canonical MYC targets involved in ribosome biogenesis, protein synthesis, and represses neuronal differentiation genes to drive oncogenesis in neuroblastoma (NB). How MYCN orchestrates ...global gene expression remains incompletely understood. Our study finds that MYCN binds promoters to up-regulate canonical MYC targets but binds to both enhancers and promoters to repress differentiation genes. MYCN binding also increases H3K4me3 and H3K27ac on canonical MYC target promoters and decreases H3K27ac on neuronal differentiation gene enhancers and promoters. WDR5 facilitates MYCN promoter binding to activate canonical MYC target genes, whereas MYCN recruits G9a to enhancers to repress neuronal differentiation genes. Targeting both MYCN's active and repressive transcriptional activities using both WDR5 and G9a inhibitors synergistically suppresses NB growth. We demonstrate that MYCN cooperates with WDR5 and G9a to orchestrate global gene transcription. The targeting of both these cofactors is a novel therapeutic strategy to indirectly target the oncogenic activity of MYCN.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in ...patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure. We compare patients achieving sustained minimal residual disease (MRD) negativity to patients who never achieved or were unable to maintain MRD negativity. We observe that the composition of the immune microenvironment in both the blood and the marrow varied substantially according to both MRD negative status and history of autologous stem cell transplant, supporting the hypothesis that the immune microenvironment influences the depth and duration of treatment response.
Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical ...trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (>99%) and specificity (>99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53. In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.
Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd ...and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48-64%) for VRd and 67% (60-75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27-42%) for VRd and 52% (45-60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75-87%) and 90% (85-95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60-78%) for VRd and 75% (65-85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81-94%) and 93% (87-99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8-61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24-51%) and 69% (58-82%) for VRd and 58% (47-71%) and 88% (80-97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.
Summary
Matrix‐assisted laser desorption ionisation time‐of‐flight mass spectrometry (MALDI‐TOF MS) may soon replace routine electrophoretic methods for monitoring monoclonal proteins in patients ...with multiple myeloma. To further evaluate the clinical utility of this assay, we compared the performance of MALDI‐TOF‐MS head‐to‐head with an established bone marrow‐based measurable residual disease assay by flow cytometry (Flow‐BM‐MRD), using Memorial Sloan Kettering Cancer Center’s 10‐color, single‐tube method. Our results suggest that MALDI‐TOF‐MS adds value to bone marrow‐based MRD testing and may be most useful for early detection of relapse in peripheral blood compared to current electrophoretic methods.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•The highest M−protein detection rates occur with MALDI-TOF MS plus FLC measurement.•MALDI-TOF MS can help accurately determine complete response status in patients.•Daratumumab can be distinguished ...from the M−protein in most samples by MALDI-TOF MS.•Relative concentration and mass difference matters for distinguishing proteins.
Daratumumab-based combination therapies have shown high rates of complete response (CR) and minimal residual disease negativity in patients with multiple myeloma. However, daratumumab, an IgGκ monoclonal antibody, interferes with electrophoretic techniques making it difficult to reliably define residual disease versus CR, especially in patients with IgGκ multiple myeloma.
Enrichment with polyclonal sheep antibody-coated magnetic microparticles combined with MALDI-TOF mass spectrometry (MALDI-TOF MS) analysis was used to detect M−proteins in serial samples from newly diagnosed multiple myeloma patients treated with daratumumab-based therapy. The performance of the MALDI-TOF MS assay was compared to that of a routine test panel (serum protein electrophoresis (SPEP), immunofixation (IFE) and serum free light chain (FLC)).
Comparison of MALDI-TOF MS to SPEP/IFE/FLC showed a concordance of 84.9% (p < 0.001). When MALDI-TOF MS and FLC results were combined, the M−protein detection rate was the same or better than the routine test panel. For the 9 patients who obtained CR during follow-up, MALDI-TOF MS detected an M−protein in 46% of subsequent samples. Daratumumab could be distinguished from the M−protein in 215/222 samples.
MALDI-TOF MS is useful in assessing CR in patients treated with monoclonal antibody-based therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
e20005
Background: DARA has been FDA approved for newly diagnosed multiple myeloma (NDMM) in combination with lenalidomide/dexamethasone (Rd), bortezomib/melphalan/dex, and bortezomib/thalidomide/dex ...since 2018. With the increase use of DARA combinations in NDMM, understanding the role of DARA retreatment at relapse needs to be examined in clinical practice. Herein, we describe a single institution experience of the efficacy of DARA-based retreatment as second line of therapy (LOT2) for patients (pts) who received DARA-based induction compared to DARA-free induction regimens. Methods: Thirty-three pts treated with DARA-based LOT2 at MSK from 1/2015 to 9/2021 were included in this retrospective analysis. Primary endpoint was overall response rate (ORR; ≥PR by IMWG criteria). Discrete patient characteristics were summarized by frequency (percentage) and continuous characteristics were summarized by median (IQR). Progression free survival (PFS) was evaluated by Kaplan-Meier method. Results: Two cohorts were identified based on prior DARA exposure: cohort 1 (N=6) received DARA-based induction without meeting DARA-refractory criteria and cohort 2 (N=27) had carfilzomib and Rd (KRd) induction (Table). Median follow-up was 13.8 and 14.5 months for cohorts 1 and 2, respectively. In cohort 1, 5 pts received DARA-KRd and 1 had DRd as first line therapy (LOT1). Median time between last dose of DARA in LOT1 and first dose of DARA in LOT2 was 17.5 months (IQR 12.1-19.8). ORR were 83% and 79% for cohorts 1 and 2, respectively. In cohort 1, ORR comprised of 1 sCR, 1 VGPR, and 3 PR. For cohort 2, there were 5 sCR/CR, 7 VGPR, and 9 PR. Median PFS was not reached in cohort 1 and 16.2 months in cohort 2. Conclusions: In a cohort of pts retreated with DARA after DARA-based induction, our findings suggest that DARA-exposed MM pts may derive benefit from DARA retreatment in subsequent lines of therapy similarly to pts who were DARA-naïve prior to DARA-based LOT2. Longer follow-up is needed to assess survival outcomes. In addition, larger confirmatory studies are warranted to further characterize response characteristics of DARA combinations in LOT2, especially as DARA-based therapy is increasingly used in treating NDMM. Table: see text
Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for ...example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes.
We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography-mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant.
At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02).
This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.
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