Similar to the responses of attending physicians in the ACEP research network study, 71% of residents experienced “excessive pushback on seeing or admitting patients”, and 90% of respondents were ...aware of at least one instance where patient care was negatively affected by poor consultant interactions. Taking into account the adverse impact on patient care and emergency physician wellness, there are steps that could be considered to reduce abuse in the emergency department. Emergency physicians would benefit from local, regional, and national organizations undertaking additional action to further investigate the scope of the problem and to work with hospital system administrators to create more clear structures through which physicians can report abuse.
Background
Cytomegalovirus‐specific T‐cell‐mediated immunity (CMV‐CMI) protects from CMV infection in allogeneic hematopoietic cell transplantation (allo‐HCT), but to date, there is no validated ...measure of CMV immunity for this population.
Methods
In this prospective, observational, pilot study, CMV T‐cell responses were evaluated monthly and at onset of graft‐versus‐host disease (GVHD) or CMV infection in CMV‐seropositive allo‐HCT recipients using a commercial flow cytometry assay, the CMV inSIGHT T‐Cell Immunity Panel (CMV‐TCIP). The primary endpoint was the time to first positive CMV‐TCIP, defined as percentage of interferon‐γ‐producing CD4+ or CD8+ CMV‐specific T cells >0.2%. Letermovir was prescribed from day +10 to ≥100.
Results
Twenty‐eight allo‐HCT recipients were enrolled. The median time to first positive CMV‐TCIP result was earlier for CD4+ (60 days interquartile range, IQR 33‒148) than for CD8+ T cells (96 days IQR 33‒155) and longer for haploidentical and mismatched transplant recipients (77 and 96 days, respectively) than for matched donors (45 and 33 days, respectively). CD4+ and CD8+ CMV‐CMI recovery was sustained in 10/10 (100%) and 10/11 (91%) patients, respectively, without GVHD, whereas CD4+ and/or CD8+ CMV‐CMI was lost in 4/6 and 2/6 patients, respectively, with GVHD requiring steroids. As a predictor of clinically significant CMV infection in patients with low‐level CMV reactivation, the sensitivity and negative predictive value of CMV‐TCIP were 90% and 87.5%, respectively, for CD4+ CMV‐TCIP and 66.7% and 62.5%, respectively, for CD8+ CMV‐TCIP.
Conclusions
There was significant variability in time to CMV‐CMI recovery post‐HCT, with slower recovery after haploidentical and mismatched HCT. CD4+ CMV‐CMI may protect against CS‐CMVi, but immunity may be lost with GVHD diagnosis and treatment.
In this single‐center, pilot study, we prospectively evaluated cytomegalovirus‐specific T‐cell‐mediated immunity (CMV‐CMI) in allogeneic hematopoietic cell transplantation recipients using a commercially available US flow cytometry assay. CMV‐CMI recovery was slower in haploidentical and mismatched donors receiving post‐transplant cyclophosphamide compared to matched donors, and CD4+ CMV‐CMI was lost with graft‐versus‐host disease diagnosis and treatment.
Background: Despite advances in novel myeloma treatments and autologous hematopoietic stem cell transplantation (ASCT), allogeneic HSCT (alloSCT) remains the only curative option for patients (pts) ...with multiple myeloma (MM). Questions remain as to the timing of alloSCT, toxicity risks and optimal conditioning regimen. The addition of bortezomib (Vel) to fludarabine (Flu) and melphalan (Mel) for conditioning prior to alloSCT is based on the demonstrated safety of Vel in combination with melphalan prior to ASCT, the synergistic effect of Vel with Mel, and the ability of Vel to selectively eliminate allo-reactive T-cells.
Methods: We present a prospective Phase II study using Flu/Mel/Vel (FMV) as a conditioning regimen for alloSCT. The primary endpoint is overall survival (OS), and secondary endpoints include progression free survival (PFS), incidence of graft-versus-host disease (GVHD) and transplant related mortality (TRM). For related donors, the conditioning regimen was Flu 30 mg/m2 days -5, -4, -3, -2, Vel 1.6 mg/m2 days -4, -1, Mel 140 mg/m2 day -2. For unrelated donors, rabbit ATG 4 mg/kg was given in divided doses days -3, -2, -1. GVHD prophylaxis consisted of methotrexate and tacrolimus. We compared pts receiving FMV to historical controls of pts receiving FM at the same dose and schedule without Vel. We also compared pts receiving FMV to all pts with MM treated with alloSCT including all regimens and donor types.
The response criteria from the IMWG and M-Smart criteria were used to determine response and risk, respectively. Chi-square tests of association and Wilcoxon rank sum tests were performed to test for differences across groups. OS/PFS probabilities were calculated using the Kaplan-Meier product limit estimator with log rank-tests. Multivariate Cox proportional hazard models examined factors associated with OS/PFS.
Results: Of the 54 pts who received FMV, 35 (65%) were male and the median age was 56 years. Twenty-seven pts had an HLA matched sibling donor and 27 had an unrelated donor. At the time of alloSCT, 5 pts were in a CR, 27 in a VGPR, 13 in a PR, 9 had < PR. Twenty eight pts (52%) had high risk disease. Twenty-nine pts (53%) received alloSCT as salvage, defined as relapsed or refractory to ASCT, and 25 pts (46%) as consolidation after ASCT. OS was 42% at 10 years. While 32 pts developed aGVHD, only 2 had ≥ Grade 3. Of the 31 pts who developed cGVHD, 23 were graded as extensive. TRM was 5% at day 100, and 15% over 10 years.
Pts in the control groups had similar baseline characteristics to the FMV group. The only significant difference was 47 pts (72%) who received FM were transplanted as salvage, and 18 (28%) as consolidation after ASCT (p=0.035). The total number of pts who did not receive FMV (non FMV) was 121, with 66 pts receiving FM. Compared to pts who received FMV, there was no difference in OS for pts who received FM or the non FMV group, 35% (p=0.55) and 48% (p=0.855) respectively. There was no difference in pts who developed aGVHD, however 9 pts (13%) had ≥ grade 3 aGVHD in the FM group (p=0.004) and 15 (12%) in the non FMV group (p=0.006). The cumulative incidence of cGVHD was similar with 51% for pts receiving FM and 60% for FMV pts (p=0.32). TRM was similar to pts who had received FMV; 18% for FM and 17% for non FMV. There were no differences between the 3 groups across disease risk, donor type, or disease status at the time of alloSCT. Multivariate analysis of the 3 groups, shows achieving a CR after alloSCT (p=0.0006) or having cGVHD (p=0.0004) predicts for improved OS, while severe aGVHD (p=0.0002) predicts for decreased OS.
Discussion: While FMV was associated with a lower incidence of severe aGVHD, the addition of bortezomib to the FM backbone did not improve PFS or OS. Day 100 TRM was low for all regimens, and the addition of Vel did not impact overall TRM. For all 175 pts, those who achieve a CR after alloSCT had a significantly improved OS. This prompts the question of whether strategies should be employed post alloSCT to maximize response to a CR, and the role of achieving MRD negativity after alloSCT also needs to be elucidated.
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Siegel:BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Biran:Amgen: Consultancy, Speakers Bureau; BMS: Research Funding; Merck: Research Funding; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Skarbnik:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
The use of ASCT is highly established as consolidation or salvage for multiple myeloma (MM) and post salvage therapy in non-Hodgkin Lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) ...with chemosensitive disease, as well as upfront consolidation in PTCL given poor outcomes after standard therapy (Philip et al., NEJM 1995, Kewalramani et al., Br J Haematol 2006, Gisselbrecht et al., J Clin Oncol 2010, Kumar et al., Leukemia 2012). Although a significant number of pts experience long-term disease-free survival following ASCT, those with high-risk disease (i.e.high-risk cytogenetics in MM, primary refractory DLBCL) are likely to present early relapses, particularly in the first 18 months post-ASCT, illustrating the need for better disease control strategies following ASCT. The rapidly rising impact of checkpoint inhibitors in oncology provides an opportunity for its usage as post-ASCT consolidation, especially given the favorable immunologic milieu found in the immediate post-ASCT setting (i.e. decreased T-regs, increased effector T-cells) and minimal expected tumor burden at that time. Here, we report preliminary safety and efficacy data of a Phase I trial evaluating I and N as post-ASCT consolidation.
Pts with the following malignancies were eligible, if they presented at least stable disease after most recent line of therapy: DLBCL: primary refractory or relapsed, PTCL: de novo stage III/IV or relapsed, MM: transplant-naïve with high-risk cytogenetics or relapse within 3 years of upfront ASCT.
Pts were enrolled prior to ASCT, starting in July 2016. Total accrual goal is 42 patients. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1.
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), I/N were started between days 14 and 28 post ASCT. The infusion schedule was:
• I: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
• N: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
At this time, 25 patients have been enrolled and received at least one dose of I/N. Additional pts are in screening and results will be updated.
Median follow-up from time of first I/N infusion is 24 weeks (range 2-49). Adverse events (AEs) were documented starting week 1, day 1 of I/N infusion. AEs deemed at least possibly related to I and/or N were termed immune-related (irAEs) with 80% of pts developing irAEs of any grade (table 1). Treatment-related AEs of any grade that led to discontinuation of I/N occurred in 6 pts (24% total: colitis 12%, pneumonitis 4%, adrenal crisis 4% and hepatotoxicity 4%). One death attributable to I/N occurred (due to recurrent pneumonitis complicated by parainfluenza). Therapy with systemic steroids for management of irAEs was required for 19 pts (76%). 70% of irAEs improved within one week and 65% resolved within 2 weeks of initiation of steroids. Median time on treatment with I/N for development of irAEs was 9 weeks (range 2-25). For pts who discontinued treatment due to toxicity, the median time on I/N was 5 weeks (range 3-14). Incidence of irAEs was similar across disease groups.
With a median follow-up of 24 weeks, OS is 92% and PFS is 88% for the entire cohort. 100% of the pts with relapsed MM after first ASCT (50% of whom had less than CR to 1st ASCT) are now in stringent complete remission (sCR). 100% of pts with primary refractory DLBCL are in CR (table 2).
The toxicity profile of consolidation with I/N following ASCT was within expectations. Although there has been a significant number of irAEs (80%) given the mechanism of action of these drugs, this rate is not higher than what has been previously reported with I/N combination in other disease settings (Larkin et al., NEJM 2015, Postow et al., NEJM 2015) and all patients except 1 had resolution of irAEs with the use of systemic steroids . With a median follow-up of 6 months, 84% of pts across disease groups are in complete remission. Interestingly, 5 of 6 patients who had early discontinuation due to AEs, presented sustained remission. Correlative studies evaluating blood immunophenotype are being reported in a separate abstract.
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Skarbnik:Novartis: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siegel:Merck: Consultancy; Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Richter:Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feldman:Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Consultancy; AbbVie: Speakers Bureau. Leslie:seattle genetics: Speakers Bureau; KITE pharma: Speakers Bureau; celgene: Speakers Bureau. McKiernan:Novartis: Speakers Bureau. McNeill:pharmacyclics: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Osteoarthritis (OA) is the most common form of arthritis and has multiple risk factors including joint injury. The purpose of this study was to characterize the histologic development of OA in a ...mouse model where OA is induced by destabilization of the medial meniscus (DMM model) and to identify genes regulated during different stages of the disease, using RNA isolated from the joint "organ" and analyzed using microarrays. Histologic changes seen in OA, including articular cartilage lesions and osteophytes, were present in the medial tibial plateaus of the DMM knees beginning at the earliest (2 week) time point and became progressively more severe by 16 weeks. 427 probe sets (371 genes) from the microarrays passed consistency and significance filters. There was an initial up-regulation at 2 and 4 weeks of genes involved in morphogenesis, differentiation, and development, including growth factor and matrix genes, as well as transcription factors including Atf2, Creb3l1, and Erg. Most genes were off or down-regulated at 8 weeks with the most highly down-regulated genes involved in cell division and the cytoskeleton. Gene expression increased at 16 weeks, in particular extracellular matrix genes including Prelp, Col3a1 and fibromodulin. Immunostaining revealed the presence of these three proteins in cartilage and soft tissues including ligaments as well as in the fibrocartilage covering osteophytes. The results support a phasic development of OA with early matrix remodeling and transcriptional activity followed by a more quiescent period that is not maintained. This implies that the response to an OA intervention will depend on the timing of the intervention. The quiescent period at 8 weeks may be due to the maturation of the osteophytes which are thought to temporarily stabilize the joint.
Abstract only
Introns are non‐coding RNAs that are readily degraded into single nucleotides within the nucleus where they can be recycled in another transcription cycle. Unspliced introns form 3‐D ...structures at their 5′ end, never separate from their splicing factors and are stable during and after pre‐mRNA modifications
(4)
. Recently it was observed that retention of introns in
Saccharomyces cerevisiae
increases when the cells are in a nutrient deficient environment, specifically stationary phase
(3
,
4
,
5)
. Transcriptomic and genetic analyses showed that intron retention promotes resistance to starvation by downregulating ribosomal protein genes downstream of nutrient‐sensing TORC1 and PKA pathways
(3)
. Yeast cells that cannot synthesize introns or have a low concentration of them fail to survive in stationary phase, suggesting that introns are necessary for the survival of the organism during starvation. Rrp6p is a 3′→5′ RNA exonuclease that associates with the nuclear exosome
(1)
. This complex participates in 3′ end formation and degradation of a variety of non‐coding RNAs and unstable transcripts
(1
,
2)
. We hypothesized that yeast cells lacking Rrp6p will retain more introns than a wild type strain, thus transcriptome analysis of this strain during starvation conditions will lead to a better understanding of intron retention. We monitored the growth of WT and rrp6‐Δ strains during prolonged stationary phase and the subsequent lag, log phases following placement into fresh media. This analysis identified the time frame at which each strain exited stationary phase and entered log phase. We collected RNA from each strain during stationary phase and early log phase and performed transcriptome analysis. Data analysis was performed using the scripting program, R, to identify introns whose expression significantly changes. Introns identified from this analysis will be confirmed using quantitative PCR.
Support or Funding Information
SJFC internal funds
The clinical impact of vascular invasion in Papillary Thyroid Carcinoma (PTC) is not well understood. Our aim was to determine if there was an association between vascular invasion and other tumor ...characteristics and patient outcomes in PTC.
A retrospective chart review was performed of 536 patients with PTC between January 2007–December 2011. Patient demographics, comorbidities, tumor characteristics, and outcomes were collected.
Vascular invasion was associated with lymphatic invasion, capsular invasion, extrathyroidal extension, and the presence of positive lymph nodes. Logistic regression revealed that tumor size was a predictor of vascular invasion. Vascular invasion in PTC tumors was associated with higher tumor recurrence rates, but there were no differences in mortality.
This study indicates that vascular invasion in PTC is associated with other aggressive pathologic features and an increased recurrence rate. For these reasons, vascular invasion should be an important tumor characteristic when determining extent of treatment.
•Vascular invasion increases recurrence rates of papillary thyroid cancer (PTC).•Larger tumor size in PTC is a predictor of vascular invasion.•PTC with vascular invasion has a higher likelihood ofoLymphatic invasionoCapsular invasionoExtrathyroidal extension within the specimenoPresence of positive lymph nodes
PURPOSEOrbital implant exposures, infections, and extrusions can occur many years following enucleation or evisceration. This study analyzes complication rates following porous orbital implant ...wrapped with a posterior auricular muscle complex graft (PAMCG).METHODSThis is a retrospective study of patients who underwent orbital implantation following enucleation using this technique between 1992 and 2013. Only cases with a minimum of 18 months of follow-up were included. No patients underwent peg implantation. Patient's demographics, follow-up time, type of implant, complications including wound dehiscence, exposure, postoperative infection, and extrusion were recorded.RESULTSThis study included 36 orbits of 36 patients with a mean age of 39.3 ± 23.2 years (range, 3-84 years). Thirty patients had hydroxyapatite implants and six had porous polyethylene. The average follow-up time was 12.6 ± 5.6 years (range, 1.5-31.0 years). There were no implant extrusions, and only one exposure resulting in orbital infection that necessitated implant removal (2.8%).CONCLUSIONWrapping porous orbital implants with PAMCG had favorable long-term outcomes over a thirty-one-year period.
ObjectivesDevelop predictive models for a paediatric population that provide information for paediatricians and health authorities to identify children at risk of hospitalisation for conditions that ...may be impacted through improved patient care.DesignRetrospective healthcare utilisation analysis with multivariable logistic regression models.DataDemographic information linked with utilisation of health services in the years 2006–2014 was used to predict risk of hospitalisation or death in 2015 using a longitudinal administrative database of 527 458 children aged 1–13 years residing in the Regione Emilia-Romagna (RER), Italy, in 2014.Outcome measuresModels designed to predict risk of hospitalisation or death in 2015 for problems that are potentially avoidable were developed and evaluated using the C-statistic, for calibration to assess performance across levels of predicted risk, and in terms of their sensitivity, specificity and positive predictive value.ResultsOf the 527 458 children residing in RER in 2014, 6391 children (1.21%) were hospitalised for selected conditions or died in 2015. 49 486 children (9.4%) of the population were classified in the ‘At Higher Risk’ group using a threshold of predicted risk >2.5%. The observed risk of hospitalisation (5%) for the ‘At Higher Risk’ group was more than four times higher than the overall population. We observed a C-statistic of 0.78 indicating good model performance. The model was well calibrated across categories of predicted risk.ConclusionsIt is feasible to develop a population-based model using a longitudinal administrative database that identifies the risk of hospitalisation for a paediatric population. The results of this model, along with profiles of children identified as high risk, are being provided to the paediatricians and other healthcare professionals providing care to this population to aid in planning for care management and interventions that may reduce their patients’ likelihood of a preventable, high-cost hospitalisation.
Objective
To better understand the contribution of age to the development of osteoarthritis (OA).
Methods
Surgical destabilization of the medial meniscus (DMM) was used to model OA in 12‐week‐old and ...12‐month‐old male C57BL/6 mice. OA severity was evaluated histologically. RNA used for microarray and real‐time polymerase chain reaction analysis was isolated from joint tissue collected from the medial side of the joint, including cartilage, meniscus, subchondral bone, and the joint capsule with synovium. Computational analysis was used to identify patterns of gene expression, and immunohistochemistry was used to evaluate tissue distribution of selected proteins.
Results
OA was more severe in older mice than in young mice. Only 55 genes showed a similar expression with DMM‐induced OA in the 2 age groups, while 493 genes showed differential expression, the majority having increased expression in older mice. Functional categories for similarly expressed genes included extracellular matrix– and cell adhesion–related genes; differentially expressed genes included those related to muscle structure and development and immune response genes. Comparison of expression in sham‐operated control joints revealed an age‐related decrease in matrix gene expression and an increase in immune and defense response gene expression. Interleukin‐33 was present in multiple joint tissue cells, while CCL21 was more localized to chondrocytes and meniscal cells. Periostin was found in the extracellular matrix of cartilage and meniscus.
Conclusion
Age affects both the basal pattern of gene expression in joint tissues and the response to surgically induced OA. Examining tissue from the joint beyond only cartilage revealed novel genes and proteins that would be important to consider in OA.
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