We have constructed de novo a high-resolution genetic map that includes the largest set, to our knowledge, of polymorphic markers (
N=14,759) for which genotype data are publicly available; that ...combines genotype data from both the Centre d'Etude du Polymorphisme Humain (CEPH) and deCODE pedigrees; that incorporates single-nucleotide polymorphisms; and that also incorporates sequence-based positional information. The position of all markers on our map is corroborated by both genomic sequence and recombination-based data. This specific combination of features maximizes marker inclusion, coverage, and resolution, making this map uniquely suitable as a comprehensive resource for determining genetic map information (order and distances) for any large set of polymorphic markers.
We present a series of unrelated patients with isolated hypomyelination, with or without mild cerebellar atrophy, and de novo TUBB4A mutations.
Patients in 2 large institutional review board-approved ...leukodystrophy bioregistries at Children's National Medical Center and Montreal Children's Hospital with similar MRI features had whole-exome sequencing performed. MRIs and clinical information were reviewed.
Five patients who presented with hypomyelination without the classic basal ganglia abnormalities were found to have novel TUBB4A mutations through whole-exome sequencing. Clinical and imaging characteristics were reviewed suggesting a spectrum of clinical manifestations.
Hypomyelinating leukodystrophies remain a diagnostic challenge with a large percentage of unresolved cases. This finding expands the phenotype of TUBB4A-related hypomyelinating conditions beyond hypomyelination with atrophy of the basal ganglia and cerebellum. TUBB4A mutation screening should be considered in cases of isolated hypomyelination or hypomyelination with nonspecific cerebellar atrophy.
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Introduction: Daratumumab (DARA) is a human IgG1k monoclonal antibody licenced for second line use as monotherapy or in combination with either lenalidomide or bortezomib (Bor) plus dexamethasone ...(D) for patients (pts) who have received at least one prior therapy. There are no published data on front line use of DARA in combination regimens. CyBorD is considered a safe and effective induction regimen for patients with newly diagnosed MM eligible for transplantation. Up to 60% of patients achieve very good partial response (VGPR) or better following 4 cycles of induction (Reeder CB et al, Blood 2010). Since our pre-clinical data showed enhanced antibody dependent cellular phagocytosis (ADCP) following Cyclophosphamide (Cy) exposure (Rigalou et al, ASH 2016), we set out to explore the feasibility of combining DARA with weekly CyBorD in newly diagnosed transplant eligible MM patients. We aim to demonstrate safety, efficacy, convenience and cost-effectiveness in a Phase 1b clinical trial of newly diagnosed patients with MM.
Methods: This ongoing phase Ib, open-label, single arm, dose escalation study has recruited 12 patients from November 2016 to June 2017 across 3 sites in Ireland (3 pts in DL 1, 3 pts in DL 2 and 6 pts in DL 3). Baseline demographic factors include: 75% males, 25% females; median age of 57.5 years (35-66 years); 83% ISS stage I, 17% ISS stage II/III. FISH analysis detected t(4;14) in 0% of pts (0/12), t(14;16) in 0% of pts (0/12) and del17p in 17% of pts (2/12). The study is designed to assess the safety and efficacy of 4 cycles of induction therapy with Cy and Bor on days 1, 8, 15 and 22, D 20/mg/day on days 1, 2, 8, 9, 15, 16, 22 and 23 and DARA 16mg/kg on days 1, 8, 15 and 22 for cycles 1 and 2 and on days 1 and 15 for cycles 3 and 4. Following the induction therapy, patients proceed with stem cell mobilization and high dose Melphalan 200mg/m2 autologous stem cell transplant (ASCT). Following SCT 2 cycles of consolidation therapy with Cy and Bor on days 1, 8, 15 and 22, D 20/mg/day on days 1, 2, 8, 9, 15, 16, 22 and 23 and DARA 16mg/kg on days 1 and 15 were administered. After consolidation therapy, all patients are scheduled to receive DARA maintenance on day 1 every 4 weeks until progression, unacceptable toxicity or withdrawal of consent (limited to a maximum duration of 2 years). Patients with high-risk features receive subcutaneous (SQ) Bor on days 1 and 15 during maintenance phase. We used a standard 3+3 design in sequential cohorts (3 dose levels (DL) of Cy and Bor: DL 1: Cy 150mg/m2 and Bor 1.3mg/m2, DL 2: Cy 300mg/m2 and Bor 1.3mg/m2 and DL 3: Cy 300mg/m2 and Bor 1.5mg/m2; and a DL -1: Cy 100mg/m2 and Bor 1.3mg/m2. Six additional patients will be enrolled in an expansion cohort as the maximum tolerated dose (MTD) has been determined as DL 3. The primary endpoints are the incidence of dose limiting toxicity (DLT) within the first cycle of combination at each dose level and complete response (CR) rate post ASCT. Secondary endpoints include: safety, CR rates at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Response will be investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810.
Results: We report the safety data from interim analysis following completion of the dose escalation phase of CyBorD-DARA trial. The most common adverse events (AE) of grade 3 severity or higher were thrombocytopenia, postoperative wound infection, urinary tract infection, hyponatraemia, back pain, bone pain. Five serious adverse events (SAE) were reported but none related to the study treatment. No DLT occurred in any group. To date all pts continue on treatment and enrolment is ongoing. Although follow up is still short, the combination shows a promising response rate. Following 4 cycles of induction therapy the first 6 patients enrolled (at DL1 and DL2) have achieved VGPR or better. Safety and efficacy data will be updated at ASH meeting.
Conclusion: DARA can be safely combined with weekly CyBorD. MTD/RP2D is Cy 300mg/m2 and Bor 1.5mg/m2 in combination with D and DARA and early analysis demonstrates promising efficacy.
O'Dwyer:Onkimmune Ltd: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; GlycoMimetics Inc: Research Funding.
The number of hospitalized immunosuppressed adults is a growing and often develop severe complications that require admission to an Intensive Care Unit (ICU). The main cause of admission is acute ...respiratory failure (ARF). The goal of the study was to determine if ARF represents an independent risk factor for hospital mortality and in particular, we sought to ascertain if any risk factors were independently and identifiably associated with a bad outcome.
We perform a retrospective study of a prospectively collected data from patients admitted to an ICU. Adult patients with known immunosuppressive condition admitted to ICU were included.
A total of 248 patients were included. Of 248 patients, 117 (47.2%) had a diagnosis of ARF at the time of ICU admission. Patients with ARF had a significantly higher in-hospital mortality (53.4% vs. 28.2% p = 0.001). Factors independently associated with hospital mortality were diagnosis of ARF at ICU admission, the presence of septic shock, use of continuous renal replacement therapy and failure of high-flow nasal canula(HFNC)/non-invasive (NIV) respiratory therapies.
We identified ARF on admission and failure of HFNC/NIV to be independently associated with increased hospital mortality in immunosuppressed patients.
•The number of hospitalized immunosuppressed adults is a growing and often develop severe complications that require admission to an Intensive Care Unit (ICU).•The main cause of admission to the ICU and mortality for these patients is acute respiratory failure (ARF).•Factors independently associated with hospital mortality were diagnosis of ARF at ICU admission, the presence of septic shock, use of continuous renal replacement therapy and failure of high-flow nasal canula(HFNC)/non-invasive (NIV) respiratory therapies.•The outcomes for immunosuppressed patients who require invasive mechanical ventilation are poor, with mortality rates in excess of 70% in some studies•In our study, we identified ARF on admission and failure of HFNC/NIV to be independently associated with increased hospital mortality in immunosuppressed patients.
Microvascular angina (MVA) is an incompletely understood clinical entity. Computational analysis of coronary Computed Tomography Angiography (CTA) has shown an association between low coronary lumen ...volume to myocardial mass (V/M) ratio and lower Fractional Flow Reserve values, independent of plaque measures. We hypothesized that low V/M ratio may be present in patients with MVA.
A retrospective case-control analysis was performed using patients fulfilling guideline criteria for MVA with controls matched for age, gender, coronary risk factors and atherosclerotic plaque burden. V/M was extracted off site (Heartflow Inc; Redwood City, CA) employing allometric scaling laws that allow the definition of the coronary circulation beyond the epicardium. FFRCT values were calculated in the major epicardial coronary arteries for each group.
A total of 30 patients with MVA and 32 matched controls were included in the study. Mean total coronary lumen volume (2302 mm3 ± 109 vs 2978 mm3 ± 134, p < 0.001) and mean myocardial mass (90.4 g ± 13.7 vs 100.4 g ± 20.1, p = 0.029) were lower in MVA patients compared to controls. Mean V/M ratio was significantly lower in MVA compared to controls (25.6 mm3/g ± 5.9 vs 30.0 mm3/g ± 6.5, p = 0.007; c-statistic 0.69). V/M ratio did not differ significantly between subclasses of angina severity (p = 0.747). No difference in mean nadir FFRCT values was found between MVA and control groups in the LAD (0.86 ± 0.07 vs 0.83 ± 0.07, p = 0.154), LCX (0.90 ± 0.05 vs 0.90 ± 0.06, p = 0.240) and RCA (0.90 ± 0.04 vs 0.90 ± 0.03, p = 0.773) vessels.
Patients with microvascular angina demonstrate a significantly lower coronary CTA-derived coronary volume/myocardial mass ratio than asymptomatic controls.
Introduction: Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including ...immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbone with which to combine DARA prior to Autologous Stem Cell Transplantation (ASCT). However, based on the ability of Cyclophosphamide (Cy) to enhance DARA mediated antibody dependent cellular phagocytosis, we hypothesized that CyBorD may provide an alternative option (Naicker, ASH 2017). We are currently exploring the preliminary safety and efficacy of CyBorD and DARA as part of an ongoing phase 1b study in newly diagnosed MM (NDMM) pts eligible for ASCT. Last year we reported on the safety of this combination with an absence of dose limiting toxicity (DLT) with weekly subcutaneous (SQ) Bortezomib (Bor) 1.5mg/m2, Cy 300mg/m2 and DARA 16mg/kg (McEllistrim, ASH 2017). We now report on the efficacy of this regimen as pre-transplant induction, including the rate of CR post ASCT.
Methods: Pts received 4 cycles of induction therapy with weekly CyBorD and DARA 16mg/kg weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Following induction therapy, pts proceeded to stem cell mobilization and ASCT followed by 2 cycles of consolidation therapy with weekly CyBorD plus DARA 16mg/kg on days 1 and 15. Following completion of consolidation therapy, all pts receive DARA maintenance every 28-days for 2 yrs or until progression, unacceptable toxicity or withdrawal of consent. Pts with high-risk features receive Bor on days 1 and 15 during maintenance phase. The primary endpoints were the incidence of DLT within the first cycle of combination at each dose level and CR rate post ASCT. Secondary endpoints included: safety, CR rate at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Responses were investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810.
Results: Eighteen pts were enrolled between Nov 2016 and Dec 2017 and received at least 1 dose of treatment. Baseline characteristics were: median age = 56 y (range 32-66); M (61%), F (39%), ISS stage I, II, III in 78%, 17% and 6% of pts, respectively. 28% patients were identified with high risk genetic features 17p deletion and/or t(4;14) by FISH and/or SKY92 (SkylineDx). Three patients discontinued therapy early (primary refractory, persistent liver toxicity, death, respectively).
Overall, treatment was well tolerated. The most common grade (gr) 3/4 hematologic treatment emergent adverse events (TEAE) were lymphopenia (44%), neutropenia (11%) and anemia (11%). The most common gr 3/4 non-hematologic TEAE were diarrhea (11%) and infection (61%). One patient died from gr 5 diffuse alveolar damage 7 weeks post ASCT. A single patient developed gr 3 liver toxicity. DARA-associated infusion reactions were ≤ gr 2 (11%).
On an intent to treat (ITT) basis 94% achieved ≥ very good partial response (VGPR) with ≥ complete response (CR) in 44% pts (Figure). Among the sixteen patients completing 4 cycles of induction ORR was 100%, ≥ VGPR (69%), ≥ CR (13%). Informative NGS data (Adaptive Biotech) are available on 11/16 patients post induction, of whom 100% are MRD negative post induction at a level of ≥ 10e4. Following the induction phase 15/16 patients readily mobilized sufficient CD34 positive progenitors and proceeded to ASCT, one patient failed repeated mobilization. One patient died prior to post ASCT response assessment and data on the last patient is pending. Thus 13/15 patients are currently evaluable for response post ASCT. Responses deepened post ASCT with 100% achieving ≥ VGPR and 62% achieving ≥ CR. Based on EBMT criteria the CR/nCR rate post ASCT was 92%. Post ASCT PET-CT scans were consistent with complete metabolic response in all 13 patients. Updated results, including MRD status post ASCT will be presented at the meeting.
Conclusions: CyBorD-DARA is a highly active, well tolerated induction therapy for NDMM patients undergoing ASCT. These data support the further development of this combination as a convenient, cost effective alternative to PI-IMiD-DARA based combinations.
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Quinn:Janssen: Honoraria. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding.
Background The prevalence of ex vivo high on-treatment platelet reactivity (HTPR) to commonly prescribed antiplatelet regimens after transient ischemic attack (TIA) or ischemic stroke is uncertain. ...Methods Platelet function inhibition was simultaneously assessed with modified light transmission aggregometry (VerifyNow; Accumetrics Inc, San Diego, CA) and with a moderately high shear stress platelet function analyzer (PFA-100; Siemens Medical Solutions USA, Inc, Malvern, PA) in a pilot, cross-sectional study of TIA or ischemic stroke patients. Patients were assessed on aspirin–dipyridamole combination therapy ( n = 51) or clopidogrel monotherapy ( n = 25). Results On the VerifyNow, HTPR on aspirin was identified in 4 of 51 patients (8%) on aspirin–dipyridamole combination therapy (≥550 aspirin reaction units on the aspirin cartridge). Eleven of 25 (44%) patients had HTPR on clopidogrel (≥194 P2Y12 reaction units on the P2Y12 cartridge). On the PFA-100, 21 of 51 patients (41%) on aspirin–dipyridamole combination therapy had HTPR on the collagen-epinephrine (C-EPI) cartridge. Twenty-three of 25 patients (92%) on clopidogrel had HTPR on the collagen–adenosine diphosphate (C-ADP) cartridge. The proportion of patients with antiplatelet HTPR was lower on the VerifyNow than PFA-100 in patients on both regimens ( P < .001). Conclusions The prevalence of ex vivo antiplatelet HTPR after TIA or ischemic stroke is markedly influenced by the method used to assess platelet reactivity. The PFA-100 C-ADP cartridge is not sensitive at detecting the antiplatelet effects of clopidogrel ex vivo. Larger prospective studies with the VerifyNow and with the PFA-100 C-EPI and recently released Innovance PFA P2Y cartridges (Siemens Medical Solutions USA, Inc) in addition to newer tests of platelet function are warranted to assess whether platelet function monitoring predicts clinical outcome in ischemic cerebrovascular disease.
Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of ...patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population.
Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model.
127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model.
Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.
Urban forested natural areas are an important component of the forest and tree canopy in northeastern United States urban areas. Although similar to native forests in surrounding regions in ...structure, composition, and function, these natural areas are threatened by multiple, co-occurring biological and climate stressors that are exacerbated by the urban environment. Furthermore, forests in cities often lack application of formal silvicultural approaches reliant upon evidence-based applied ecological sciences. These include both urban- and climate-adapted silvicultural techniques to increase the resilience and sustainability of native forests in cities. With this in mind, we convened a group of urban forest practitioners and researchers from along a latitudinal gradient in the northeastern United States to participate in a workshop focused on co-developing long-term, replicated ecological studies that will underlie the basis for potential silvicultural applications to urban forests. In this article we review the process and outcomes of the workshop, including an assessment of forest vulnerability, and adaptive capacity across the region, as well as shared management goals and objectives. We discuss the social and ecological challenges of managing urban oak-dominated mixed hardwood forests relative to non-urban forests and identify potential examples of urban- and climate-adapted silviculture strategies created by practitioners and researchers. In doing so, we highlight the challenges and need for basic and long-term applied ecological research relevant to silvicultural applications in cities.
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