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Abstract ObjectiveThe objective of this study was to identify the predictors of in-hospital mortality among patients with diffuse alveolar hemorrhage (DAH).Patients and MethodsWe conducted a retrospective review of 89 patients hospitalized for DAH at our institution between 2001 and 2017: 49 patients who died during hospitalization and 40 patients who survived were compared. We reviewed their presenting signs and symptoms, clinical course, radiologic and pathologic findings, along with medical management. We then performed univariate and multivariate analyses to identify the risk factors associated with in-hospital mortality.ResultsWe identified 12 factors to be associated with mortality when comparing survivor vs non-survivor cohorts: smoking (27 [67%] vs 21 [42%], p = 0.02), malignancy (7 [17%] vs 24 [49%], p = 0.002), interstitial lung disease (0 vs 7 [14%], p = 0.01), liver failure (1 [2%] vs 14 [28%], p = 0.001), autoimmune diseases (16 [40%] vs 4 [8%], p =0.0006), thrombocytopenia (3 [7%] vs 35 [71%], p <0.0001), ICU admission (23 [57%] vs 40 [85%], p=0.004), mean duration of ICU stay (3.5 days [± 6.7] vs 5.5 days [± 5.5], p = 0.4), steroid use (36 [90%] vs 31 [63%], p = 0.003), use of plasma exchange (6 [15%] vs 0, p = 0.005), use of mechanical ventilation (15 [37%] vs 36 [75%], p value = 0.0007) and development of acute respiratory distress syndrome (ARDS) (9 [22%] vs 37 [77%], p <0.0001), respectively. On multivariate analysis, thrombocytopenia (OR 52.08: 95% CI, 8.59-315.71; p <0.0001) and ARDS (OR 11.71: 95% CI, 2.60-52.67; p = 0.0013) were associated with higher odds of mortality in DAH while steroid use (OR 0.05: 95% CI, 0.007-0.39; p = 0.0004) was associated with a lower risk of in-hospital mortality in patients with DAH.ConclusionIn DAH, thrombocytopenia and ARDS were predictors of in-hospital mortality whereas the use of steroid was associated with a more favorable prognosis.

Background: Here we describe an online network of patients with cancer, clinicians and researchers, layered on top of a comprehensive real world database of treatments and outcomes, continuously updated in near real time, and initially focused on multiple myeloma. Methods: Patients with multiple myeloma register at www.all4cure.com and sign HIPAA release forms to provide access to all of their medical records from all of the institutions from which they have received care. From the medical records, a structured dataset of treatments and lab results is extracted by a myeloma-dedicated team for display on each patient's de-identified, personalized dashboard. A discussion panel allows more than 1200 participating patients, clinicians and researchers to post comments or questions regarding each patient's specific circumstances. For each patient, lines of therapy and responses are determined according to IMWG and published criteria (Blood [2015] 126: 921-922). Here we report initial results from the treatments and responses among patients with multiple myeloma and plasma cell leukemia. Results: A total of 493 patients includes 26 with monoclonal gammopathy of undetermined significance (MGUS), 51 with smoldering myeloma, 408 with multiple myeloma, and 8 with primary plasma cell leukemia. Among patients with multiple myeloma, 42 (10.3%) had antecedent MGUS and/or smoldering myeloma. The average age is 65.6 (+/- 9.7). 50.9% are male and 49.1% are female. 42 states in the U.S. and 8 other countries are represented. Two patients with multiple myeloma had not started treatment by the time of this report. The remaining 414 patients with multiple myeloma or plasma cell leukemia received 1 to 16 lines of therapy. Among the 414 patients that received at least one line of therapy, a remarkable 89 distinct first line therapies were administered. The most common first line therapies were lenalidomide, bortezomib, dexamethasone (n=92), cyclophosphamide, bortezomib, dexamethasone (n=50), lenalidomide, bortezomib, dexamethasone + autologous stem cell transplant + lenalidomide maintenance (n=41), lenalidomide and dexamethasone (n=29), and bortezomib and dexamethasone (n=22). 62 patients received a first line therapy that was not received by any other patient in our database. This variation was attributable to participation in clinical trials, variation in the availability of drugs over time and different geographic locations, and the very large number of distinct combinations associated with multi-agent regimens. Seventy six percent of patients with multiple myeloma or plasma cell leukemia received a second line of therapy, 52% received a third line of therapy, 34% received a fourth line of therapy, 23% received a fifth line of therapy, and 18% received a sixth line of therapy. We observed a trend toward a decline in favorable responses with successive lines of therapy (Table 1) consistent with previous reports, with a correlation coefficient between the line of therapy and overall response rate of -0.74. Among the 76 patients who received 6 or more lines of therapy (247 lines of therapy in total), only 7 achieved stringent complete responses (sCRs), of which 5 were associated with a CAR-T therapy. Table 1 also shows a trend toward more rapid changes in treatment associated with later lines of therapy. 57 of 493 patients (12%) are deceased. Conclusions: Our findings reveal remarkable variation in the treatment of myeloma and provide a potentially valuable resource of up to date and current clinical features, prognosis, treatments, side effects, and outcomes of patients with myeloma in the real world. Table 1. Summary of lines of therapy and outcomes across 414 patients with multiple myeloma and plasma cell leukemia. The percentages of patients achieving sCR, ≥ PR (overall response rate - ORR), and ≥MR (clinical benefit rate - CBR) are shown for each line of therapy. Also depicted is the interval mortality and the mean and median number of days between the beginning of a line therapy and the beginning of the next line of therapy. Table Disclosures Richter: Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy; X4 pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive biotechnologies: Consultancy; Secura bio: Consultancy; Astra Zeneca: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy. Chhun:All4Cure: Current Employment. Zheng:All4Cure: Current Employment. Piboonvaranggoon:All4Cure: Current Employment. Mallick:All4Cure: Current Employment. Wren:All4Cure: Current Employment. Nam:All4Cure: Current Employment. Lopez Barquilla:All4Cure: Current equity holder in private company. Blau:All4Cure: Current equity holder in private company. Cowan:Janssen: Consultancy, Research Funding; Abbvie: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Research Funding. Bensinger:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Merck: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; MedImmune: Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Other; Sanofi: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Anderson:Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees. Blau:All4Cure: Current Employment, Current equity holder in private company.

AbstractObjectiveWe sought to evaluate the feasibility and safety of carotid access transcatheter aortic valve replacement (TAVR) by performing a meta‐analysis of published cases.BackgroundSeveral case series and regional data have provided initial basis for carotid access TAVR in patients with prohibitive femoral approach. We performed this meta‐analysis to provide further evidence of feasibility and safety of carotid TAVR.MethodsWe searched PubMed, EMBASE, CINAHL, and Cochrane CENTRAL for any study on carotid access TAVR involving ⩾5 patients since inception till March 1, 2020. Random‐effects model was used to compute overall effects. The outcomes analyzed were all‐cause mortality, Transient ischemic attack (TIA)/stroke, need for permanent pacemaker (PPM) implantation, pericardial tamponade, access site complications, major bleeding, and length of stay.ResultsThere was a total of 17 retrospective studies (n = 2082) with a median follow‐up of 1 month. Mean age of the patient was 80 years. Mean Euroscore and STS scores were 15 ± 6.2 and 7.9 ± 3.3, respectively. The procedural success rate was 99%. The rate of all‐cause mortality was 6.7% (range 4.6–9.7%, p < .001, I2 = 67%). Incidence of TIA/stroke was 3.9% (range 3.1–4.8%, p < .001, I2 = 0%) and PPM implantation was 16.7% (range 12.5–21.9%, p < .001, I2 = 56%). Rate of pericardial tamponade, vascular complication, and major bleeding were 1.7, 2.5, and 7%, respectively. Average length of hospital stay was 7.7 days.ConclusionOur results show that transcarotid approach is a feasible option in patients with prohibitive femoral access for TAVR.

We retrospectively reviewed all pertinent extracorporeal membrane oxygenation (ECMO) studies (January 1995 to September 2017) of adults with sepsis as a primary indication for intervention and its association with morbidity and mortality. Collected data included study type, ECMO configuration, outcomes, effect size, and other features. Advanced age was a risk factor for death. Compared with nonsurvivors, survivors had a lower median Sepsis-Related Organ Failure Assessment score on day 3 (15 vs. 18, p = 0.01). Biomarkers in survivors and nonsurvivors, respectively, were peak lactate (from two studies: 4.5 vs. 15.1 mmol/L, p = 0.03; 3.6 ± 3.7 vs. 3.3 ± 2.4 mmol/L, p = 0.850) and procalcitonin levels (41 vs. 164 ng/ml, p = 0.008). Bacteremia was associated with catheter colonization, and 90.5% of a group without bloodstream infections survived to discharge; ECMO weaning was possible for less than half the bloodstream infection group. Myocarditis portended favorable outcomes for patients with sepsis who received ECMO. Extracorporeal membrane oxygenation was used in immunosuppressed patients with refractory cardiopulmonary insufficiency from severe sepsis with successful weaning from ECMO for most patients. Overall survival varied substantially among studies (15.38–71.43%). Existing studies do not present well-defined patterns supporting use of ECMO in sepsis because of sample sizes and disparate study designs.

In this open‐label study, we evaluated the effect of upfront macitentan and riociguat combination in newly diagnosed pulmonary arterial hypertension (PAH) patients. In 15 consecutive PAH patients, we collected clinical and hemodynamic data at baseline, visit 1 (median 4 months) and visit 2 (median 12 months). Survival and transplantation status were analyzed over 36 months. Statistical analysis included student t‐test and 95% confidence interval (CI) (t‐statistic or Clopper‐Pearson). Kaplan‐Meier was used to estimate survival rate. There were 11/15 women (mean age 56 years), in World Health Organization (WHO) functional class (FC) III (n = 14) or IV (n = 1). The 6 min walk distance increased from 281.6 m (baseline) to 315.7 m (visit 1) and visit 2 (313.9 m), representing a 34‐ and 32‐m change (P < 0.05), respectively, associated with Borg score improvements. Brain natriuretic peptide decreased: 318.2 pg/mL (baseline) to 122.0 pg/mL (visit 1) and 98.6 pg/mL (visit 2) (P < 0.05). WHO FC improved in eight patients (53%, 95% CI 27%–79%). Pulmonary vascular resistance (9.2 to 5.7 Wood Units) and mean pulmonary artery pressure (47.3 to 38.9 mmHg) decreased; cardiac index increased (2.3 to 3.0 L/min/m2) (baseline to visit 2, all P < 0.05). All patients had intermediate and high risk score (baseline); at 1‐year follow‐up, dual therapy led to reduction to low risk score in 7/15 (47%) patients. There were no unexpected or serious side effects. Three patients died due to unrelated causes; one patient received a lung transplant. Transplant‐free survival rate (36 months) was 85%. Preliminary evidence is provided for effectiveness of initial macitentan and riociguat combination therapy in PAH.

AbstractExtracellular vesicles (EVs) are membrane‐bound vesicles released from cells into the extracellular environment. There is emerging interest in the use of EVs as potential therapeutic interventions. We sought to evaluate the safety of EVs that may be therapeutically used by performing in vitro toxicological assessments. EVs were obtained from mesenchymal stem cells (MSC‐EV) or from bovine milk (BM‐EV) by differential ultracentrifugation, and quantitated using nanoparticle tracking analysis. Genotoxic effects, hematological effects, immunological effects and endotoxin production were evaluated at two dose levels. Neither MSC‐EVs nor BM‐EVs elicited detectable genotoxic effects using either the alkaline comet assay or micronucleus assay. Hemolysis was observed with BM‐EVs but not with MSC‐EVs. MSC‐EVs did not have any significant effect on either spontaneous or collagen‐induced platelet aggregation. In contrast, BM‐EVs were noted to increase collagen‐induced platelet aggregation, even though no spontaneous increase in platelet aggregation was noted. Both types of EVs induced leukocyte proliferation, which was greater with BM‐EV. Neither MSC‐EVs nor BM‐EVs induced HL‐60 phagocytosis, although BM‐EVs decreased zymosan‐induced phagocytosis. Furthermore, neither MSC‐EVs nor BM‐EVs induced nitric oxide production. Unlike MSC‐EVs, BM‐EVs tested positive for endotoxin and induced complement activation. There are significant differences in toxicological profiles between MSC‐EVs and BM‐EVs that may reflect variations in techniques for EV isolation, EV content or cross‐species differences. The safety of MSC‐EV supports their use for disease therapeutics, whereas detailed safety and toxicological assessment will be necessary before the use of BM‐EVs. Copyright © 2016 John Wiley & Sons, Ltd.