Background: Although diffuse alveolar damage and respiratory failure are the key features of coronavirus disease 2019 (COVID-19), the involvement of other organs such as the kidney has also been reported. The reports of the incidence of acute kidney injury (AKI) in COVID-19 patients vary widely. In this study, we report our unique experience with AKI in COVID-19 patients in a low socioeconomic and predominantly ethnic minority group and provide its incidence, risk factors, and prognosis to expand the current understanding of this complication. Methods: In this single-center, retrospective cohort study, we analyzed the data of 469 COVID-19 patients admitted to the Brookdale University Hospital in Brooklyn, NY, from March 18 through April 23, 2020. Information regarding demographics, comorbidities, medications, clinical and laboratory data, and outcomes was collected from the electronic medical records. Both univariate and multivariate analyses were performed to determine the association of AKI with in-hospital mortality. Results: The median age was 66 years (interquartile range [IQR] 25–75; range 19–101 years), and 268 (57.14%) patients were male. Estimated glomerular filtration rate (eGFR) as determined by the Modification of Diet in Renal Disease Study Equation was low (<60 mL/min/1.73 m2) in 207 (44.1%) patients. During hospitalization, 128 (27.3%) patients developed AKI, and the incidence was significantly higher in those patients presenting with a low eGFR (N = 81, 39.1%; p < 0.001). Male sex, hypertension, the use of angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatories, hemodynamic instability, mechanical ventilation, acute respiratory distress syndrome, and admission elevated ferritin, creatinine kinase, brain natriuretic peptide, and troponin 1 were identified as the risk factors for in-hospital AKI. Ninety-seven (28.45%) patients died in the non-AKI group versus 91 (71.1%) in the AKI group (p < 0.001). The Cox proportional hazard model after adjusting for age, gender, comorbidities, hemodynamic status, and PF ratio (arterial oxygen partial pressure [PaO2]/fractional inspired oxygen [FiO2]) determined that on admission, an elevated blood urea nitrogen (hazard ratio [HR]: 1.75; 95% confidence interval [CI] 1.23–2.48), a low eGFR (HR 1.43; CI 1.1–2.03), AKI stage 1 (HR 1.14; CI 0.64–2.03), AKI stage 2 (HR 1.86; CI 1.03–3.56), and AKI stage 3 (HR 2.1; CI 1.3–2.81) were independent risk factors for in-hospital mortality. Renal replacement therapy (RRT) did not improve survival in stage III AKI. Conclusion: AKI in our hospitalized COVID-19 patients was common and carried a high mortality, especially in patients with AKI stage 3. RRT did not improve survival. Policy changes and planning for this high incidence of AKI in COVID-19 patients and its associated high mortality are necessary at the local and national levels.
Histone deacetylase inhibitors (HDACi) have been proposed as therapies for certain cancers and as an anti-reservoir therapy for HIV+ individuals with HAART, yet, their roles in glial inflammatory and innate antiviral gene expression have not been defined. In this study, we examined the effects of two non-selective HDACi, trichostatin A and valproic acid, on antiviral and cytokine gene expression in primary human microglia and astrocytes stimulated with TLR3 or TLR4 ligand. HDACi potently suppressed the expression of innate antiviral molecules such as IFNβ, interferon-simulated genes, and proteins involved in TLR3/TLR4 signaling. HDACi also suppressed microglial and astrocytic cytokine and chemokine gene expression, but with different effects on different groups of cytokines. These results have important implications for the clinical use of HDACi.
Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: This is a phase I first in human, dose escalation trial of MCARH171. Patients received conditioning chemotherapy with cyclophosphamide (Cy) 3 gm/m2 as a single dose or fludarabine 30 mg/m2 daily and Cy 300 mg/m2 daily for 3 days followed by MCARH171 infusion in 1-2 divided doses. The trial followed a standard 3+3 design with 4 dose levels where patients received the following mean doses per cohort: (1) 72x106, (2) 137x106, (3) 475x106, (4) 818x106 viable CAR+ T cells. The primary objective was to demonstrate safety, and secondary objectives included efficacy and expansion, and persistence of CAR T cells using PCR from the peripheral blood. The last accrued patient received MCARH171 on Dec 6, 2017 and the data cut-off is July 16, 2018. The study is closed to accrual. Results: 11 patients with relapsed and/or refractory MM were treated. Median number of prior lines of therapy was 6 (range: 4-14), and all patients received prior therapy with a proteasome inhibitor, IMiD, anti-CD38 monoclonal antibody, and high dose melphalan/stem cell transplant. Nine (82%) patients had high-risk cytogenetics and 9 (82%) were refractory to their immediate prior line of treatment. One patient was not evaluable for DLTs given the need for early radiation and steroids for impending spinal cord compression by tumor. There are no DLTs reported. Cytokine release syndrome (CRS) grade 1-2 occurred in 4 patients (40%), grade 3 occurred in 2 (20%), and there was no grade 4-5 CRS. Grade 2 encephalopathy occurred in 1 patient (10%) in the setting of high fevers which resolved in less than 24 hours. There was no grade 3 or higher neurotoxicity observed. Tocilizumab was administered to 3 patients; 2 in cohort 2, and 1 in cohort 3. Laboratory values correlating with CRS reaching grade 3 or requiring Tocilizumab (N=4) compared to those with no or milder CRS (N=6) included peak CRP (mean: 28.5 vs 4.6 mg/dL, p<0.001), IFNg (mean peak fold increase: 271 vs 11-fold, p<0.0001), and peak IL6 before Tocilizumab, as IL6 elevation artificially increases after use (mean: 435 vs 68.7 pg/mL, p<0.005). No significant change was seen in ferritin or fibrinogen compared to baseline. Overall response rate was 64% and the median duration of response was 106 days (range: 17 to 235 days). The peak expansion and persistence of MCARH171 as well as durable clinical responses were dose dependent. Patients who were treated on the first two dose cohorts (≤150 X106 CAR T cells) had a lower peak expansion in the peripheral blood (mean 14,098 copies/µL; N=6), compared to patients who were treated on the third or fourth dose cohort 3-4 (≥450 X106 CAR T cells; N=5), where the mean peak expansion was 90,208 copies/µL (p<0.05). Among the 5 patients who received higher doses (450 X106), 5/5(100%) patients responded. The duration of responses was also related to the cell dose, with 3 of 5 patients (60%) treated in the cohorts receiving ≥450 X106 had clinical responses lasting >6 months compared to only 1 of 6 (16.7%) patients who received lower doses. Two patien have ongoing responses (VGPR) at 7.5+ and 10+ months of follow up. To normalize for dose administered we compared the pharmacokinetics of only patients treated at dose levels 3-4 ( ≥450 X106 CAR T cells). Here, we demonstrate that peak expansion correlated to clinical efficacy, with the 3 durable responders all having peak expansion >85,000 copies/µL (mean: 131,732 copies/µL); compared to transient responders, where the maximum peak expansion was 33,213 copies/µL (mean: 27,922; Figure 1). Conclusions: MCARH171 has an acceptable safety profile with no DLTs reported. A dose-response relationship with toxicity was not clearly observed, as noted by distribution of tocilizumab use across dose cohorts. However, a dose-response relationship was observed with promising clinical efficacy at dose levels of ≥450 X106 CAR T cells. Controlling for dose level, peak expansion correlated with durability of response. These results further support the development of CAR T cells for heavily pre-treated patients with relapsed and refractory MM. Disclosures Mailankody: Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Korde:Amgen: Research Funding. Lesokhin:Takeda: Consultancy, Honoraria; Squibb: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Park:Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Shire: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Riviere:Fate Therapeutics Inc.: Research Funding; Juno Therapeutics, a Celgene Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding.
The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.
Cardiac papillary fibroelastomas (CPFs) are the second most common primary cardiac tumors and the most common cardiac valvular tumors. Although they are histologically benign and usually asymptomatic, CPFs can lead to serious and life-threatening complications like myocardial infarction, stroke, pulmonary embolus, cardiac arrest etc. CPFs represent a rare entity in clinical medicine and literature regarding their management is limited. We report two cases which illustrate such complications arising from undiagnosed CPFs on the aortic valve. We further stress on the importance of identifying CPFs early so that they can be managed appropriately based on recommendations from the available literature.
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by constitutive activation of extracellular signal-regulated kinase (ERK). Genomic characterization has identified activating point mutations including mutually exclusive BRAFV600E and activating MAP2K1 mutations to be responsible for ERK activation in a majority of pediatric LCH patients. Here, we report the discovery of a novel BRAF kinase fusion, PACSIN2-BRAF, in a child with multisystem LCH. This is the second reported case of an activating BRAF kinase fusion and indicates a recurrent pathologic mechanism. Genomic evaluation for activating kinase fusions should be strongly considered in pediatric LCH patients lacking more common mutations. K E Y W O R D SBRAF, kinase fusion, Langerhans cell histiocytosis, LCH, myeloid neoplasia, PACSIN2
False-negative (FN) intraoperative frozen section (FS) results of sentinel lymph nodes (SLN) have been reported to be more common after neoadjuvant chemotherapy (NAC) in the primary surgical setting. We evaluated SLN FS assessment in breast cancer patients treated with NAC to determine the FN rate and the histomorphologic factors associated with FN results. Patients who had FS SLN assessment following NAC from July 2008 to July 2017 were identified. Of the 711 SLN FS cases, 522 were negative, 181 positive, and 8 deferred. The FN rate was 5.4% (28/522). There were no false-positive results. Of the 8 deferred cases, 5 were positive on permanent section and 3 were negative. There was a higher frequency of micrometastasis and isolated tumor cells in FN cases (P<0.001). There was a significant increase in tissue surface area present on permanent section slides compared with FS slides (P<0.001), highlighting the inherent technical limitations of FS and histologic under-sampling of tissue which leads to most FN results. The majority (25/28, 89%) of FN cases had metastatic foci identified exclusively on permanent sections and were not due to a true diagnostic interpretation error. FN cases were more frequently estrogen receptor positive (P<0.001), progesterone receptor positive (P=0.001), human epidermal growth factor receptor-2 negative (P=0.009) and histologic grade 1 (P=0.015), which most likely reflects the lower rates of pathologic complete response in these tumors. Despite its limitations, FS is a reliable modality to assess the presence of SLN metastases in NAC treated patients.
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