Citations

Background: Hypertension (HTN) control rate is a core clinical quality measure. It is presently assessed by manual review of a random sample of patients with HTN billing claims. There is an increasing push by regulators towards the use of electronic medical records (EMR) to assess quality of care. Purpose: To use EMR to obtain a more in-depth assessment of quality of hypertension care. Methods: Cross sectional study involving adults with HTN seen at 2 or more office visits in 2009 by eligible primary or specialist providers at a large medical group practice. We measured the proportion of HTN patients with blood pressure (BP) at goal (BP < 140/90 mm Hg) at their last hypertension visit (LHV). Results: Of a total of 10,401 patients, 5970 (57%) were controlled and 1959 (19%) were uncontrolled at their LHV. Control could not be assessed in 2472 (24%) as BP values were unavailable from the vital signs section of the visit notes in the EMR. Of a random sample of 250 patients with unavailable BP, only 94 (37.6%) had BP values documented in other parts of the visit note. In 29 patients (11.6%) billing for HTN was done without adequate evidence that it was addressed at that visit. Control rates were highest for primary care providers where measurement and documentation of BP was a focus - Family Medicine 77% controlled, 1% unavailable; Primary Care Internal Medicine 71% controlled, 4% unavailable. A considerable proportion of patients in the other four provider groups did not have BP available from their last hypertension visit - Cardiology 59% controlled, 22% unavailable; Nephrology 38% controlled, 47% unavailable; Preventive Medicine 48% controlled, 39% unavailable; General Internal Medicine 41% controlled, 45% unavailable. Control rates were similar across provider groups when patients with unavailable BP were excluded: Family Medicine 78%, Primary Care 74%, Cardiology 75%, Nephrology 73%, Preventive Medicine 79%, and General Medicine 75%. Conclusions: Up to a quarter of HTN patients did not have properly documented BP in the EMR at their LHV. For those with measurements recorded, control rates were similar across primary care and specialty clinics, but measurement rates were higher for primary care practices. Use of the EMR facilitates efficient and granular assessment of the measurement process and control rates for HTN among various provider groups.

Introduction: Elevated plasma levels of lipoprotein(a) [Lp(a)] are associated with increased risk for coronary artery disease (CAD), but the strength of the association and whether it is independent of other risk factors remains controversial. Differences in prospective studies may be partially explained by variability in methods used to measure Lp(a). Methods: We utilized two different analytical methods (electrophoretic and immunologic) to measure Lp(a) and determine the predictive value of Llp(a) in assessing angiographic coronary artery disease (CAD) and association with major adverse events in 500 patients. Results: In univariate analyses, median Lp(a) cholesterol and Lp(a) mass were significantly associated with angiographic CAD. In a multivariable model, Lp(a) cholesterol remained a significant correlate of CAD (OR 1.61, 95% CI 1.13-2.31, P = 0.009) while Lp(a) mass was not (OR 1.18, 95% CI 0.95-1.47, P = 0.14). Additionally, on multivariable analysis, the presence of a detectable amount of Lp(a) cholesterol (> or =2.5 mg/dL) was more strongly correlated with CAD than HDL cholesterol < 40 mg/dL, and, along withLp(a) cholesterol, was strongly correlated with major adverse events (OR 2.08 95% CI 1.22-3.56, P = 0.007 and OR 1.22, 95% CI 1.05-1.42, P = 0.012, respectively). Conclusions: Lp(a) cholesterol measured electrophoretically is independently correlated with angiographic CAD and presence of major adverse events, and may be used as an alternative or supplement to Lp(a) mass analysis.

Abstract Background: Metastatic undifferentiated pleomorphic sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, in the 2nd line setting and beyond, efficacy remains limited. Pazopanib, the only approved treatment in the refractory setting has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: MSI-H cancer and biliary tract cancer. The activity of envafolimab is similar to other PD-1 antibodies administered intra-venously. Envafolimab demonstrated a 32% ORR in MSI-H colorectal cancer that failed three approved chemotherapeutics, similar to the ORR of 28% and 33%, with nivolumab and pembrolizumab, respectively. The rationale for the ENVASARC trial is based on the previously reported efficacy of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ~25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n=80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks intra-venously for four doses (cohort B; n=80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Citation Format: Sandra D'Angelo, Steven Robinson, Joelle Lam, Bonne Adams, James Freddo, Charles P. Theuer, Robert Maki. ENVASARC: A Pivotal Trial of Envafolimab, and Envafolimab in Combination with Ipilimumab, in Patients with Advanced or Metastatic Undifferentiated Pleomorphic Sarcoma or Myxofibrosarcoma who have Progressed on Prior Chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT239.

Abstract Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, including GSK3901961 and GSK3845097, incorporate further genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, enhancing T-cell persistence and increasing helper functions such as Type 1 T-helper anti-tumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of these two therapies and possible subsequent ones. Substudy 1 will assess GSK3901961 in patients with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in patients with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Table 1 lists eligibility criteria. Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting. Funding: GSK (209012; NCT04526509) Initial screening criteriaInclusion criteriaExclusion criteriaSubstudies 1 and 2 (SS and NSCLC)≥18 years of agePrior malignancy that is not in complete remission or clinically significant systemic illnessMeasurable disease per RECIST v1.1 criteriaPrevious treatment with genetically modified NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting antibodyExpression of HLA-A*02:01, A*02:05, or A*02:06Prior gene therapy using an integrating vectorExpression of NY-ESO-1/LAGE-1a in tumor archival or fresh biopsyPrevious allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplantSubstudies 1 and 2 (SS only)Histologically confirmed advanced (metastatic or unresectable) SS diagnosisCentral nervous system metastasesPresence of t(X;18) translocation(Allowed for NSCLC participants on a case-by-case basis)Received, completed, or intolerant to treatment with anthracycline or anthracycline with ifosfamide for advanced (metastatic or unresectable) disease and has progressedSubstudy 1 (NSCLC only)Histologically or cytologically confirmed Stage IV NSCLCReceived or failed ≥3 lines of systemic therapyReceiving or previously received ≥1 prior line(s) of standard of care treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to doublet taxane and platinum chemotherapyPresence of actionable genetic aberration (activation epithelial growth factor receptor, anaplastic lymphoma kinase/c-ros oncogene 1) per NCCN guidelines Citation Format: Adam J. Schoenfeld, Mehmet Altan, Taofeek K. Owonikoko, Sandra D'Angelo, Brian H. Ladle, Jonathan Noujaim, Kai He, David Liebner, Adrian G. Sacher, John B.A.G. Haanen, Jeffrey Yachnin, Chao Huang, Brian A. Van Tine, Aisha Hasan, Thomas Faitg, Emily Butler, Aiman Shalabi, Steven Attia, Dejka M. Araujo. Master protocol to assess the safety and recommended Phase 2 dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT219.

AbstractIrritable bowel syndrome (IBS) is a gut‐brain disorder in which symptoms are shaped by serotonin acting centrally and peripherally. The serotonin transporter gene SLC6A4 has been implicated in IBS pathophysiology, but the underlying genetic mechanisms remain unclear. We sequenced the alternative P2 promoter driving intestinal SLC6A4 expression and identified single nucleotide polymorphisms (SNPs) that were associated with IBS in a discovery sample. Identified SNPs built different haplotypes, and the tagging SNP rs2020938 seems to associate with constipation‐predominant IBS (IBS‐C) in females. rs2020938 validation was performed in 1978 additional IBS patients and 6,038 controls from eight countries. Meta‐analysis on data from 2,175 IBS patients and 6,128 controls confirmed the association with female IBS‐C. Expression analyses revealed that the P2 promoter drives SLC6A4 expression primarily in the small intestine. Gene reporter assays showed a functional impact of SNPs in the P2 region. In silico analysis of the polymorphic promoter indicated differential expression regulation. Further follow‐up revealed that the major allele of the tagging SNP rs2020938 correlates with differential SLC6A4 expression in the jejunum and with stool consistency, indicating functional relevance. Our data consolidate rs2020938 as a functional SNP associated with IBS‐C risk in females, underlining the relevance of SLC6A4 in IBS pathogenesis.

Background: Insulin-like growth factor binding protein7 (IGFBP-7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) reflect G1-cell cycle arrest and are used as biomarkers for AKI. Recent studies show that these biomarkers rise in ischemic conditions and suggest that they actually may limit the severity of AKI. We tested the hypothesis that renal vein [IGFBP-7]*[TIMP-2] correlate with reductions in renal blood flow (RBF) and post-stent single kidney (SK)-GFR changes in patients with RVD undergoing contrast-based imaging and stent revascularization Methods: Inpatient studies were performed during 150 mEq Na+ intake and ACE/ARB Rx in patients with hemodynamically severe RVD (n=29, Doppler velocity = 318 ± 100cm/sec, and eGFR= 34.7 ± 11.7 mL/ min) scheduled for renal artery stenting, and compared to essential hypertensive (EH) healthy controls (n=32). Cortical and medullary RBFs (by multidetector CT) and renal vein levels of IGFBP-7 and TIMP-2 were measured before renal artery stenting and 3 months later Results: Pre-stenting IGFBP-7 and TIMP-2 levels were elevated in RVD compared to EH (18.5±2. vs 15.7±1.5 and 97.4±23.1vs 62.7±9.2 ng/mL respectively, P <0.0001). Baseline renal vein levels of IGFBP-7 * TIMP-2 correlated inversely with pre-stent RBF (r= - 0.53, P=0.01) and directly with the change (%) in SK-GFR observed 3 months after stenting Conclusion: IGFBP-7 and TIMP-2 levels are elevated in patients with chronic RVD as a function of the baseline reduction in RBF, and associate with subsequent improvement in SK-GFR 3 months after revascularization. These data are consistent with renovascular occlusion inducing cell-cycle arrest that serves to protect kidney function.

Inositol hexaphosphate (IP6 or phytic acid) is thought to be the active ingredient in legumes and cereals that provides anti‐cancer activity. Our goal is to understand the influence of IP6 on mucin expression (Muc1 and Muc2, specifically) in the mouse intestine. C57BL/6 mice were randomized into 3 groups of 6 mice. Mice were orally dosed with IP6 (0, 1, 2 g/kg BW) for 5 days and sacrificed on the sixth day. Sections of the small intestine were removed, fixed in methacarn, sectioned and stained with Alcian blue‐PAS to visualize mucins. Mucosa from the jejunum and colon were removed and total RNA prepared using Trizol®. cDNA was prepared using random hexamers and TaqMan minor groove binding probes were used for real time PCR amplification of message for Muc1 and Muc2. Expression of Muc1 in the jejunum was minimal whereas that of Muc2 increased 1.4‐fold at the higher IP6 dose rate. In the colon, expression of both Muc1 and Muc2 increased in mice dosed with IP6. Expression of Muc1 increased 1.6‐fold and 3.8‐fold in mice dosed with 1 and 2 g/kg IP6, respectively. Expression of Muc2 increased 2.0‐fold and 1.7‐fold in mice dosed with 1 and 2 g/kg IP6, respectively. Alcian blue‐PAS stained sections of the colon showed an increase in mucus. Thus, IP6 seems to increase the expression of Muc1 and Muc2 in the mucosa lining of the small intestine, particularly in the colon. Research was supported by East Tennessee State University and Mayo Clinic.

Background There is heterogeneity in the names and anatomical descriptions of regional anesthetic techniques. This may have adverse consequences on education, research, and implementation into clinical practice. We aimed to produce standardized nomenclature for abdominal wall, paraspinal, and chest wall regional anesthetic techniques. Methods We conducted an international consensus study involving experts using a three-round Delphi method to produce a list of names and corresponding descriptions of anatomical targets. After long-list formulation by a Steering Committee, the first and second rounds involved anonymous electronic voting and commenting, with the third round involving a virtual round table discussion aiming to achieve consensus on items that had yet to achieve it. Novel names were presented where required for anatomical clarity and harmonization. Strong consensus was defined as ≥75% agreement and weak consensus as 50% to 74% agreement. Results Sixty expert Collaborators participated in this study. After three rounds and clarification, harmonization, and introduction of novel nomenclature, strong consensus was achieved for the names of 16 block names and weak consensus for four names. For anatomical descriptions, strong consensus was achieved for 19 blocks and weak consensus was achieved for one approach. Several areas requiring further research were identified. Conclusions Harmonization and standardization of nomenclature may improve education, research, and ultimately patient care. We present the first international consensus on nomenclature and anatomical descriptions of blocks of the abdominal wall, chest wall, and paraspinal blocks. We recommend using the consensus results in academic and clinical practice.

Purpose We create a viable, mechanically expanded autograft long head biceps tendon (LHBT) scaffold for biologically augmenting the repair of torn rotator cuffs. Methods The proximal aspect of the tenotomized LHBTs was harvested from patients during rotator cuff repair surgery and was mechanically formed into porous scaffolds using a surgical graft expander. LHBT scaffolds were evaluated for change in area, tensile properties, and tenocyte viability before and after expansion. The ability of endogenous tenocytes derived from the LHBT scaffold to promote tenogenic differentiation of human adipose‐derived mesenchymal stromal cells (ADMSCs) was also determined. Results Autograft LHBTs were successfully expanded using a modified surgical graft expander to create a porous scaffold containing viable resident tenoctyes from patients undergoing rotator cuff repair. LHBT scaffolds had significantly increased area (length: 24.91 mm [13.91, 35.90] × width: 22.69 mm [1.87, 34.50]; P = .011) compared with the native LHBT tendon (length: 27.16 mm [2.70, 33.62] × width: 6.68 mm [5.62, 7.74]). The structural properties of the autograft were altered, including the ultimate tensile strength (LHBT scaffold: .56 MPa [.06, 1.06] vs. native LHBT: 2.35 MPa [1.36, 3.33]; P = .002) and tensile modulus (LHBT scaffold: 4.72 MPa [−.80, 1.24] versus native LHBT: 37.17 MPa [24.56, 49.78]; P = .001). There was also a reduction in resident tenocyte percent viability (LHBT scaffold: 38.52% [17.94, 59.09] vs. native LHBT: 68.87% [63.67, 74.37]; P =.004). Tenocytes derived from the LHBT scaffold produced soluble signals that initiated ADMSC differentiation into an immature tenocyte‐like phenotype, as indicated by an 8.7× increase in scleraxis ( P = .040) and a 3.6× increase in collagen type III mRNA expression ( P = .050) compared with undifferentiated ADMSC controls. Conclusions The ability to produce a viable autologous scaffold from the proximal biceps tendon having dimensions, porosity, mechanical characteristics, native ECM components, and viable tenocytes that produce bioactive signals conducive to supporting the biologic augmentation of rotator cuff repair surgery has been demonstrated. Clinical Relevance This biologically active construct may help to improve the quality of healing and regeneration at the repair site of rotator cuff tears, especially those at high risk for retear.

AbstractRegenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta-analysis summarized the effect of cell-based interventions in DKD animal models and treatment-related factors modifying outcomes. Electronic databases were searched for original investigations applying cell-based therapy in diabetic animals with kidney endpoints (January 1998-May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random-effects models. Subgroup analyses tested treatment-related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non-MSC (15%), and cell-derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell-based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial-mesenchymal-transition, oxidative stress). Preconditioning, xenotransplantation, and disease-source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell-based interventions in diabetic animals improved kidney function and reduced injury with treatment-related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.