Citations

Abstract Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) mediate growth of MM cells via activation of the mitogen-activated protein kinase (MAPK), JAK2/STAT3, and phosphatidylinositol 3′-kinase/Akt kinase (PI3-K/Akt) signaling cascades. We have previously demonstrated the in vitro and in vivo activity of Revlimid™ (CC-5013), an immunomodulatory analog (IMiD) of thalidomide, in MM. In the present study, we have examined the anti-MM activity of rapamycin, a specific mTOR inhibitor, combined with Revlimid™. This combination was highly synergistic at 0.1nmol/L of rapamycin with 0.1mmol/L of Revlimid™, and remained synergistic at higher concentrations. Based on the Chou-Talalay method, combination indices of < 1 were noted for all dose ranges of Revlimid™ and rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional (doxorubicin, melphalan, dexamethasone) chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by IL-6, IGF-1, or adherence to bone marrow stromal cells (BMSCs). Cytotoxicity triggered by a combination of rapamycin with Revlimid™ resulted in apoptosis of MM cells. Furthermore, differential signaling cascades, including the MAPK and PI3-K/Akt pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies therefore provide the framework for the clinical evaluation of targeted agents like mTOR inhibitors combined with immunomodulatory agents like Revlimid™ to improve patient outcome in MM.

Abstract Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P &lt; .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Background This single‐arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28‐day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty‐seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%‐58%), which was superior to the null hypothesis rate of 30%, but the 2‐sided P value (exact test) was .09 (1‐sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3‐35.0 months), and the median progression‐free survival was 7.9 months (95% CI, 3.7‐12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.

Background There exists a wide interindividual variability in blood pressure ( BP ) response to β 1 ‐blockers. To identify the genetic determinants of this variability, we performed a pharmacogenomic genome‐wide meta‐analysis of genetic variants influencing β 1 ‐blocker BP response. Methods and Results Genome‐wide association analysis for systolic BP and diastolic BP response to β 1 ‐blockers from 5 randomized clinical trials consisting of 1254 patients with hypertension of European ancestry were combined in meta‐analysis and single nucleotide polymorphisms (SNPs) with P <10 −4 were tested for replication in 2 independent randomized clinical trials of β 1 ‐blocker–treated patients of European ancestry (n=1552). Regions harboring the replicated SNP s were validated in a β 1 ‐blocker–treated black cohort from 2 randomized clinical trials (n=315). A missense SNP rs28404156 in BST 1 was associated with systolic BP response to β 1 ‐blockers in the discovery meta‐analysis ( P =9.33×10 −5 , β=−3.21 mm Hg) and replicated at Bonferroni significance ( P =1.85×10 −4 , β=−4.86 mm Hg) in the replication meta‐analysis with combined meta‐analysis approaching genome‐wide significance ( P =2.18×10 −7 ). This SNP in BST 1 is in linkage disequilibrium with several SNP s with putative regulatory functions in nearby genes, including CD 38 , FBXL 5 , and FGFBP 1 , all of which have been implicated in BP regulation. SNP s in this genetic region were also associated with BP response in the black cohort. Conclusions Data from randomized clinical trials of 8 European ancestry and 2 black cohorts support the assumption that BST 1 containing locus on chromosome 4 is associated with β 1 ‐blocker BP response. Given the previous associations of this region with BP , this is a strong candidate region for future functional studies and potential use in precision medicine approaches for BP management and risk prediction.

Abstract Context Conventional hypoparathyroidism treatment with oral calcium and active vitamin D is aimed at correcting hypocalcemia but does not address other physiologic defects caused by PTH deficiency. Objective To evaluate long-term safety and tolerability of recombinant human PTH (1-84) [rhPTH(1-84)]. Design Open-label extension study; 5-year interim analysis. Setting 12 US centers. Patients Adults (N = 49) with chronic hypoparathyroidism. Intervention(s) rhPTH(1-84) 25 or 50 µg/d initially, with 25-µg adjustments permitted to a 100 µg/d maximum. Main Outcome Measure(s) Safety parameters; composite efficacy outcome was the proportion of patients with ≥50% reduction in oral calcium (or ≤500 mg/d) and calcitriol (or ≤0.25 µg/d) doses, and albumin-corrected serum calcium normalized or maintained compared with baseline, not exceeding upper limit of normal. Results Forty patients completed 60 months of treatment. Mean albumin-corrected serum calcium levels remained between 8.2 and 8.7 mg/dL. Between baseline and month 60, levels ± SD of urinary calcium, serum phosphorus, and calcium-phosphorus product decreased by 101.2 ± 236.24 mg/24 hours, 1.0 ± 0.78 mg/dL, and 8.5 ± 8.29 mg2/dL2, respectively. Serum creatinine level and estimated glomerular filtration rate were unchanged. Treatment-emergent adverse events (AEs) were reported in 48 patients (98.0%; hypocalcemia, 36.7%; muscle spasms, 32.7%; paresthesia, 30.6%; sinusitis, 30.6%; nausea, 30.6%) and serious AEs in 13 (26.5%). At month 60, 28 patients (70.0%) achieved the composite efficacy outcome. Bone turnover markers increased, peaked at ∼12 months, and then declined to values that remained above baseline. Conclusion Treatment with rhPTH(1-84) for 5 years demonstrated a safety profile consistent with previous studies and improved key biochemical parameters.

Selection of antihypertensive treatment according to self-defined ethnicity is recommended by some guidelines but might be better guided by individual genotype rather than ethnicity or race. We compared the extent to which variation in blood pressure response across different ethnicities may be explained by genetic factors: genetically defined ancestry and gene variants at loci known to be associated with blood pressure. We analyzed data from 5 trials in which genotyping had been performed (n=4696) and in which treatment responses to β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, thiazide or thiazide-like diuretic and calcium channel blocker were available. Genetically defined ancestry for proportion of African ancestry was computed using the 1000 genomes population database as a reference. Differences in response to the thiazide diuretic hydrochlorothiazide, the β-blockers atenolol and metoprolol, the angiotensin-converting enzyme inhibitor lisinopril, and the angiotensin receptor blocker candesartan were more closely associated to genetically defined ancestry than self-defined ethnicity in admixed subjects. A relatively small number of gene variants related to loci associated with drug-signaling pathways ( KCNK3, SULT1C3, AMH, PDE3A, PLCE1, PRKAG2 ) with large effect size (−3.5 to +3.5 mm Hg difference in response per allele) and differing allele frequencies in black versus white individuals explained a large proportion of the difference in response to candesartan and hydrochlorothiazide between these groups. These findings suggest that a genomic precision medicine approach can be used to individualize antihypertensive treatment within and across populations without recourse to surrogates of genetic structure such as self-defined ethnicity.

There are contrasting data on concomitant Impella device in cardiogenic shock patients treated with venoarterial extracorporeal membrane oxygenation (VA ECMO) (ECPELLA). This study sought to compare early mortality in patients with cardiogenic shock treated with ECPELLA in comparison to VA ECMO alone. We reviewed the published literature from 2000 to 2018 for randomized, cohort, case-control, and case series studies evaluating adult patients requiring VA ECMO for cardiogenic shock. Five retrospective observational studies, representing 425 patients, were included. Venoarterial extracorporeal membrane oxygenation with concomitant Impella strategy was used in 27% of the patients. Median age across studies varied between 51 and 63 years with 59–88% patients being male. Use of ECPELLA was associated with higher weaning from VA ECMO and bridging to permanent ventricular assist device or cardiac transplant in three and four studies, respectively. The studies showed moderate heterogeneity with possible publication bias. The two studies that accounted for differences in baseline characteristics between treatment groups reported lower 30 day mortality with ECPELLA versus VA ECMO. The remaining three studies did not adjust for potential confounding and were at high risk for selection bias. In conclusion, ECPELLA is being increasingly used as a strategy in patients with cardiogenic shock. Additional large, high-quality studies are needed to evaluate clinical outcomes with ECPELLA.

Background This study sought to evaluate the 15‐year national utilization, trends, predictors, disparities, and outcomes of palliative care services ( PCS ) use in cardiogenic shock complicating acute myocardial infarction. Methods and Results A retrospective cohort from January 1, 2000 through December 31, 2014 was analyzed using the National Inpatient Sample database. Administrative codes for acute myocardial infarction–cardiogenic shock and PCS were used to identify eligible admissions. The primary outcomes were the frequency, utilization trends, and predictors of PCS . Secondary outcomes included in‐hospital mortality and resources utilization. Multivariable regression and propensity‐matching analyses were used to control for confounding. In this 15‐year period, there were 444 253 acute myocardial infarction–cardiogenic shock admissions, of which 4.5% received PCS . The cohort receiving PCS was older, of white race, female sex, and with higher comorbidity and acute organ failure. The PCS cohort received fewer cardiac procedures, but more noncardiac organ support therapies. Older age, female sex, white race, higher comorbidity, higher socioeconomic status, admission to a larger hospital, and admission after 2008 were independent predictors of PCS use. Use of PCS was independently associated with higher in‐hospital mortality (odds ratio 6.59 [95% CI 6.37–6.83]; P <0.001). The cohort with PCS use had >2‐fold higher in‐hospital mortality, 12‐fold higher use of do‐not‐resuscitate status, lesser in‐hospital resource utilization, and fewer discharges to home. Similar findings were observed in the propensity‐matched cohort. Conclusions PCS use in patients with acute myocardial infarction–cardiogenic shock is low, though there is a trend towards increased adoption. There are significant patient and hospital‐specific disparities in the utilization of PCS .