Citations

Abstract Poly ADP-ribose polymerase (PARP) inhibitors, including talazoparib, potentiate temozolomide efficacy in multiple tumor types; however, talazoparib-mediated sensitization has not been evaluated in orthotopic glioblastoma (GBM) models. This study evaluates talazoparib ± temozolomide in clinically relevant GBM models. Talazoparib at 1–3 nmol/L sensitized T98G, U251, and GBM12 cells to temozolomide, and enhanced DNA damage signaling and G2–M arrest in vitro. In vivo cyclical therapy with talazoparib (0.15 mg/kg twice daily) combined with low-dose temozolomide (5 mg/kg daily) was well tolerated. This talazoparib/temozolomide regimen prolonged tumor stasis more than temozolomide alone in heterotopic GBM12 xenografts [median time to endpoint: 76 days versus 50 days temozolomide (P = 0.005), 11 days placebo (P < 0.001)]. However, talazoparib/temozolomide did not accentuate survival beyond that of temozolomide alone in corresponding orthotopic xenografts [median survival 37 vs. 30 days with temozolomide (P = 0.93), 14 days with placebo, P < 0.001]. Average brain and plasma talazoparib concentrations at 2 hours after a single dose (0.15 mg/kg) were 0.49 ± 0.07 ng/g and 25.5±4.1 ng/mL, respectively. The brain/plasma distribution of talazoparib in Bcrp−/− versus wild-type (WT) mice did not differ, whereas the brain/plasma ratio in Mdr1a/b−/− mice was higher than WT mice (0.23 vs. 0.02, P < 0.001). Consistent with the in vivo brain distribution, overexpression of MDR1 decreased talazoparib accumulation in MDCKII cells. These results indicate that talazoparib has significant MDR1 efflux liability that may restrict delivery across the blood–brain barrier, and this may explain the loss of talazoparib-mediated temozolomide sensitization in orthotopic versus heterotopic GBM xenografts. Mol Cancer Ther; 16(12); 2735–46. ©2017 AACR.

AbstractVenous thromboembolism (VTE) is a frequent complication of cancer associated with morbidity, mortality, increased hospitalizations and higher health care costs. Cancer patients at increased risk for VTE can be identified using a validated risk assessment score, and the incidence of VTE can be reduced in high-risk settings using anticoagulation. Rivaroxaban is a potent, oral, direct, factor Xa inhibitor approved for the prevention and treatment of thromboembolic events, including VTE. CASSINI is a double-blind, randomized, parallel-group, multicentre study comparing rivaroxaban with placebo in adult ambulatory patients with various cancers who are initiating systemic cancer therapy and are at high risk of VTE (Khorana score ≥ 2). Patients with primary brain tumours or those at risk for bleeding are excluded. Approximately 700 patients will be randomized 1:1 to rivaroxaban 10 mg daily or placebo for up to 6 months if there is no evidence of VTE from compression ultrasonography (CU) during screening or from routine care imaging within 30 days prior to randomization. Mandatory CU will also be performed at weeks 8 and 16 (±7 days), and at study end (±3 days). The primary efficacy hypothesis is that anticoagulation with rivaroxaban reduces the composite of objectively confirmed symptomatic or asymptomatic, lower-extremity, proximal deep-vein thrombosis (DVT); symptomatic, upper-extremity DVT; symptomatic or incidental pulmonary embolism; and VTE-related death compared with placebo. The primary safety objective is to assess major bleeding events (Clinical trial information: NCT02555878).

The use of venovenous extracorporeal membrane oxygenation (VV-ECMO) has traditionally been limited to a narrow set of clinical circumstances, such as acute hypoxic respiratory failure, submassive pulmonary embolism, and cardiopulmonary collapse. Within the pediatric population, there have been cases of VV-ECMO in the context of extrinsic airway compression by a mediastinal mass, typically in the setting of either a lymphoma or germ cell tumors. However, the use of VV-ECMO for adults with extrinsic airway compression is comparatively limited. More specifically, VV-ECMO has been used as a bridge for tracheal reconstruction in both children and adults. Although, it has not been used in adults in the context of palliative endobronchial stent placement. We present a case of a 49-year-old woman with refractory multiple myeloma and extramedullary plasmacytoma presenting with acute hypoxic respiratory failure from extrinsic airway compression by a mediastinal plasmacytoma. We were able to use VV-ECMO to assist with endobronchial stent placement, followed by radiation therapy, and ultimately hospital discharge. In this article, we also review the literature surrounding VV-ECMO for extrinsic airway compression.

AbstractIntroductionExisting studies predominantly consider the association of late‐life lipid levels and subsequent cognitive change. However, midlife rather than late‐life risk factors are often most relevant to cognitive health.MethodsWe quantified the association between measured serum lipids in midlife and subsequent 20‐year change in performance on three cognitive tests in 13,997 participants of the Atherosclerosis Risk in Communities study.ResultsElevated total cholesterol, low‐density lipoprotein cholesterol, and triglycerides were associated with greater 20‐year decline on a test of executive function, sustained attention, and processing speed. Higher total cholesterol and triglycerides were also associated with greater 20‐year decline in memory scores and a measure summarizing performance on all three tests. High‐density lipoprotein cholesterol was not associated with cognitive change. Results were materially unchanged in sensitivity analyses addressing informative missingness.DiscussionElevated total cholesterol, low‐density lipoprotein cholesterol, and triglycerides in midlife were associated with greater 20‐year cognitive decline.

There is mounting evidence that forward heart failure as manifested by low cardiac output alone does not define the degree of renal dysfunction in cardiorenal syndrome. As a result, the term “congestive renal failure” was coined in 2012 by Ross to depict the role of renal venous hypertension in type 1 acute cardiorenal syndrome. If so, aggressive decongestive therapies, either through mechanical ultrafiltration with dialysis machines or pharmacologic ultrafiltration with potent diuretics, would lead to improved cardio and renal outcomes. Nevertheless, as recently as 2012, a review of this literature had concluded that a renal venous hypertension-directed approach using diuretics to manage cardio-renal syndrome was yet to be fully investigated. We, in this review, with three consecutive case series, describe our experience with pharmacologic decongestive diuresis in this paradigm of care and argue for studies of such therapeutic interventions in the management of cardiorenal syndrome. Finally, based on our observations in the Renal Unit, Mayo Clinic Health System, in Northwestern Wisconsin, we have hypothesized that patients with cardiorenal syndrome presenting with accelerated rising Pro B Naturetic Peptide levels appear to represent a group that would have good cardio- and renal-outcomes with such decongestive pharmacologic therapies.

Study Objective The extended‐release ( ER ) form of venlafaxine is preferred because of improved patient adherence, but the immediate‐release (IR) form is frequently used after Roux‐en‐Y gastric bypass ( RYGB ) surgery because of concerns for malabsorption. The objective of this study was to determine whether a statistically significant and predictable change in the bioavailability of venlafaxine ER capsules occurs after RYGB . Design Prospective nonblinded single‐dose pharmacokinetic study. Setting Clinical research unit at a large tertiary care medical practice. Patients Ten adult pre–bariatric surgery patients who met the criteria for noncomplicated RYGB were enrolled and served as their own controls. Interventions Patients were administered one venlafaxine ER 75‐mg capsule at two visits—the first visit at least 1 week before undergoing RYGB and the second visit 3–4 months after RYGB . Blood samples were collected at predetermined intervals over 48 hours after each dose, and the pharmacokinetics of venlafaxine were measured. Measurements and Main Results Plasma levels of venlafaxine and its primary metabolite, O ‐desmethylvenlafaxine ( ODV ), were compared at baseline and 3–4 months after RYGB . The areas under the serum concentration–time curves from 0–24 hours ( AUC 0–24 ) for venlafaxine (mean ± SD 734 ± 602 vs 630 ± 553 ng·hr/ml, p=0.22) and ODV (mean ± SD 894 ± 899 vs 1083 ± 972 ng·hr/ml, p=0.07) were similar before and after RYGB . Using a bioequivalence approach, differences in pre‐ RYGB and post‐ RYGB values of AUC 0–24 , peak serum concentration, and time to peak serum concentration were not statistically significant for either venlafaxine or ODV. Conclusion This study suggests that RYGB does not significantly alter the amount of venlafaxine or its active metabolite, ODV , absorbed from a venlafaxine ER capsule or the time over which it is absorbed.

Objective To describe self-reported disease understanding for newly diagnosed patients with atrial fibrillation (AF) and assess (1) how disease understanding changes over the first 6 months after diagnosis and (2) the relationship between patient understanding of therapies at baseline and treatment receipt at 6 months among treatment-naïve patients. Methods We analysed survey data from SATELLITE (Survey of Patient Knowledge and Personal Priorities for Treatment), a substudy of patients with new-onset AF enrolled in the national Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) II registry across 56 US sites. Patients were surveyed at the baseline and 6-month follow-up clinic visits using Likert scales. Results Among 1004 baseline survey responses, patients’ confidence in their understanding of rhythm control, ablation, anticoagulation and cardioversion was suboptimal, with ‘high’ understanding ranging from 8.5% for left atrial appendage closure to 71.3% for rhythm therapy. Of medical history and demographic factors, education level was the strongest predictor of reporting ‘high’ disease understanding. Among the 786 patients with 6-month survey data, significant increases in the proportion reporting high understanding were observed (p<0.05) only for warfarin and direct oral anticoagulants (DOACs). With the exception of ablation, high understanding for a given therapeutic option was not associated with increased use of that therapy at 6 months. Conclusions About half of patients with new-onset AF understood the benefits of oral anticoagulant at the time of diagnosis and understanding improved over the first 6 months. However, understanding of AF treatment remains suboptimal at 6 months. Our results suggest a need for ongoing patient education. Clinical trial registration Clinicaltrials.gov. Identifier: NCT01701817.

Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.