Citations

Abstract Purpose: Effective sensitizing strategies potentially can extend the benefit of temozolomide (TMZ) therapy in patients with glioblastoma (GBM). We previously demonstrated that robust TMZ-sensitizing effects of the [poly (ADP-ribose) polymerase] (PARP) inhibitor veliparib (ABT-888) are restricted to TMZ-sensitive GBM xenografts. The focus of this study is to provide an understanding for the differential sensitization in paired TMZ-sensitive and -resistant GBM models. Experimental Design: The impact of veliparib on TMZ-induced cytotoxicity and DNA damage was evaluated in vitro and in vivo in models of acquired TMZ resistance (GBM12TMZ-mgmtHigh, GBM12TMZ-mgmtLow, and U251TMZ), inherent TMZ resistance (T98G), and TMZ-sensitive (U251 and GBM12). In vivo drug efficacy, pharmacokinetics, and pharmacodynamics were analyzed using clinically relevant dosing regimens. Results: Veliparib enhanced TMZ cytotoxicity and DNA-damage signaling in all GBM models in vitro with more pronounced effects in TMZ-resistant lines at 3 to 10 μmol/L veliparib. In vivo, combined TMZ/veliparib, compared with TMZ alone, significantly delayed tumor growth and enhanced DNA-damage signaling and γH2AX levels in the sensitive GBM12 xenograft line but not in the resistant GBM12TMZ lines. The pharmacokinetic profile of veliparib was similar for GBM12 and GBM12TMZ tumors with Cmax (∼1.5 μmol/L) in tissue significantly lower than concentrations associated with optimal in vitro sensitizing effects for resistant tumors. In contrast, robust suppression of PARP-1 expression by shRNA significantly increased TMZ sensitivity of U251TMZ in vitro and in vivo. Conclusions: In vitro cytotoxicity assays do not adequately model the therapeutic index of PARP inhibitors, as concentrations of veliparib and TMZ required to sensitize TMZ-resistant cancer cells in vivo cannot be achieved using a tolerable dosing regimen. Clin Cancer Res; 20(14); 3730–41. ©2014 AACR.

Background Prior studies demonstrate reduced cortical thickness and volume in migraineurs. However, the effect of age on cortical thickness has not been assessed in migraineurs. In this study we investigated whether the process of aging on cortical thickness affects migraineurs differently compared to age-matched healthy controls, i.e. whether aging exacerbates cortical thinning in migraineurs. Methods Cortical thickness was estimated using a general linear model vertex-by-vertex approach for 32 healthy controls (mean age = 35.3 years; SD = 11.6) and 27 episodic migraine patients (mean age = 33.6 years; SD = 12.3). Results were modeled using a main effect analysis to estimate the effect of age on cortical thickness for each group separately, and an age-by-group analysis to estimate differences in age-related cortical thinning between migraine patients and normal controls. Results Although migraineurs and normal controls both have expected age-related thinning in many regions along the cortical mantle, migraineurs have age-related thinning of regions that do not thin in healthy controls, including: bilateral postcentral, right fusiform, and right temporal pole areas. Cortical thinning of these regions is more prominent with advancing age. Conclusion Results suggest that migraine is associated with atypical cortical aging, suggesting that the migraine disease process interacts with aging to affect cortical integrity.

Context: Molecular markers hold the promise of improved diagnostic yield in thyroid fine-needle biopsy. The Afirma gene expression classifier (GEC), available commercially, reports a negative predictive value of 94% in the diagnosis of benign nodules after indeterminate cytology. However, there are currently no independent studies of the performance of this assay. Objective: The aim was to assess the performance of the Afirma GEC in an academic medical center. Design: Samples for the GEC were collected according to the manufacturer's recommended protocol from patients undergoing thyroid fine-needle aspiration. We requested GEC analysis on nodules reported cytologically as follicular neoplasm or atypia or follicular lesion of undetermined significance from patients willing to defer surgery. Patients: All patients undergoing thyroid fine-needle aspiration during the study period, whose cytology was reported as follicular neoplasm or atypia of undetermined significance/follicular lesion of undetermined significance, were offered access to the test and recruited to this study. Intervention: Patients whose GEC was “benign” were offered ultrasound follow-up in lieu of surgery. Those with a “suspicious” GEC were advised to undergo diagnostic lobectomy. Setting: The study was conducted at a large academic medical center. Main Outcome Measure: We measured the rate of benign and suspicious calls from the Afirma GEC and histological diagnosis after surgery. Results: A total of 72 nucleic acid samples were sent for GEC analysis. In 12 (17%) of these samples, there was insufficient mRNA, leaving 60 Afirma results for analysis. Of these, 16 (27%) were benign, whereas 44 (73%) were suspicious. The rate of confirmed malignancy in GEC-suspicious nodules was only 17%. Conclusion: The Afirma GEC demonstrates a lower than expected rate of benign reports in follicular or Hürthle cell neoplasm and a lower than anticipated malignancy rate within GEC-suspicious nodules. These data suggest that the positive predictive value of the GEC is lower than previously reported and call into question the performance of the test when applied in the context of specialized academic cytopathology.

Objective. Guidelines on antiplatelet medication use during endoscopy are based on limited evidence. We investigate the risk of bleeding and ischemic events in patients undergoing endoscopic mucosal resection (EMR) of esophageal lesions in the setting of scheduled cessation and prompt resumption of clopidogrel. Design. Single centre retrospective review. Patients. Patients undergoing EMR of esophageal lesions. Interventions. Use of clopidogrel before EMR and resumption after EMR. Patients cease antiplatelets and anticoagulants 7 days before EMR and resume clopidogrel 2 days after EMR in average risk patients. Main Outcomes. Gastrointestinal bleeding (GIB) and ischemic events (IE) within 30 days of EMR. Results. 798 patients underwent 1716 EMR. 776 EMR were performed on patients on at least 1 antiplatelet/anticoagulant (APAC). 17 EMR were performed following clopidogrel cessation. There were 14 GIB and 2 IE. GIB risk in the setting of recent clopidogrel alone (0%) was comparable to those not on APAC (1.1%) (P=1.0). IE risk on clopidogrel (6.3%) was higher than those not on APAC (0.1%) (P=0.03). Limitations. Retrospective study. Conclusions. Temporary cessation of clopidogrel before EMR and prompt resumption is not associated with an increased risk of gastrointestinal bleeding but may be associated with increased ischemic events.

Abstract Myeloid dendritic cells (mDC) activated with a B7-DC-specific cross-linking IgM Ab (B7-DC XAb) take up and retain Ag and interact with T cell compartments to affect a number of biologic changes that together cause strong antitumor responses and blockade of inflammatory airway disease in animal models. The molecular events mediating the initial responses in mDC remain unclear. In this study we show that B7-DC XAb caused rapid phosphorylation of the adaptor protein DAP12 and intracellular kinases Syk and phospholipase C-γ1. Pretreatment of mDC with the Syk inhibitor piceatannol blocked B7-DC XAb-induced Ag uptake with a concomitant loss of tumor protection in mice. Vaccination with tumor lysate-pulsed wild-type B7-DC XAb-activated mDC, but not TREM-2 knockout XAb-activated mDC, protected mice from lethal melanoma challenge. Multimolecular caps appeared within minutes of B7-DC XAb binding to either human or mouse mDC, and FRET analysis showed that class II, CD80, CD86, and TREM-2 are recruited in tight association on the cell surface. When TREM-2 expression was reduced in wild-type mDC using short hairpin RNA or by using mDC from TREM-2 knockout mice, in vitro DC failed to take up Ag after B7-DC XAb stimulation. These results directly link TREM-2 signaling with one change in the mDC phenotype that occurs in response to this unique Ab. The parallel signaling events observed in both human and mouse mDC support the hypothesis that B7-DC cross-linking may be useful as a therapeutic immune modulator in human patients.

Abstract Rationale Provider decisions about patients to be discharged from the intensive care unit (ICU) are often based on subjective intuition, sometimes leading to premature discharge and early readmission. The Stability and Work Load Index for Transfer (SWIFT) score, as a risk stratification tool, has moderate ability to predict patients at risk of ICU readmission. Objectives To describe findings following the incorporation of the SWIFT score into the discharge workflow of a medical ICU. Methods The study involved 5,293 consecutive patients discharged alive from the medical ICU of an academic medical center. The SWIFT score and associated percentage risk for readmission were incorporated into daily rounds for purpose of discharge decision-making. We measured readmission rates before and after implementation and observed changes in provider discharge decisions for individual patients after SWIFT discussions. Measurements and Main Results Baseline (n = 1,906) and implementation (n = 1,938) cohorts differed with respect to APACHE III scores (P = 0.03). In the implementation cohort, 26.2% of subjects had SWIFT scores greater than 15 and thus were predicted to have a higher risk of unplanned readmissions. In this high-risk group, 25% had SWIFT discussed in their discharge planning. There was modification of provider discharge decisions in 108 (30%) of cases in which the SWIFT was discussed. SWIFT score values above a prespecified cutoff of 15 were associated with physician tendency to prolong ICU stay or to discharge to a monitored setting (P < 0.001). There was no difference in 24-hour or 7-day readmission rates between the baseline and implementation cohorts (1.9 vs. 2.4%, P = 0.24; 6.5 vs. 7.4%, P = 0.26, respectively) even after adjustment for severity of illness. Conclusions Using the SWIFT score as an adjunct to clinical judgment, physicians modified their discharge decisions in one-third of subjects. Introducing such tools into the discharge workflow may present change management challenges that limit the evaluation of their impact on readmission rates and other relevant ICU outcomes.