Citations

Abstract Monoclonal antibodies that target the programmed death-1 (PD-1)–programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to IL2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1–positive tumor-infiltrating lymphocytes were identified in 50% (13 of 26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P = 0.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation, and patients with these tumors may be good candidates for treatment with anti–PD-1/PD-L1 therapies. Cancer Immunol Res; 3(12); 1303–7. ©2015 AACR.

BACKGROUND: Although under-reported and understudied, unplanned extubations carry a significant risk of patient harm and even death. They are an important yardstick of quality control of care of intubated patients in the ICU. A unit-based risk assessment and multidisciplinary approach is required to decrease the incidence of unplanned extubations. METHODS: As part of a quality-improvement initiative of Children's Hospital at Montefiore, all planned and unplanned extubations in a multidisciplinary 20-bed pediatric ICU were evaluated over a 12-month period (January to December 2010). At the end of 6 months, an interim analysis was performed, and high-risk patient groups and patient care factors were identified. These factors were targeted in the second phase of the project. RESULTS: Over this period, there were a total of 267 extubations, of which 231 (87%) were planned extubations and 36 (13%) were unplanned. A patient care policy targeting the risk factors was instituted, along with extensive nursing and other personnel education in the second phase. As a result of this intervention, the unplanned extubation rate in the pediatric ICU decreased from 3.55 to 2.59/100 intubation days. All subjects who had an unplanned extubation during nursing procedures or transport required re-intubation, whereas none of the unplanned extubations during ventilator weaning required re-intubation. CONCLUSIONS: A targeted approach based on unit-specific risk factors is most effective in quality-improvement projects. A specific policy for sedation and weaning can be very helpful in managing intubated patients and preventing unintended harm.

AbstractAbstract In a randomized trial of 130 surgical patients, use of a decision aid consisting of laminated cards with pros and cons of continuing smoking, attempting temporary abstinence, or attempting to quit smoking improved measures of decisional quality but did not change perioperative tobacco use behavior. Background: Decision aids can increase patient involvement in decision-making about health care. The study goal was to develop and test a decision aid for use by clinicians in discussion options for changing smoking behavior before and after elective surgery. Methods: In formative work, a decision aid was designed to facilitate patient–clinician discussion regarding three options: continue smoking, attempt a period of temporary abstinence, and attempt to quit smoking for good. A randomized, two-group pilot study was then conducted in smokers evaluated in preparation for elective surgery in a preoperative clinic to test the hypothesis that the decision aid would improve measures of decisional quality compared with usual care. Results: The final decision aid consisted of three laminated cards. The front of each card included a colorful graphic describing each choice; the reverse including two to three pros and cons for each decision, a simple graphic illustrating the effects of smoking on the body, and a motivational phrase. In the randomized trial of 130 patients, the decision aid significantly ( P < 0.05) improved measures of decisional quality and patient involvement in decision making (Cohen’s d effect sizes of 0.76 and 1.20 for the Decisional Conflict Scale and Observing PatienT involvement In decisiON-making scale, respectively). However, the decision aid did not affect any aspect of perioperative smoking behavior, including the distribution of or adherence to choices. Conclusions: Although the use of a decision aid to facilitate clinician–patient discussions regarding tobacco use around the time of surgery substantially improved measures of decisional quality, it alone did not change perioperative tobacco use behavior.

Abstract Background: The development of novel chemotherapeutic agents has significantly improved the prognosis and survival of patients with breast cancer. ER positive or luminal tumors represent around two thirds of all breast cancers and these cancers are comprised of different histologies including differing gene expression and mutational profiles. This study examined biomarkers involved in immune evasion including PD-L1 and its association with other biological pathways as potential treatment options for luminal breast cancer patients. Methods: We analyzed 1311 breast samples using a multiplatform approach including whole genome mRNA expression (HumanHT-12 v4 BeadChip Illumina Inc., San Diego, CA), protein expression (immunohistochemistry), gene copy number changes (in situ hybridization) and gene sequencing and an additional 304 breast samples were tested for PD-1 and PD-L1 by IHC. The mRNA expression data was based on whole tumor and represents cell type heterogeneity. Heat map analysis was done to look at differential gene expression between the PD-L1 high vs low luminal breast cancers. Results: Based on expression of ER, PR and HER2 by IHC, we subdivided the data into sub- cohorts. Elevated mRNA expression of immune markers including PD-L1, CTLA4, B7H-3, and IDO1 was noted in the ER+HER2- luminal population including ER+ PR- and ER+PR+ cohort. Positive correlation was found between PD-L1 and other immune regulators including CTLA-4, B7-H3 and IDO1 (Spearman correlations of 0.49, 0.36 and 0.46). Protein expression of PD-L1 was found to be specific to the HER2 negative cohort with no expression in the HER2 positive cohort regardless of ER status. Within the ER+HER2- cohort, PD-L1 expression was 5% {ER+PR+ was 5% (4/81) and the ER+PR- was 6% (2/34)}. In contrast, PD-L1 expression was higher in the triple negative cohort, 17% (13/75). The expression of PD-1 on the other hand was present throughout the different cohorts. PD-1 expression ranged from 43% in the ER+HER2- cohort {41% (14/34) in ER+PR-HER2-; 43% (35/81) in ER+PR+HER2-} to 33% in the ER+HER2+ cohort {44% (4/9) in ER+PR-Her2+; and 17% (1/6) in ER+PR+HER2+}. In the ER-HER2+ cohort PD-L1 expression was 75%{6/8 in ER-PR-HER2+ and 0/0 in ER-PR+HER+} and 63%(47/75) in the triple negative cohort. Pathway analysis of the PD-L1 negative vs positive luminal population identified 127 genes involved in various cancer pathways including EGFR and VEGF signaling network (P=7.47e-09). Conclusions: The expression of immune regulatory targets in the breast cancer population suggests that immune- targeted therapies with anti PD-1/PD-L1, CTLA4, B7-H3 and IDO1 may be effective especially in the luminal cohort. Our study further shows that ER+HER2- breast cancer patients may be better candidates for immunotherapy with checkpoint inhibitors as compared to ER+HER2+ due to lack of PD-L1 expression in the HER2 positive cohort. Further validation of our findings is ongoing. Citation Format: Gargi D Basu, Anatole Ghazalpour, Randal Vader, Sandeep Reddy, Karen Anderson, Ann McCullough, Barbara Pockaj. Expression of novel immunotherapeutic targets in luminal breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-08.

Abstract Cigarette smoking is a major risk factor in the development of non–small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers. Nicotine, the major addictive component of tobacco smoke, can induce proliferation, invasion, and epithelial-to-mesenchymal transition (EMT) in NSCLC cell lines and promote metastasis of NSCLC in mice. Here, we demonstrate that the scaffolding protein β-arrestin-1 is necessary for nicotine-mediated induction of mesenchymal genes vimentin and fibronectin as well as EMT regulators ZEB1 and ZEB2. Nicotine induced changes in cell morphology and ablate tight junctions consistent with EMT; β-arrestin-1, but not β-arrestin-2, was required for these changes. β-Arrestin-1 promoted the expression of the mesenchymal genes, as well as ZEB1 and ZEB2, through the mediation of the E2F1 transcription factor; this required Src kinase activity. Stimulation of multiple NSCLC cell lines with nicotine led to enhanced recruitment of β-arrestin-1 and E2F1 on vimentin, fibronectin, and ZEB1 and ZEB2 promoters. Furthermore, there was significantly more β-arrestin-1 and E2F1 associated with these promoters in human NSCLC tumors, and β-arrestin-1 levels correlated with vimentin and fibronectin levels in human NSCLC samples. A549-luciferase cells lacking β-arrestin-1 showed a significantly reduced capacity for tumor growth and metastasis when orthotopically implanted into the lungs of SCID-beige mice. Taken together, these studies reveal a novel role for β-arrestin-1 in the growth and metastasis of NSCLC. Cancer Res; 75(6); 1009–20. ©2015 AACR.

AbstractBackground and ObjectivesPrevious studies have established the relationship between tobacco use and pain severity among patients suffering from chronic pain. Unfortunately, many physicians feel underprepared to counsel patients on smoking cessation. The purpose of this study was to identify the attitudes, beliefs, and practices of pain medicine fellowship directors in regard to tobacco control interventions and trainee education.MethodsProgram directors of ACGME‐accredited pain medicine fellowships were surveyed via a web‐based form to assess current practices in tobacco intervention and to gauge interest in incorporating tobacco control into their current fellowship training curriculum.ResultsOf the respondents, the majority indicated that they frequently asking their patients about tobacco use and advise them to quit. In addition, most agreed that presenting tobacco control is a responsibility of pain physicians. However, few consistently provided any assistance with quitting. Finally, the majority of program directors felt that pain medicine fellowships should include tobacco control training and were interested in incorporating an educational module about smoking and pain into their training program.ConclusionsThis survey of pain medicine fellowship program directors indicates that although smoking cessation interventions are not being consistently applied in academic pain practices, there is a strong interest in doing so. Furthermore, the majority of program directors recognized the importance of incorporating tobacco control training into pain medicine fellowships. This recognition may provide an opportunity to develop a web‐based training module that could be easily incorporated into the upcoming milestones in pain medicine training.

BackgroundEndocardial ablation approaches targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) have been proposed. However, the potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance. We hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins.Methods and ResultsWe reviewed 155 OHTs (mean age 52 ± 11 years, 72% males) and used 1:1 age‐, sex‐, and date‐of‐surgery‐matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls. Postoperative AF occurred in 10/155 (6.5%) OHT patients. The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13–0.57], vs CABG: OR 0.38 [0.17–0.81], P = 0.003; and on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13–0.60], vs CABG: OR 0.14 [0.04–0.47], P = 0.0009).ConclusionsRisk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but only OHT causes disruption of autonomic innervation, this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation.