Citations

Abstract Purpose: Recent studies suggest that SIRT1-activating compounds (STAC) are a promising class of anticancer drugs, although their mechanism of action remains elusive. The main goal of this study is to determine the role of STACs as a potential therapy for pancreatic cancer. In addition, we also explored the mechanism by which these compounds affect pancreatic cancer. Experimental design: Using in vitro (cell culture experiments) and in vivo (xenograft experiments) approaches, we studied the role of SIRT1 agonists (STAC) in human pancreatic cancer cell viability and growth. Results: We show that SIRT1 is highly expressed in pancreatic cancer cells and that the STACs SRT1720, SRT1460, and SRT3025 inhibited cell growth and survival of pancreatic cancer cells. STACs enhanced the sensitivity of pancreatic cells to gemcitabine and paclitaxel, indicating that these drugs could be used in combination with other chemotherapy drugs. We also show that STACs were very effective in inhibiting tumor xenograft growth. In mechanistic studies, we observed that STACs activated a SIRT1 lysosomal–dependent cell death. Furthermore, the effect of STACs on cell viability was also dependent on the expression of the endogenous SIRT1 inhibitor DBC1. Conclusions: Taken together, our results reveal an essential role for SIRT1 and lysosomes in the death pathway regulated by STACs in pancreatic cancer cells. Clin Cancer Res; 22(10); 2496–507. ©2015 AACR.

The purpose of this study was to assess the impact of decisions made at operation for primary neck tumor on survival and cause of death—specifically, whether bilateral dissection, unilateral dissection, or delayed dissection influences eventual outcome. Of 244 patients with primary cancer of the supraglottis who were treated surgically, 22 (9%) had no neck treatment, 188 (77%) had unilateral neck dissection, and 34 (14%) had bilateral simultaneous neck dissection. Dissection on one or both sides of the neck was required later in 6 (27%) of the 22 patients with no neck treatment and in 32 (17%) of the 188 patients who had unilateral dissection. There were no differences among the treatment groups in the incidence of death from any cause or in the incidence of death from cancer, although neck stage did differ from group to group. The influence of delayed metastasis on survival was analyzed to explain these findings. Multivariate analysis demonstrated that death occurred at a rate 1.81 times higher in a person with a positive neck stage than in a person of the same age who had a negative stage. Also, death occurred at a rate 1.5 times higher for a person 10 years older than for a person with the same stage of disease. The influence of stage on the probability of need for a second dissection indicated that a patient with a positive neck stage had a 6.3 times greater likelihood of requiring a subsequent neck dissection than a person with a negative neck stage.

Purpose Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. Patients and Methods Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). Results The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). Conclusion The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

Embolic coiling is one of the most effective treatments for cerebral aneurysms (CAs), largely due to the hemodynamic modifications that the treatment effects in the aneurysmal environment. However, coiling can have very different hemodynamic outcomes in aneurysms with different geometries. Previous work in the field of biofluid mechanics has demonstrated on a general level that geometry is a driving factor behind aneurysmal hemodynamics. The goal of this study was to relate two specific geometric factors that describe CAs (i.e., dome size (DS) and parent-vessel contact-angle (PV-CA)) and one factor that describes treatment (i.e., coil packing density (PD)) to three clinically relevant hemodynamic responses (i.e., aneurysmal root-mean-square velocity (Vrms), aneurysmal wall shear stress (WSS), and cross-neck flow (CNF)). Idealized models of basilar tip aneurysms were created in both virtual and physical forms to satisfy two-level multifactorial experimental designs. Steady and pulsatile flow hemodynamics were then evaluated in the virtual models using computational fluid dynamics (CFD) (before and after virtual treatment with finite element (FE) embolic coil models), and hemodynamics were also evaluated in the physical models using particle image velocimetry (PIV) (before and after treatment with actual embolic coils). Results showed that among the factors considered, PD made the greatest contributions to effects on hemodynamic responses in and around the aneurysmal sac (i.e., Vrms and WSS), while DS made the greatest contributions to effects on hemodynamics at the neck (i.e., CNF). Results also showed that while a geometric factor (e.g., PV-CA) may play a relatively minor role in dictating hemodynamics in the untreated case, the same factor can play a much greater role after coiling. We consider the significance of these findings in the context of aneurysmal recurrence and rupture, and explore potential roles for the proposed methods in endovascular treatment planning.

Abstract Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109

ObjectivesWe sought to develop a scoring system that predicts the risk of serious adverse events (SAE's) for individual pediatric patients undergoing cardiac catheterization procedures.BackgroundSystematic assessment of risk of SAE in pediatric catheterization can be challenging in view of a wide variation in procedure and patient complexity as well as rapidly evolving technology.MethodsA 10 component scoring system was originally developed based on expert consensus and review of the existing literature. Data from an international multi‐institutional catheterization registry (CCISC) between 2008 and 2013 were used to validate this scoring system. In addition we used multivariate methods to further refine the original risk score to improve its predictive power of SAE's. Results: Univariate analysis confirmed the strong correlation of each of the 10 components of the original risk score with SAE attributed to a pediatric cardiac catheterization (P < 0.001 for all variables). Multivariate analysis resulted in a modified risk score (CRISP) that corresponds to an increase in value of area under a receiver operating characteristic curve (AUC) from 0.715 to 0.741.ConclusionThe CRISP score predicts risk of occurrence of an SAE for individual patients undergoing pediatric cardiac catheterization procedures. © 2015 Wiley Periodicals, Inc.

Objective: To identify differences in terms of quality of life, the American Urological Association Symptom Index (AUA), or adverse events (AEs) among patients with prostate cancer treated with either standard fractionation or hypofractionation proton-beam therapy. Materials and Methods: Patients were prospectively randomized to receive 38 Gy relative biological effectiveness (RBE) in 5 treatments (n=49) or 79.2 Gy RBE in 44 treatments (n=33). All patients had low-risk prostate cancer and were treated with proton therapy using fiducial markers and daily image guidance. Results: Median follow-up for both groups was 18 months; 33 patients had follow-up of 2 years or longer. Baseline median (range) AUA was 4.7 (0 to 13) for the 38 Gy RBE arm and 4.8 (0 to 17) for the 79.2 Gy RBE arm. We observed no difference between the groups regarding the Expanded Prostate Index Composite urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment. The only significant difference was the AUA score at 12 months (8 for the 38 Gy RBE arm vs. 5 for the 79.2 Gy RBE arm; P=0.04); AUA scores otherwise were similar between groups. No grade 3 or higher AEs occurred in either arm. Conclusions: Patients treated with proton therapy in this randomized trial tolerated treatment well, with excellent quality-of-life scores, persistent low AUA, and no grade 3 or higher AEs on either arm. We showed no apparent clinical difference in outcomes with hypofractionated proton-beam therapy compared with standard fractionation on the basis of this interim analysis.