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ObjectiveFew data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product‐based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4‐year (2008–2012) EDSSP.MethodsParticipating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6‐month period. Reporting rates were calculated per 100 person‐years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution.ResultsThirty‐seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person‐years (95% CI 0.95–1.19). The rates for SAEs and IMEs were 0.54 per 100 person‐years (95% CI 0.45–0.63) and 0.53 per 100 person‐years (95% CI 0.49–0.62), respectively.ConclusionThe EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product‐based registry.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of the nurse in preparation of esophageal resection (ER); the management of patients who develop high‐grade dysplasia after having undergone Nissen fundoplication; the trajectory of care for the patient with esophageal cancer; the influence of the site of tumor in the choice of treatment; the best location for esophagogastrostomy; management of chylous leak after esophagectomy; the optimal approach to manage thoracic esophageal leak after esophagectomy; the choice for operational approach in surgery of cardioesophageal crossing; the advantages of robot esophagectomy; the place of open esophagectomy; the advantages of esophagectomy compared to definitive chemoradiotherapy; the pathologist report in the resected specimen; the best way to manage patients with unsuspected positive microscopic margin after ER; enhanced recovery after surgery for ER: expedited care protocols; and long‐term quality of life in patients following esophagectomy.

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes‐type shrinkage estimator. Six SNPs showed interactions with associated p ‐values ( p int ) <1.1 × 10 −3 . None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER‐negative BC risk in women ≥170 cm (OR = 1.22, p = 0.017), but inversely associated with ER‐negative BC risk in women <160 cm (OR = 0.83, p = 0.039, p int = 1.9 × 10 −4 ). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 × 10 −4 ), and absent in women who had had just one (OR = 0.96, p = 0.19, p int = 6.1 × 10 −4 ). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 × 10 −5 ), but no association was observed in current smokers (OR = 1.07, p = 0.14, p int = 3.4 × 10 −4 ). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.

Abstract Resistance to temozolomide (TMZ) in the majority of glioblastoma multiforme (GBM) is mediated by O6-methylguanine methyltransferase (MGMT). In this study, the efficacy of TMZ, a mono-functional methylating agent, was compared to a bi-functional TMZ analog (DP68) and a corresponding mono-functional TMZ analog (DP86) in established glioma lines (T98, U251), primary GBM xenograft lines (GBM12, GBM22, GBM6) and a TMZ-resistant model with high level MGMT expression (GBM12TMZ). Using a combination of CyQuant and neurosphere assays, the IC50 with TMZ treatment for MGMT expressing lines (U251, GBM12, GBM22) was much lower than non-expressing lines (T98, G6, G12TMZ), while all lines were sensitive to DP68 regardless of MGMT status (see Table). In the same assays, cells were less sensitive to DP86, but cytotoxicity was also independent of MGMT status. In both U251 and T98, DP68 resulted in a time-and dose-dependent induction of markers for DNA damage and checkpoint activation (P-H2AX, ATM, KAP1, Chk1 and Chk2) and a pronounced S-phase arrest within 24 hours of treatment. Based on these results and the hypothesis that DP68 induces DNA cross-links, siRNA knockdown was used to further dissect the importance of the ATM and ATR signaling pathways and the Fanconi Anemia (FA) cross-link repair pathway for DP68 cytotoxicity. Compared to no treatment, 1 microM DP68 resulted in 100% relative absorbance in siCONtrol transfected U251 cells, 41% for siATR, 35% for siFANCD2 and 90% for siATM. In contrast, only siATR and not siFAND2 nor siATM sensitized U251 cells to DP86. Similarly, inhibition of ATR (VE-821), but not ATM (KU-60019) potently sensitized cells to DP68 (see Table). Taken together, the inhibitory effects of DP68 are superior to TMZ in the GBM cell lines tested, regardless of MGMT expression. Furthermore, the siRNA and western blotting suggest that recovery from DP68 is dependent on ATR and the FA repair pathway. TMZ (IC50, microM) DP68 (IC50, microM)) DP86 (IC50, microM)) CyQuant Ctrl 1uM VE-821 1uM KU-60019 Ctrl 1uM VE-821 1uM KU-60019 Ctrl 1uM VE-821 1uM KU-60019 U251 25 20 20 2.5 0.8 2.1 70 40 65 T98 &gt;320 200 260 9 2 7 115 60 115 Neurosphere Ctrl VE-821 KU-60019 Ctrl VE-821 KU-60019 Ctrl VE-821 KU-60019 G12 4 3.2 4.2 0.9 0.08 0.7 18 6 18 G22 40 NA NA 1 NA NA 40 NA NA G6 160 NA NA 0.5 NA NA 15 NA NA G12TMZ &gt;300 NA NA 2 NA NA 22 NA NA Citation Format: Ann C. Mladek Tuma, Yulian Ramirez, Dimitrios Pletsas, Richard T. Wheelhouse, Roger M. Phillips, Ross H. Alonzo, Kaitlyn Knudson, Jann N. Sarkaria. Cytotoxicity of a novel bi-functional temozolomide analog, DP68, is independent of MGMT status in glioblastoma models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4476. doi:10.1158/1538-7445.AM2013-4476

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.

Abstract The dismal prognosis of patients diagnosed with metastatic cancer points to our limited arsenal of effective anticancer and anti-metastasis therapies. Chemotherapy, radiation and targeted therapies are largely ineffective against metastatic cancer, resulting in the deaths of more than half million cancer patients each year. Oncogenic EGFR/HER2/K-RAS/B-RAF pathway activation is a major menace that drives aggressive cancer cell dissemination, tumor invasion and systemic metastasis. Therefore, finding novel approaches and new drug targets to inhibit hyperactive EGFR/HER2/K-RAS/B-RAF signaling is an urgent goal and major challenge in the struggle against metastatic diseases. Guided by the insights and principles learned from the evolutionarily conserved RAS signal transduction cascade in Drosophila, we targeted the most downstream signaling module in the EGFR/HER2/K-RAS/B-RAF signaling pathway, the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), a highly conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper EGFR/HER2/K-RAS/B-RAF signal transduction. We found that inhibiting SIAH function is highly effective in halting cancer cell dissemination, altering cell adhesion and motility, inhibiting tumor invasion and cancer metastasis of human cancer cells. Importantly, our anti-SIAH-based anticancer strategy is effective in reducing tumor burdens in the late-stage and aggressive tumor growth and metastasis in the preclinical models. These exciting results and new findings demonstrate that SIAH is a highly attractive, mechanistically logical and great therapeutic target for developing novel anti-ERBB/K-RAS/B-RAF and anticancer therapies against invasive and metastatic cancer. Through our work, SIAH has emerged as a new, potent and promising drug target against metastatic diseases. As a highly evolutionarily conserved E3 ligase and the most downstream “gatekeeper” of EGFR/HER2/K-RAS/B-RAF signaling pathway, SIAH is ideally and logically positioned to become a next-generation anticancer and anti-metastasis drug target in the clinic. By simultaneously attacking the tumor-driving and metastasis-promoting ERBB/K-RAS signaling pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules, we aim to make a difference and save lives from the deadliest forms of human metastatic cancers in the future. Citation Format: Amy H. Tang, Yang Liao, Minglei Bian, Vasilena Zheleva, Zena M. Urban, Monicah M. Njogu, Xiaofei Gao, Oscar A. Gonzalez, Justin J. Odanga, Bruce E. Knudsen, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen. Make a difference and save lives in human metastatic cancer by attacking the Achilles heel in the oncogenic ERBB/K-RAS signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A88.

Abstract Hyperactive ERBB/K-RAS signaling is a major menace that drives aggressive tumor growth and metastasis in human cancer. Currently, there are no effective ways to treat late-stage and relapsed human cancers that have oncogenic ERBB/K-RAS mutations that often confer drug resistance, aggressive tumor growth, systemic metastasis, and poor clinical outcome. Therefore, finding novel approaches and new drug targets to inhibit oncogenic ERBB/K-RAS activation is an urgent goal and the major challenge in cancer therapy and treatment. Instead of targeting an upstream signaling module such as EGFR/HER2/KRAS/B-RAF, we targeted the most downstream signaling module in the EGFR/HER2/K-RAS pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper EGFR/HER2/K-RAS/B-RAF signal transduction. Guided by the insights and fundamental principles learned from the Drosophila RAS signaling pathway, we conducted preclinical studies to dissect SIAH function in the context of ERBB/K-RAS-mediated tumorigenesis and metastasis in human cancer cells and human cancer biospecimens. We found that (1) SIAH is a great prognostic and predictive biomarker for human cancer, and (2) inhibiting SIAH function is highly effective to block tumorigenesis and metastasis against the well-established, late-stage and metastatic pancreatic cancer and triple negative breast cancer (TNBC). These findings demonstrate that SIAH is an attractive and logical new therapeutic target for novel anti-ERBB/oncogenic K-RAS and anticancer therapy in human cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic ERBB/K-RAS activation in human cancer cells. Using anti-SIAH molecules to block K-RAS signaling in human cancer is an excellent example of science going “from the bench (basic research in fruit flies) to the bedside (preclinical studies and ultimately clinical trials)”. As a highly evolutionarily conserved E3 ligase and the most downstream “gatekeeper” of EGFR/HER2/K-RAS/B-RAF signaling pathway, SIAH is uniquely and logically positioned to become a next-generation anti-ERBB/anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles' heel in human cancer. Knowledge gained from our study has great promise and immediate translational values. Anti-SIAH-based small molecule inhibitors may aid in expanding our arsenal of novel anticancer therapies. By attacking the oncogenic ERBB/K-RAS/B-RAF pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we will be in a position to control the late-stage, relapsed and metastatic human cancers. If successful, we hope to develop anti-SIAH-based therapy and translate our findings to the cancer clinics to treat cancer patients with metastatic diseases in the near future. Citation Format: Minglei Bian, Yang Liao, Vasilena Zheleva, Xiaofei Gao, Zena M. Urban, Monicah M. Njogu, Justin J. Odanga, Andrew J. Isbell, Rebecca L. Schmidt, Rie Takahashi, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen, Amy H. Tang. Attacking the most downstream “gatekeeper” signaling module in the oncogenic ERBB/K-RAS signaling pathway to block tumorigenesis and metastasis in human cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C62.

Abstract Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.