Citations

Abstract BACKGROUND: Burkitt lymphoma (BL) represents approximately 40% of all childhood and adolescent non-Hodgkin lymphoma (Miles/Cairo, BJH, 2012). Children with relapsed or progressive BL develop chemotherapy-resistant disease and can rarely be cured with salvage therapy (Cairo et al, JCO, 2012). Bruton's tyrosine kinase (BTK) is a regulator of normal B-cell development and is activated upon B-cell receptor (BCR) stimulation. Chronic active BCR signaling through BTK activation can be inhibited by the selective and covalent BTK inhibitor, ibrutinib (Young et al, Nat Rev, 2013). Ibrutinib has been highly effective in the treatment of refractory patients with CLL and MCL and has been approved by the FDA for patients with CLL or MCL who have received at least one prior therapy (USPI) (Byrd et al, NEJM, 2013 and Wang et al, NEJM, 2013). BL, however, is associated with tonic or possibly chronic active BCR signaling; while, both CLL and MCL have chronic active BCR signaling. We have previously demonstrated ibrutinib significantly decrease BL proliferation and viability in vitro (Lee/Cairo et al, ASH, 2014) OBJECTIVE: We hypothesize that ibrutinib may be a potential adjuvant agent in the treatment of BL. Therefore, we investigated the in vivo anti-tumor activity of ibrutinib in BL xenografted NOD/SCID (NSG) mice. METHODS: The luciferase expression plasmid (ffluc-Zeo), kindly provided by L. Cooper, MD) was transfected into Raji cells. Cells were subcutaneously injected into NSG mice (6-8wks old, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ, Jackson lab). Tumor cells engraftment and progression were examined by Bioluminescent Imaging using the Xenogen IVIS-200 (Caliper Life Sciences). Mice were orally gavaged with vehicle control or Ibrutinib (1.25, 12.5 and 25mg/kg/day, generously provided by Janssen R&D, LLC) for 10 days. Statistical probability of survival and curve were determined by Kaplan Meier method. RESULTS: We observed a significant decrease in tumor luminescence intensity following ibrutinib treated BL xenografted NSG mice at day 20 (12.5mg/kg, p<0.001 and 25mg/kg, p<0.05) and at day 25 (12.5mg/kg, p<0.05 and 25mg/kg, p<0.05) compared to vehicle control. Furthermore, ibrutinib (12.5 mg/kg) treated mice significantly prolonged survival compared to vehicle control mice (p<0.05). The median survival of mice following ibrutinib treatment (1.25, 12.5 and 25 mg/kg) were 31.5, 37.5 and 22.5 days, respectively, compared to control (24 days). CONCLUSIONS: Ibrutinib significantly decreased tumor progression and significantly increased the survival in BL xenografted NSG mice following 12.5mg/kg ibrutinib treatment. These results indicate that ibrutinib may be a potential adjuvant agent therapy in the treatment of BL. Future directions will be investigated the efficacy of ibrutinib in combination with dexamethasone in BL xenografted NSG mice. Citation Format: Sanghoon Lee, Changhong Yin, Timmy O'Connell, Matthew Barth, Janet Ayello, Lauren Harrison, Carmella van de Ven, Rodney Miles, Paul Galardy, Stanton C. Goldman, Megan Lim, Michelle Hermiston, Linda McAllister-Lucas, Lisa G. Roth, Sherrie L. Perkins, Mitchell S. Cairo. Ibrutinib significantly improves survival in a human Burkitt lymphoma (BL) xenograft NSG mouse model: Ibrutinib may be a potential adjuvant agent in the treatment of BL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2015-2608

Abstract Background: Squamous cell carcinoma is a common type of lung cancer and accounts for about 25-30% of all non-small cell lung cancers. Metformin is a drug commonly prescribed as first-line treatment for type-2 diabetes, with some evidence showing that the drug can also act directly on cancer cells. One of the mechanisms of action is through activation of the AMP-activated protein kinase (AMPK) which is involved in control of energy homeostasis in cells. The goal of this study was to determine metformin response in different cell lines and different cellular contexts, and to use that information to work towards the generation of a metformin “sensitivity index” that could be used guide individualized chemoprevention. Methods: We performed cell survival analysis on squamous cell carcinoma lines, skin fibroblast lines and differentiated IPS cell lines to identify differences in metformin response both for different cell lines and for cells in different cell context. Microarray profiling was used to determine differentially expressed genes that are regulated by metformin treatment in order to generate signatures of metformin response. Results: Cell survival analysis showed that different cell lines respond differently to metformin, and cells of identical genotypes in a variety of differentiated states or cellular contexts also show differential response to metformin. Gene expression profiling of metformin treated cells identified differentially expressed genes that may mediate metformin response. Conclusion: Differences in response to metformin treatment across a variety of cell lines and cellular contexts suggest heterogeneity that may be patient-specific. Using genes that are differentially expressed following metformin treatment, we identified a 55-gene set that can be used as a metformin “sensitivity index” to stratify patients into metformin responders and non-responders and guide individualized chemoprevention. Citation Format: Michael K. Asiedu, Matthew R. Barron, Marie Christine Aubry, Dennis Wigle. Metformin as a chemoprevention agent for lung squamous cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1897. doi:10.1158/1538-7445.AM2015-1897

Abstract Emerging evidence demonstrates that the DNA repair kinase DNA-PK exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PK functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PK inhibits tumor metastases. Clinical assessment revealed that DNA-PK is significantly elevated in advanced disease, and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PK in advanced tumors is highly activated, independently of DNA damage indicators. Combined, these findings put forth new paradigms for DNA-PK function, identify DNA-PK as a potent driver of tumor progression and metastases, and nominate DNA-PK as a therapeutic target for advanced malignancies. Citation Format: Jonathan F. Goodwin, Vishal Kothari, Justin M. Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher McNair, Michael S. Magee, Robert B. Den, Ziqi Zhu, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen. DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2015-1860

Abstract Ig secretion by terminally differentiated B cells is an important component of the immune response to foreign pathogens. Its overproduction is a defining characteristic of several B cell malignancies, including Waldenström macroglobulinemia (WM), where elevated IgM is associated with significant morbidity and poor prognosis. Therefore, the identification and characterization of the mechanisms controlling Ig secretion are of great importance for the development of future therapeutic approaches for this disease. In this study, we define a novel pathway involving the oncogenic transcription factor GLI2 modulating IgM secretion by WM malignant cells. Pharmacological and genetic inhibition of GLI2 in WM malignant cells resulted in a reduction in IgM secretion. Screening for a mechanism identified the IL-6Rα (gp80) subunit as a downstream target of GLI2 mediating the regulation of IgM secretion. Using a combination of expression, luciferase, and chromatin immunoprecipitation assays we demonstrate that GLI2 binds to the IL-6Rα promoter and regulates its activity as well as the expression of this receptor. Additionally, we were able to rescue the reduction in IgM secretion in the GLI2 knockdown group by overexpressing IL-6Rα, thus defining the functional significance of this receptor in GLI2-mediated regulation of IgM secretion. Interestingly, this occurred independent of Hedgehog signaling, a known regulator of GLI2, as manipulation of Hedgehog had no effect on IgM secretion. Given the poor prognosis associated with elevated IgM in WM patients, components of this new signaling axis could be important therapeutic targets.

Context Several immunohistochemical markers are available to establish the diagnosis of hepatocellular carcinoma. Judicious selection is essential to achieve a reliable diagnosis in limited tissue provided by liver biopsy. Objective To compare the efficacy of 5 hepatocellular markers for the diagnosis of hepatocellular carcinoma across various levels of differentiations. Design Immunohistochemistry for hepatocyte paraffin antigen 1 (Hep Par 1), polyclonal carcinoembryonic antigen (CEA), glypican-3, arginase-1, and bile salt export pump transporter was performed in 79 hepatocellular carcinomas, yielding 93 observations (13 well-differentiated [14%], 41 moderately differentiated [44%], and 39 poorly differentiated [42%] tumors). Results Arginase-1 and Hep Par 1 had the highest sensitivity for well-differentiated hepatocellular carcinoma, whereas arginase-1 and glypican-3 had the highest sensitivity for poorly differentiated hepatocellular carcinoma. When staining of more than 50% of the tumor was considered a positive result, arginase-1 remained the most sensitive marker for all differentiations, whereas sensitivity for Hep Par 1 in poorly differentiated hepatocellular carcinoma dropped to 30% and that of glypican-3 in well-differentiated hepatocellular carcinoma was 15%. The addition of Hep Par 1 and/or polyclonal CEA to arginase-1 did not lead to an increase in sensitivity for any differentiation. The combined use of arginase-1 and glypican-3 yielded 100% sensitivity for poorly differentiated hepatocellular carcinoma. Conclusion Arginase-1 was the most sensitive marker in all differentiations of hepatocellular carcinoma. Glypican-3 had high sensitivity for poorly differentiated cases and its combined use with arginase-1 enabled identification of nearly all cases of poorly differentiated hepatocellular carcinoma. Although bile salt export pump transporter has good overall sensitivity, it has a limited role in establishing hepatocellular differentiation when added to a panel of arginase-1 with either glypican-3 or Hep Par 1.

ObjectiveThe aim of this study was to determine whether the frequency of TAR DNA‐binding protein 43 (TDP‐43) deposition in Alzheimer's disease (AD) differs across pathologically defined AD subtypes (hippocampal sparing [HpSp]; typical and limbic) and further examine the relationship between TDP‐43, pathological subtype, and clinical features in AD.MethodsWe identified all cases with pathologically confirmed AD (NIA‐Reagan intermediate‐high probability, Braak stage IV–VI) independent of cognitive status (n = 188). Neurofibrillary tangle counts were performed using thioflavin‐S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD pathology (n = 19); typical AD pathology (n = 136); and limbic AD pathology (n = 33). TDP‐43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP‐43 and TDP‐43 stage. All cases were clinically subclassified at presentation as amnestic AD dementia versus atypical AD dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP‐43, accounting for possible interactions between pathological subtype and TDP‐43.ResultsTDP‐43 deposition was frequent in typical (59%) and limbic AD pathologies (67%), but not HpSp AD pathology (21%; p = 0.003). The observed associations of TDP‐43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p = 0.01), but not TDP‐43 (p = 0.69).InterpretationAlthough the frequency of TDP‐43 deposition in AD varies by pathological subtype, the observed effects of TDP‐43 on clinical/magnetic resonance imaging features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP‐43. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

The aims of this study were to determine the functional impact and financial burden of isolated and recurrent dislocation after total hip arthroplasty (THA). Our secondary goal was to determine whether there was a difference between patients who were treated non-operatively and those who were treated operatively.We retrospectively reviewed 71 patients who had suffered dislocation of a primary THA. Their mean age was 67 years (41 to 92) and the mean follow-up was 3.8 years (2.1 to 8.2).Because patients with recurrent dislocation were three times more likely to undergo operative treatment (p < 0.0001), they ultimately had a significantly higher mean Harris Hip Score (HHS) (p = 0.0001), lower mean Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores (p = 0.001) and a higher mean SF-12 score (p < 0.0001) than patients with a single dislocation. Likewise, those who underwent operative treatment had a higher mean HHS (p < 0.0001), lower mean WOMAC score (p < 0.0001) and a higher mean SF-12 score (p < 0.0001) than those who were treated non-operatively.Recurrent dislocation and operative treatment increased costs by 300% (£11 456; p < 0.0001) and 40% (£5217; p < 0.0001), respectively.The operative treatment of recurrent dislocation results in significantly better function than non-operative management. Moreover, the increase in costs for operative treatment is modest compared with that of non-operative measures.Cite this article: Bone Joint J 2015; 97-B:1046–9.

Abstract Background: Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations. Methods: We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls). Results: Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P &lt; 0.05 and FDR &lt; 0.05). These results were replicated (P &lt; 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network. Conclusion: We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development. Impact: Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574–84. ©2015 AACR.

OBJECT Vasopressor-induced hypertension (VIH) is an established treatment for patients with aneurysmal subarachnoid hemorrhage (SAH) who develop vasospasm and delayed cerebral ischemia (DCI). However, the safety of VIH in patients with coincident, unruptured, unprotected intracranial aneurysms is uncertain. METHODS This retrospective multiinstitutional study identified 1) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who required VIH therapy (VIH group), and 2) patients with aneurysmal SAH and 1 or more unruptured, unprotected aneurysms who did not require VIH therapy (non-VIH group). All patients had previously undergone surgical or endovascular treatment for the presumed ruptured aneurysm. Comparisons between the VIH and non-VIH patients were made in terms of the patient characteristics, clinical and radiographic severity of SAH, total number of aneurysms, number of ruptured/unruptured aneurysms, aneurysm location/size, number of unruptured and unprotected aneurysms during VIH, severity of vasospasm, degree of hypervolemia, and degree and duration of VIH therapy. RESULTS For the VIH group (n = 176), 484 aneurysms were diagnosed, 231 aneurysms were treated, and 253 unruptured aneurysms were left unprotected during 1293 total days of VIH therapy (5.12 total years of VIH therapy for unruptured, unprotected aneurysms). For the non-VIH group (n = 73), 207 aneurysms were diagnosed, 93 aneurysms were treated, and 114 unruptured aneurysms were left unprotected. For the VIH and non-VIH groups, the mean sizes of the ruptured (7.2 ± 0.3 vs 7.8 ± 0.6 mm, respectively; p = 0.27) and unruptured (3.4 ± 0.2 vs 3.2 ± 0.2 mm, respectively; p = 0.40) aneurysms did not differ. The authors observed 1 new SAH from a previously unruptured, unprotected aneurysm in each group (1 of 176 vs 1 of 73 patients; p = 0.50). Baseline patient characteristics and comorbidities were similar between groups. While the degree of hypervolemia was similar between the VIH and non-VIH patients (fluid balance over the first 10 days of therapy: 3146.2 ± 296.4 vs 2910.5 ± 450.7 ml, respectively; p = 0.67), VIH resulted in a significant increase in mean arterial pressure (mean increase over the first 10 days of therapy relative to baseline: 125.1% ± 1.0% vs 98.2% ± 1.2%, respectively; p < 0.01) and systolic blood pressure (125.6% ± 1.1% vs. 104.1% ± 5.2%, respectively; p < 0.01). CONCLUSIONS For small, unruptured, unprotected intracranial aneurysms in SAH patients, the frequency of aneurysm rupture during VIH therapy is rare. The authors do not recommend withholding VIH therapy from these patients.