Citations

OBJECT Neuroophthalmological morbidity is commonly associated with large and giant cavernous and supraclinoid internal carotid artery (ICA) aneurysms. The authors sought to evaluate the neuroophthalmological outcomes after treatment of these aneurysms with the Pipeline Embolization Device (PED). METHODS The Pipeline for Uncoilable or Failed Aneurysms (PUFS) trial was an international, multicenter prospective trial evaluating the safety and efficacy of the PED. All patients underwent complete neuroophthalmological examinations both before the PED procedure and at a 6-month follow-up. All examinations were performed for the purpose of this study and according to study criteria. RESULTS In total, 108 patients were treated in the PUFS trial, 98 of whom had complete neuroophthalmological follow-up. Of the patients with complete follow-up, 39 (40%) presented with a neuroophthalmological baseline deficit that was presumed to be attributable to the aneurysm, and patients with these baseline deficits had significantly larger aneurysms. In 25 of these patients (64%), the baseline deficit showed at least some improvement 6 months after PED treatment, whereas in 1 patient (2.6%), the deficits only worsened. In 5 patients (5%), new deficits had developed at the 6-month follow-up, while in another 6 patients (6%), deficits that were not originally assumed to be related to the aneurysm had improved by that time. A history of diabetes was associated with failure of the baseline deficits to improve after the treatment. The aneurysm maximum diameter was significantly larger in patients with a new deficit or a worse baseline deficit at 6 months postprocedure. CONCLUSIONS Patients treated with the PED for large and giant ICA aneurysms had excellent neuroophthalmological outcomes 6 months after the procedure, with deficits improving in most of the patients, very few deficits worsening, and few new deficits developing.

Purpose To (1) determine the incidence of symptomatic venous thromboembolic events (VTEs) after knee arthroscopy and arthroscopy‐assisted procedures at a single institution and (2) determine associated risk factors for VTEs in these patients. Methods The records of patients who underwent knee arthroscopy at a single institution between 1988 and 2008 were reviewed. Chemoprophylaxis was not routinely used. Confirmed VTEs occurring within 4 weeks after the index arthroscopy procedure were included. A 2:1 matched control group was generated to include patients in whom knee arthroscopy was performed by the same surgeon either on the same day or immediately before each case resulting in a VTE. Preoperative and perioperative data were collected with respect to demographic data, medical history, medications, and surgical and anesthesia data. Univariate and multivariate analyses were performed. Results During the study period, 12,595 patients underwent knee arthroscopy. Among these patients, 43 cases of VTEs (35 deep venous thromboses [DVTs], 5 pulmonary embolisms [PEs], and 3 DVTs that progressed to PEs) occurred, resulting in an incidence of 0.30% (95% confidence interval [CI], 0.22% to 0.41%) for DVT, 0.06% (95% CI, 0.03% to 0.12%) for PE, and 0.34% (95% CI, 0.25% to 0.46%) for VTEs overall. Factors associated with an elevated risk of symptomatic postoperative VTEs included a history of malignancy ( P = .01; odds ratio [OR], 6.3), a history of VTEs ( P = .02; OR, 5.2), or the presence of more than 2 classic risk factors for VTEs ( P = .01; OR, 13.6). Conclusions In this study, symptomatic VTEs were rare and occurred infrequently, with an incidence of 0.34% (95% CI, 0.25% to 0.46%), after knee arthroscopy and arthroscopy‐assisted cases in the absence of routine chemoprophylaxis. Patients with a history of VTEs, a history of malignancy, or 2 or more classic risk factors are at increased risk of VTEs after knee arthroscopy, and chemoprophylaxis should be considered in these select patients. Level of Evidence Level III, case‐control study.

ABSTRACT While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension ( P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension ( P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) ( P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection.

Abstract Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study–identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10–1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m2, 1.50; 95% CI, 1.13–2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m2, 1.82; 95% CI, 1.26–2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m2, 1.18; 95% CI, 0.73–1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024–31. ©2015 AACR.

Abstract Progression from adenoma to colon cancer is a multi-step process and the role of microRNAs in this transformation is not completely understood. We used both in vitro and in vivo approaches to demonstrate the role of miRNAs in the transformation of adenoma to adenocarcinoma. Reporter assays were used to show the direct interaction of miRNAs to target gene. A Tet-inducible TripZ system and miRzips constructs were used in the in vitro function and xenograft studies. Kaplan-Meier survival curves and Cox regression were used to analyze the survival data in colon cancer patients. Here, we show that the combination of miR-503 and miR-182 contributes to the transformation of colon adenoma to adenocarcinoma by cooperatively regulating the tumor suppressor gene, FBXW7. We found that miR-182 was upregulated in both colon adenoma and adenocarcinoma, whereas miR-503 was upregulated only in adenocarcinoma, indicating a potential hierarchical and stepwise expression of these miRNAs in the regulation of FBXW7. Furthermore, we showed that colon adenoma derived non-tumorigenic AAC1 cells were transformative and tumorigenic in mice when expressing Tet-inducible miR-503. Finally, the combination of miR-503 and miR-182 transcript levels was predictive of poor outcome in colon cancer patients. We conclude that a step-wise expression of miR-182 and miR-503 in benign adenoma synergistically regulates the driver gene FBXW7, thus contributing to the progression of colon adenoma to adenocarcinoma. Citation Format: Lihua Li, Aaron Sarver, Rohini Khatri, Praveensingh Hajeri, Iris Kamenev, Stephen Thibodeau, Clifford J. Steer, Subbaya Subramanian. MicroRNAs miR-503 and -182 regulate FBXW7 contributing to the malignant transformation to colon adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4368. doi:10.1158/1538-7445.AM2014-4368

Abstract Treatment of glioblastoma multiforme (GBM) continues to be a challenge due to its infiltrative nature, tumor heterogeneity, and lack of therapeutic agents that penetrate the blood-brain barrier (BBB). While the primary tumor is permeable to some degree, the ability of GBM cells to invade areas of parenchyma with an intact BBB indicates development of BBB-penetrable compounds is a necessity. The multifunctional protein MDM2 holds promise as a therapeutic target in a variety of cancers and plays a critical role in controlling cell survival, invasion, and DNA repair. MDM2 antagonists such as nutlin3a and RG7112 are being used to interrogate the impact of modulating MDM2 function in combination with front-line therapy. Our objective was to investigate whether MDM2 antagonists, alone or in combination with temozolomide (TMZ), can augment cell death in orthotopic GBM xenograft models. In vitro data indicate that TMZ and nutlin3a are synergistic in decreasing cell viability in wild type (wt) p53 U87-MG, primary human wt p53 GBM10 and mutant (mt) p53 GBM43 cells. Pharmacodynamic studies demonstrated that the mechanism of action for promoting cell death following exposure to TMZ/nutlin3a was multifactorial. Comet assays indicated that repair of TMZ-mediated DNA damage was significantly delayed in wt and mt p53 GBM cells treated with TMZ/nutlin3a compared to TMZ alone and the base excision repair protein Ape1 was downregulated in cells treated with TMZ/nutlin3a. Pharmacokinetic studies guided development of rational dosing regimens in which 2-3 five-day cycles of TMZ followed by nutlin3a 4 hours later were investigated. In ectopic U87-MG xenografts, nutlin3a sensitized xenografts to TMZ-mediated cell death. Orthotopic studies employing U87-MG, GBM10, and GBM43 tumors are being utilized to determine if nutlin3a levels detectable in the brain via HPLC-MS/MS(API 4000) are sufficient to modulate MDM2 function in the context of TMZ and increase survival. In the TMZ-resistant GBM10 (wtp53, MGMTpos, and PTENnull) orthotopic model, there was a modest increase in median survival from 63 days with TMZ to 73 days with TMZ/nutlin3a. Higher and more sustained brain levels of MDM2 antagonists will likely be necessary to improve survival. The MDM2 antagonist RG7112 has an improved PK profile and structural analysis of RG7112 and nutlin3a via QikProp 3.0 (www.schrodinger.com) indicates that RG7112 also has an improved predicted brain/blood partition coefficient (plog BB) compared to nutlin3a (RG7112 = -0.17; nutlin3a = -0.415). Studies are in progress to assess the brain penetration of RG7112 and its effect on GBM growth in vivo. Taken together, our data suggest that modulation of MDM2 function in the context of cytotoxic therapy has the potential to alter mechanisms involved in DNA repair that can promote cell death and improve survival. Citation Format: Haiyan Wang, Shanbao Cai, Barbara J. Bailey, Lawrence M. Gelbert, M. Reza Saadatzadeh, Aaron A. Cohen-Gadol, Jann N. Sarkaria, Paul Territo, Taxiarchis M. Georgiadis, T. Zachary Gunter, Samy Meroueh, Eric C. Long, David R. Jones, Lindsey D. Mayo, Shannon Harlan, Karen E. Pollok. Sensitization of temozolomide-mediated glioblastoma cell death by targeting MDM2: Assessment of PD biomarkers, brain penetration, and efficacy in humanized orthotopic xenograft models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2741. doi:10.1158/1538-7445.AM2014-2741

Abstract Introduction: We recently reported the percentage of mammographic density (MD) to be a breast cancer risk factor across tumor characteristics and age groups. Yet, we noted stronger associations for tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women. We extend this initial study to investigate whether these associations with aggressive disease are due to the underlying associations of absolute dense or non-dense area, or both, with breast cancer risk. Methods: Data were pooled from six studies including 3517 women with invasive breast cancer and 8558 without. Dense area and non-dense area were assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We standardized dense and non-dense area measurements made within each study and categorized into quartiles based on the control distribution for pooled analyses. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (ER, PR) status by age (<55, 55-64, and ≥65 years), adjusting for continuous age, body mass index, and study site. Results: Absolute dense area was associated with increased breast cancer risk [odds ratios (ORs) Q1 vs Q2: 0.67, Q3 vs Q2: 1.25, Q4 vs Q2: 1.62] and non-dense area was associated with decreased breast cancer risk (ORs: Q1 vs Q2: 1.44, Q3 vs Q2: 0.89, Q4 vs Q2: 0.71) overall and across all age groups. Positive associations for absolute dense area were observed across all invasive tumor characteristics. Stronger associations were noted for larger tumors across all ages (p-trend <0.01). Among women <55 years, stronger associations were observed for ER+ vs ER- [p-heterogeneity (het) = 0.02] and PR+ vs PR- tumors (p-het = 0.02). Non-dense area was inversely associated with all tumor characteristics evaluated except for tumors <1.1 cm, for which no association was present. The inverse association was stronger for larger tumors, particularly for women <55 years (p-trend <0.01). Also among women <55 years, a stronger inverse association with non-dense area was observed for ER- vs. ER+ tumors (p-het = 0.02). Conclusion: These results suggest the strong association we previously observed of high percent MD and ER-negative disease in women <55 years could be explained by the low amount of non-dense area in these women. Further research is warranted to clarify the possible differential associations of absolute dense and non-dense area on breast cancer risk according to tumor characteristics. Citation Format: Kimberly A. Bertrand, Christopher G. Scott, Rulla M. Tamimi, Matthew R. Jensen, V. Shane Pankratz, Aaron Norman, John Shepherd, Yunn-Yi Chen, Karla Kerlikowske, Celine M. Vachon. Dense and non-dense mammographic area and risk of breast cancer by age and tumor characteristics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3279. doi:10.1158/1538-7445.AM2014-3279

Abstract Glioblastoma multiforme (GBM) comprises the largest group of brain tumors which are drug resistant and respond very poorly to the current therapies. In this study, we used sulforaphane (SFN), a multi-targeting agent with cancer preventive and anti-cancer activities and showed that it targets GBM established cell lines, early primary cultures, and CD133+ GBM stem cells as well as in GBM stem-like spheroids. SFN at 5-50 μM triggered significant inhibition of cell survival and induced apoptotic cell death in GBM cells and CD133+ stem cells isolated from four GBM cell lines. SFN induced apoptosis in U87MG cells was associated with caspase-7 activation. Moreover, SFN triggered formation of intracellular reactive oxygen species (ROS) and when the cells were pre-treated with 10 mM N-acetyl cysteine (NAC), ROS production and cell survival in cells treated with 5-10 μM were similar to the control untreated U87MG cells, revealing that SFN-triggered cell death is ROS-dependent. Moreover, SFN-generated ROS in U87MG cells were formed at the Mitochondrial Respiratory Chain (MRC) level. SFN also increased expression of the TRAIL receptor DR5 in GBM cells, U87MG and SF767 cells by 24 h post-exposure. Moreover, as revealed by comet assay, SFN increased single- and double-strand DNA breaks in GBM. Compared to untreated control cells, a significantly higher amount of γ-H2AX foci and as consequence higher number of DNA double-strand breaks (DSBs) breaks were observed in the SFN-treated sample. In vivo studies, using NOD/SCID mice revealed that SFN administration via oral gavage at 100 mg/kg for 3 cycles significantly decreases the growth of ectopic xenografts established from the early passage primary cultures of GBM10. Our results show that SFN robustly inhibits growth of GBM cells in vitro and in vivo and induces cell death in established cell cultures, early passage primary cultures, as well as it is effective in eliminating GBM cancer stem cells, which play a major role in drug resistance and disease recurrence. These results suggest that use of SFN alone or in combination with other agents, may potentially improve survival of brain tumor patients. Citation Format: Khadijeh Bijangi-Vishehsaraei, Mohammad R. Saadatzadeh, Haiyan Wang, Malgorzata M. Kamocka, Wenjing Cai, Aaron A. Cohen-Gadol, Stacey L. Halum, Karen E. Pollok, Jann N. Sarkaria, Ahmad R. Safa. Sulforaphane depresses proliferation and induces cell death in glioblastoma multiforme (GBM) cells, GBM stem cell-like spheroids, and tumor xenografts through modulation of multiple cell signaling pathways. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2267. doi:10.1158/1538-7445.AM2014-2267