Citations

Abstract Previous preclinical studies and a phase I clinical trial suggested that myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia. Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once a day for 2 weeks, and then twice a day for 6 months. The primary endpoint was change in dysplasia rate after 6 months of intervention on a per-participant basis. Other trial endpoints reported herein include Ki-67 labeling index, blood and bronchoalveolar lavage fluid (BAL) levels of proinflammatory, oxidant/antioxidant biomarkers, and an airway epithelial gene expression signature for PI3K activity. Seventy-four (n = 38 myo-inositol and n = 36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (P = 0.76). Compared with placebo, myo-inositol intervention significantly reduced IL6 levels in BAL over 6 months (P = 0.03). Among those with a complete response in the myo-inositol arm, there was a significant decrease in a gene expression signature reflective of PI3K activation within the cytologically normal bronchial airway epithelium (P = 0.002). The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent. Cancer Prev Res; 9(12); 906–14. ©2016 AACR.

Abstract Introduction: Multiple myeloma (MM) is a malignancy of plasma cells that is still considered incurable due to the 90% relapse rate in patients. Despite the advent of new agents the majority of MM patients relapse secondary to therapy resistance. The potential of reovirus (RV) as a novel therapeutic agent for MM under in vitro, in vivo and ex vivo conditions has been demonstrated by us and a phase I clinical trial of MM with RV therapy has shown indications of efficacy. Recently we have shown that RV could synergize with several standard of care MM drugs such as bortezomib (BTZ), carfilzomib (CFZ) and dexamethasone and importantly, enhance its therapeutic potential in therapy resistant human MM cell lines in vitro. Utilizing the syngeneic Vk*MYC BTZ resistant transplantable MM mouse model, we demonstrate that mice harbouring BTZ insensitive MM tumors significantly respond to RV treatment. Our data indicate that this RV treatment sensitivity is manifested via, direct oncolysis in conjunction with immune modulatory effects. Methods: Vk*MYC myeloma cells (Vk12598) were injected via tail vein (IV) into 3 groups of C57BL/6 wt recipient mice. Seven days post tumor injection, mice were treated with PBS (vehicle) or live (LV) or dead reovirus (DV) (5×10⁁8 PFU) administered IV every 6 days in a total of 5 doses. Serum gamma globulins (M-spike) were assessed weekly by serum protein electrophoresis. Mice were sacrificed on day 35 post tumour injection and their spleens and bone marrow (BM) were harvested. Splenic and BM cells were stained for CD45+/CD45R-/CD138+ (MM tumors), CD4+/CD8+ (T cells), CD3+/NKG2D+ (NKT cells), CD11b+Ly6C+ (monocytic myeloid derived suppressor cells (Mo-MDSC) and CD11b+Ly6G+ (polymorphonuclear (PMN) - MDSCs) and analyzed by flow cytometry. Results: Mice treated with RV demonstrated highly significant (P<0.001) reductions in their M-spikes at 4 and 5 weeks post treatment. RV treatment led to a significant NKT cell accumulation in splenic and BM of RV treated mice in comparison to vehicle treated mice suggestive of immune activation due to RV. Further, RV treatment led to a significant increase in BM Mo-MDSC number but not PMN-MDSC numbers. Interestingly, significant down regulation of splenic PMN-MDSCs was seen with RV treatment. Conclusions: Our results indicate reovirotherapy is successful in a validated syngeneic BTZ resistant MM model. These results have important implications for future clinical trials. Currently we are conducting further experiments to assess the immune modulatory (such as T - memory and T - regulatory cells) contributions of RV in this model. Citation Format: Chandini M. Thirukkumaran, Zhong Qiao Shi, Joanne Luider, Karen Kopciuk, Marta Chesi, Leif Bergsagel, Yuan Dong, Chunfen Zhang, Ahmed Mostafa, Kathy Gratton, Satbir Thakur, Don Morris. Successful oncolytic virotherapy in a bortezomib resistant syngeneic mouse model of multiple myeloma: Implications for translational significance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 541.

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.

BACKGROUND: Objectives were to determine whether the use of ultrasound guidance offers any clinical advantage in the performance of neuraxial or peripheral nerve blocks in children in terms of increasing the success rate or decreasing the rate of complications. METHODS: We searched the following databases to March 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), EMBASE (OvidSP), and Scopus (to January 2015). We included all parallel randomized controlled trials that evaluated the effect of ultrasound guidance to perform a regional blockade technique in children. We assessed the selected studies for risk of bias with the Cochrane collaboration tool. We graded the level of evidence for each outcome according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group scale. RESULTS: We included 20 studies (1241 participants). Ultrasound guidance increases the success rate by decreasing the occurrence of a failed block: risk difference −0.11 (95% confidence interval [CI], −0.17 to −0.05); I 2 64%; number needed for additional beneficial outcome for peripheral nerve blocks 6 (95% CI, 5–8). The younger the child, the greater the benefit. From 8 studies (414 participants), pain scores at 1 hour in the postanesthesia care unit were reduced when ultrasound guidance was used; however, the clinical relevance of the difference was unclear (equivalent to −0.2 on a scale from 0 to 10). From 8 studies (358 participants), block duration was longer when ultrasound guidance was used: standardized mean difference (SMD) 1.21 (95% CI, 0.76–1.65: I 2 73%; equivalent to 62 minutes). Here again, younger children benefited the most from ultrasound guidance. Time to perform the procedure was reduced when ultrasound guidance was used for prescanning before a neuraxial block (SMD −1.97; 95% CI, −2.41 to −1.54; I 2 0%; equivalent to 2.4 minutes) or as an out-of-plane technique (SMD −0.68; 95% CI, −0.96 to −0.40; I 2 0%; equivalent to 94 seconds). From 2 studies (122 participants), ultrasound guidance reduced the number of needle passes required to perform the block: SMD −0.90 (95% CI, −1.27 to −0.52; I 2 0%; equivalent to 0.6 needle pass per participant). From 2 studies (204 participants), we could not demonstrate a difference in the incidence of bloody puncture when ultrasound guidance was used for neuraxial blockade, but we found that the number of participants was well below the optimal information size (risk difference −0.07, 95% CI, −0.19 to 0.04). No major complications were reported for any of the 1241 participants. We rated the quality of evidence as high for success, pain scores at 1 hour, block duration, time to perform the block, and number of needle passes. We rated the quality of evidence as low for bloody punctures. CONCLUSIONS: Ultrasound guidance seems advantageous, particularly in young children, for whom it improves the success rate and increases block duration. Additional data are required before conclusions can be drawn on the effect of ultrasound guidance in reducing the rate of bloody puncture.

Endovascular Stimulation for Treatment of HypotensionBackgroundWe have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure.MethodsThe pre‐study protocol for endovascular stimulations included 2 minutes of stimulation (1–150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation.ResultsIn 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P < 0.0001), renal vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15–150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings.ConclusionsStimulation of intra‐abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research.

Abstract Introduction: Malignant phyllodes tumors are rare breast malignancies (0.1% of all breast tumors) with limited effective treatment options for recurrent and metastatic disease. Recent trials indicated a potential for anti-angiogenic therapy in soft tissue sarcomas, which led us to investigate these pathways. Materials and Methods: Thirty-five malignant phyllodes tumors (including two cases with matched primary and metastatic tumors) were profiled using gene sequencing (Next-generation and Sanger), gene copy number analysis (in-situ hybridization), whole genome RNA expression, and protein expression (immunohistochemical assay). Results: RNA microarray assay showed consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin2, VCAM1, PDGFRA, PTTG1, and CYP3A5 in all cases analyzed (n=5). No mutations in KDR (VEGFR2) were detected (0/26). EGFR protein overexpression was observed in 25/26 (96%) of cases with amplification of the EGFR gene in 8 cases (33%). EGFR gene mutations were identified in 2 cases (8%) including one case with presumed pathogenic V774M mutation and one case with EGFRvIII mutation. The most common mutations included those of TP53 (50%) and PIK3CA (15%) while other mutations (BRCA1, BRCA2, RET, CDH1, MLH1, ATM) were rare affecting single phyllodes cases. Two cases with matched primary and metastatic cancers harbored the same mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Conclusions: Comprehensive multiplatform profiling approach to phyllodes tumors identifies various molecular alterations of which some are potentially actionable. Our data suggests that anti-angiogenic therapy may also be effective in patients with malignant phyllodes tumor. Evaluation of EGFR pathway discovered consistent protein over-expression but rare activating mutations, which necessitates refinement in patient selection targeting these pathways. Citation Format: Gatalica Z, Vranic S, Ghazalpour A, Xiu J, Ocal I, McGill J, Bender R, Discianno E, Sanati S, Reddy S, Pockaj B. Comprehensive multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-19.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.