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// Randy C. Bowen 1 , Nancy Ann B. Little 1 , Joshua R. Harmer 1 , Junjie Ma 2 , Luke G. Mirabelli 1 , Kyle D. Roller 1 , Andrew Mackay Breivik 1 , Emily Signor 1 , Alec B. Miller 1 and Hung T. Khong 1 1 Department of Oncology, University of Utah, Salt Lake City, Utah, USA 2 Department of Pharmacotherapy, University of Utah, Salt Lake City, Utah, USA Correspondence to: Hung T. Khong, email: // Keywords : neutrophil-to-lymphocyte ratio, gastrointestinal cancers, prognostic indicator, overall survival, biomarkers Received : August 19, 2016 Accepted : February 20, 2017 Published : March 16, 2017 Abstract An accurate, time efficient, and inexpensive prognostic indicator is needed to reduce cost and assist with clinical decision making for cancer management. The neutrophil-to-lymphocyte ratio (NLR), which is derived from common serum testing, has been explored in a variety of cancers. We sought to determine its prognostic value in gastrointestinal cancers and performed a meta-analysis of published studies using the Meta-analysis Of Observational Studies in Epidemiology guidelines. Included were randomized control trials and observational studies that analyzed humans with gastrointestinal cancers that included NLR and hazard ratios (HR) with overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and/or cancer-specific survival (CSS). We analyzed 144 studies comprising 45,905 patients, two-thirds of which were published after 2014. The mean, median, and mode cutoffs for NLR reporting OS from multivariate models were 3.4, 3.0, 5.0 (±IQR 2.5-5.0), respectively. Overall, NLR greater than the cutoff was associated with a HR for OS of 1.63 (95% CI, 1.53-1.73; P < 0.001). This association was observed in all subgroups based on tumor site, stage, and geographic region. HR for elevated NLR for DFS, PFS, and CSS were 1.70 (95% CI, 1.52-1.91, P < 0.001), 1.64 (95% CI, 1.36-1.97, P < 0.001), and 1.83 (95% CI, 1.50-2.23, P < 0.001), respectively. Available evidence suggests that NLR greater than the cutoff reduces OS, independent of geographic location, gastrointestinal cancer type, or stage of cancer. Furthermore, DFS, PFS, and CSS also have worse outcomes with elevated NLR.

// Adam L. Cohen 1, * , Abhijit Ray 2, * , Matthew Van Brocklin 3 , David M. Burnett 3 , Randy C. Bowen 4 , Donna L. Dyess 5 , Thomas W. Butler 5 , Theresa Dumlao 6 and Hung T. Khong 1 1 Department of Medicine, Division of Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 2 Division of Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 3 Department of Surgery, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 4 Department of Medicine, University of Utah, Salt Lake City, UT, USA 5 University of South Alabama, Mitchell Cancer Institute, Mobile, AL, USA 6 Banner MD Anderson Cancer Center, Gilbert, AZ, USA * These authors have contributed equally to this work Correspondence to: Hung T. Khong, email: hung.khong@hci.utah.edu Keywords: nab-paclitaxel, azacitidine, solid tumor, phase I clinical trials, SPARC Received: August 19, 2016 Accepted: November 18, 2016 Published: December 26, 2016 ABSTRACT Background: Secreted protein acidic and rich in cysteine (SPARC), an albumin-binding protein, is downregulated by hypermethylation in many cancers. Hypomethylating agents such as azacitidine can upregulate SPARC in tumors, which may enhance the accumulation of albumin-bound drugs at tumor site. The objectives of this phase I trial was to determine the safety and maximum tolerated dose and to assess any clinical activity of the combination of azacytidine and weekly nanoparticle-albumin-bound (nab®) paclitaxel. Methods: Patients received escalating azacytidine doses daily for 5 days, followed by nab-paclitaxel at the standard 100mg/m2 weekly dose for 3 weeks in 4-week cycles. Dose-limiting toxicities (DLTs) were monitored during the first cycle. Serum was obtained at baseline, during and after treatment for correlative study. Results: All sixteen total patients enrolled were evaluable for toxicity, while 13 patients were evaluable for response. Two of five patients treated with 100mg/m2 of azacytidine had DLT of prolonged grade 4 neutropenia. Therefore, the MTD of azacitidine in this regimen is 75 mg/m 2 . Three additional patients were treated with no grade 4 toxicity in cycle 1. Clinical activity included 1 complete response (CR) in refractory DLBCL, 2 CR in ovarian cancer, 4 partial responses (PR) in ovarian and endometrial cancer, 4 stable diseases (SD) in lung, sarcoma and pancreatic cancer, 1 unconfirmed PR in breast cancer, and 1 progression of disease in CLL/SLL. Conclusions: Priming with azacitidine 75 mg/m 2 daily for 5 days, followed by weekly nab-paclitaxel 100 mg/m 2 weekly was well tolerated and results in dramatic responses pre-treated cancer patients.