None.

Patient‐reported outcomes regarding symptom burden may provide valuable information in addition to physician assessment. Systematic collection of patient‐reported outcomes may be an important metric to identify unmet needs and improve quality of patient care. To understand common symptoms of patients seen in radiation oncology clinic, we examined the prospectively collected modified Edmonton Symptom Assessment Scale (ESAS‐r) data to explore symptom clusters. Our clinic established use of a modified Edmonton Symptom Assessment Scale in August 2015. All outpatients presenting for radiation oncology services completed the form at each clinic visit. Symptom clusters are defined by two or more symptoms that are interrelated and occur simultaneously with a high degree of predictability. A sample of 916 de‐identified surveys was assessed statistically using principal component analysis (PCA) with varimax rotation to determine independent clustering between the symptoms queried. We found four major clusters of symptoms: Tiredness (tired, drowsiness; PC1), Loss of Appetite (nausea, lack of appetite; PC2), Low Well‐Being (overall & spiritual well‐being; PC3), and Depression (depression, anxiety; PC4). These accounted for 46%, 9.2%, 7.6%, and 7% of total variance, respectively. Internal consistency using Cronbach's alpha was 0.87, 0.7, 0.82, and 0.87, respectively. The most frequent write‐in item was itchiness, present in 24% of the 148 patients responding. Assessment of patients seen in a large radiation oncology clinic revealed several symptom clusters. {Tiredness and drowsiness} represents a major symptom cluster. Itchiness may be underrecognized.

Background: Malignant Peripheral Nerve Sheath Tumor (MPNST) is a malignant sarcoma that derives from a peripheral nerve or plexiform neurofibroma. Neurofibromatosis type 1 (NF-1) patients are particularly susceptible, with a higher risk, earlier onset, and worse prognosis. The major factor associated with MPNST and NF-1 is Neurofibromin 1, coded by the NF1 gene. NF1 mutation results in RAS hyperactivation. Chemotherapy for MPNST is currently limited, with poor prognosis for metastatic or unresectable tumors. Thus, the development of promising treatment solutions for MPNST to translate to clinical trials is required. Methods: Here, we seek to identify efficacious chemotherapeutic treatments for MPNST with a combination of drug screening and biological pathway analysis. We used our previously established preclinical system to test FDA approved or promising developmental agents against five cell line models for MPNST. We screened sixty agents with diverse mechanisms of action below published maximum plasma concentrations, and measured effects with a CellTiter-Glo viability assay. Promising agents were then tested in two-drug combinations, allowing for determination of synergism. We then examined the molecular effects of the top candidates with use of antibody arrays that permit detection of a series of phosphorylated proteins. Results: The group of most efficacious drugs was enriched with agents that target factors downstream of RAS, including MEK, mTOR, and PI3K inhibitors, with microtubule inhibitors, genotoxics, and HDAC inhibitors also demonstrating good results. Strong synergism was observed across our cell line models particularly in combinations containing the dual mTORC1/2 inhibitor INK128. Interestingly, drug sensitivity varied greatly between cell lines, correlating with relative NF1 protein and RAS-GTP levels. We analyzed the activation of the RAS pathway in response to drug treatment with antibody arrays and found that, following treatment, relative phosphorylation signal was more decreased compared to controls in cell lines with lower relative NF1 protein levels. Doxorubicin was able to reduce phosphorylation signal compared to controls to a level near comparable to targeted inhibitors, which could contribute to doxorubicin’s current usefulness against MPNSTs. Importantly, we identified combination treatments that were able to greatly reduce the relative phosphorylation signal of RAS pathway members versus control. Combinations containing INK128 resulted in the most pathway shutdown. These findings suggest that MPNSTs may be susceptible to combination treatments targeting RAS pathway members. Moreover, it may be possible to use pathway analysis as a diagnostic tool to predict drug tolerance. Citation Format: Elliot Kahen, Darcy Welch, Diana Yu, Christopher Cubitt, Jae Lee, Andrew Brohl, Damon R. Reed. RAS pathway activation and sensitivity to therapeutic agents is correlated with NF1 residual activity in malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1340. doi:10.1158/1538-7445.AM2017-1340

Background: Esophageal adenocarcinoma (EAC) is an aggressive malignancy with an increasing incidence in the US. Progression of Barrett's Esophagus (BE) to EAC occurs via a stepwise process, and consequently periodic esophageal biopsies are utilized in order to monitor patients with BE. While a small percent of BE patients will progress to dysplasia and cancer, the majority of them will continue to have long-standing BE without progression. In the absence of dysplasia, the behavior of BE cannot be predicted based on evaluation of histologic features alone. Studies have demonstrated the utility of microRNAs in differentiating between the specific evolutionary events in the progression of BE to dysplasia and cancer. To date, there has yet to be a comparison between cases of BE that have not progressed to dysplasia or carcinoma, or cases of BE-Non-progression (BEN), and cases of BE that have progressed to dysplasia and/or carcinoma, or cases of BE- Progression (BEP). Through miRNA profiling, we have determined an assay of candidate miRNAs that reliably differentiate cases of BEN from BEP. Methods: Fifty cases of BE were profiled with two different miRNA profiling techniques: the HTG EdgeSeq miRNA WT Assay and the nanoString Assay. There were 15 cases of BEN (follow up >7 years) as well as of 11 cases of BEP (progression to dysplasia and/or EAC within 3 years). These cases were used for miRNA discovery and miRNA prediction model training. Another independent patient data set of 24 BE cases (13 cases of BEN and 11 cases of BEP; namely Normalized Nano), was profiled with nanoString miRNA Assay. This set was used as an independent validating cohort. Results: Six significant miRNAs were identified and confirmed using two different statistical methods (Limma test and Wilcoxen rank sum test). Family-wise error rate for type I error (FWER) was set to less than 0.05 in order to minimize the probability of discovering false positives. The final miRNA model demonstrated a high prediction performance at the optimal cutoff with a specificity of 80% and 50%; as well as sensitivity 100% and 75% for the two sets in order to capture a high proportion of the BEPs. We then independently validated this miRNA signature with the Normalized Nano set, which demonstrated a sensitivity of 70% and a specificity of 67.5% in this independent validation. While the prediction performance was weaker, we consistently validated its prediction power and clinical utility on an independent patient cohort with a completely different miRNA profiling technique. Conclusion: The reliability of these candidate miRNAs support further investigation in a larger population of patients, and may have potentially prognostic utility in the evaluation of BE patients with the goal of early detection of BE progression. Citation Format: James Saller, Kun Jiang, Kevin Neill, Zachary Mayer, Jae Lee, Luis Pena, F. Scott Corbett, Jose Pimiento, Mokenge Malafa, Anthony Magliocco, Domenico Coppola. An miRNA signature selects patients at risk for Barrett's Esophagus progression to dysplasia and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5410.