Tumor Heterogeneity as a Predictor of Response to Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) is the standard of care for locally advanced adenocarcinoma of the rectum, but it is currently unknown which patients have disease that will respond. This study tested the correlation between response to nCRT and intratumoral heterogeneity using next-generation sequencing assays. PATIENTS AND METHODS: DNA was extracted from formalin-fixed, paraffin-embedded biopsy samples from a cohort of patients with locally advanced rectal adenocarcinoma (T3/4 or N1/2 disease) who received nCRT. High read-depth sequencing of \u3e 400 cancer-relevant genes was performed. Tumor mutations and variant allele frequencies were used to calculate mutant-allele tumor heterogeneity (MATH) scores as measures of intratumoral heterogeneity. Response to nCRT was pathologically scored after surgical resection. RESULTS: Biopsy samples from 21 patient tumors were analyzed. Eight patients had disease noted to have complete response, 2 moderate, 4 minimal, and 7 poor. Higher MATH scores correlated with poorer response to treatment, demonstrating significantly increased tumor heterogeneity compared to complete response (P = .039). CONCLUSION: The application of MATH scores as a measure of tumor heterogeneity may provide a useful biomarker for treatment response in locally advanced rectal cancer

Nanoscale Hybrid Electrolytes with Viscosity Controlled Using Ionic Stimulus for Electrochemical Energy Conversion and Storage

As renewable energy is rapidly integrated into the grid, the challenge has become storing intermittent renewable electricity. Technologies including flow batteries and CO 2 conversion to dense energy carriers are promising storage options for renewable electricity. To achieve this technological advancement, the development of next generation electrolyte materials that can increase the energy density of flow batteries and combine CO 2 capture and conversion is desired. Liquid-like nanoparticle organic hybrid materials (NOHMs) composed of an inorganic core with a tethered polymeric canopy (e.g., polyetheramine (HPE)) have a capability to bind chemical species of interest including CO 2 and redox-active species. In this study, the unique response of NOHM-I-HPE-based electrolytes to salt addition was investigated, including the effects on solution viscosity and structural configurations of the polymeric canopy, impacting transport behaviors. The addition of 0.1 M NaCl drastically lowered the viscosity of NOHM-based electrolytes by up to 90%, reduced the hydrodynamic diameter of NOHM-I-HPE, and increased its self-diffusion coefficient, while the ionic strength did not alter the behaviors of untethered HPE. This study is the first to fundamentally discern the changes in polymer configurations of NOHMs induced by salt addition and provides a comprehensive understanding of the effect of ionic stimulus on their bulk transport properties and local dynamics. These insights could be ultimately employed to tailor transport properties for a range of electrochemical applications

RON kinase isoforms demonstrate variable cell motility in normal cells

Introduction: Aberrant RON (Recepteur d'Origine Nantais) tyrosine kinase activation causes the epithelial cell to evade normal growth pathways, resulting in unregulated cell proliferation, increased cell motility and decreased apoptosis. Wildtype (wt) RON has been shown to play a role in metastasis of epithelial malignancies. It presents an important potential therapeutic target for colorectal, breast, gastric and pancreatic cancer. Little is known about functional differences amongst RON isoforms RON155, RON160 and RON165. The purpose of this study was to determine the effect of various RON kinase isoforms on cell motility. Methods: Cell lines with stable expression of wtRON were generated by inserting the coding region of RON in pTagRFP (tagged red fluorescence protein plasmid). The expression constructs of RON variants (RON155, RON160 and RON165) were generated by creating a mutagenesis-based wtRON-pTag RFP plasmid and stably transfected into HEK 293 cells. The wound closure scratch assay was used to investigate the effect on cell migratory capacity of wild type RON and its variants. Results: RON transfected cells demonstrated increased cell motility compared to HEK293 control cells. RON165 cell motility was significantly increased compared to RON160 (mean percentage of wound covered 37.37% vs. 32.40%; p = 0.03). Conclusions: RON tyrosine kinase isoforms have variable cell motility. This may reflect a difference in the behavior of malignant epithelial cells and their capacity for metastasis

KRAS biomarker testing disparities in colorectal cancer patients in New Mexico

Introduction: American Society of Clinical Oncology (ASCO) guidelines recommend that all patients with metastatic colorectal cancer (mCRC) receive KRAS testing to guide anti-EGFR monoclonal antibody treatment. The aim of this study was to assess for disparities in KRAS testing and mutational status. Methods: The New Mexico Tumor Registry (NMTR), a population-based cancer registry participating in the National Cancer Institute’s Surveillance, Epidemiology and End Results program, was queried to identify all incident cases of CRC diagnosed among New Mexico residents from 2010 to 2013. Results: Six hundred thirty-seven patients were diagnosed with mCRC from 2010–2013. As expected, KRAS testing in Stage 4 patients presented the highest frequency (38.4%), though testing in stage 3 (8.5%), stage 2 (3.4%) and stage 1 (1.2%) was also observed. In those with metastatic disease, younger patients (≤ 64 years) were more likely to have had testing than patients 65 years and older (p < 0.0001). Patients residing in urban areas received KRAS testing more often than patients living in rural areas (p = 0.019). No significant racial/ethnic disparities were observed (p = 0.66). No significant differences were seen by year of testing. Conclusion: Age and geographic disparities exist in the rates of KRAS testing, while sex, race/ethnicity and the year tested were not significantly associated with testing. Further study is required to assess the reasons for these disparities and continued suboptimal adherence to current ASCO KRAS testing guidelines

Operating room staff and surgeon documentation curriculum improves wound classification accuracy

Background: Misclassification of wounds in the operating room (OR) can adversely affect surgical site infection (SSI) reporting and reimbursement. This study aimed to measure the effects of a curriculum on documentation of surgical wound classification (SWC) for operating room staff and surgeons. Methods: Accuracy of SWC was determined by comparing SWC documented by OR staff during the original operation to SWC determined by in-depth chart review. Patients 18 years or older undergoing inpatient surgical procedures were included. Two plan-do-act-study (PDSA) cycles were implemented over the course of 9 months. A total of 747 charts were reviewed. Accuracy of SWC documentation was retrospectively assessed across 248 randomly selected surgeries during a 5-week period prior to interventions and compared to 244 cases and 255 cases of post-intervention data from PDSA1 and PDSA2, respectively. Changes in SWC accuracy were assessed pre- and post-intervention using the kappa coefficient. A p-value for change in agreement was computed by comparing pre- and post-intervention kappa. Results: Inaccurate documentation of surgical wound class decreased significantly following curriculum implementation (kappa improved from 0.553 to 0.739 and 0.757; p = 0.001). Classification accuracy improved across all wound classes; however, class III and IV wounds were more frequently misclassified than class I and II wounds, both before and after the intervention. Conclusion: Implementation of a multidisciplinary documentation curriculum resulted in a significant decrease in SWC documentation error. Improved accuracy of SWC reporting may facilitate a better assessment of SSI risk in a complex patient population

High levels of tumor-associated neutrophils are associated with improved overall survival in patients with stage II colorectal cancer

<div><p>Conflicting reports regarding whether high tumor-associated neutrophils (TAN) are associated with outcomes in colorectal cancer (CRC) exist. Previous investigators have counted TAN using non-neutrophil-specific immunohistochemistry (IHC) stains. We examined whether TAN levels as determined by multi-field manual counting would predict prognosis. IRB approval was obtained and two pathologists, blinded to stage/outcome, counted TAN in 20 high power fields (HPF) per specimen. TAN score was defined as the mean of these counts. High TAN was defined as at or greater than the median score for that stage. Demographics, tumor characteristics, and overall survival (OS) were obtained from the records and examined for association with TAN score. IHC for arginase expression was performed in a subset of samples. 221 patients were included. Stage II patients with high TAN scores had an OS of 232 months as compared to those with low TAN (OS = 85 months, p = 0.03). The survival benefit persisted in multivariable analysis (HR 0.48, CI 0.25–0.91, p = 0.026) controlling for age and sex. Women had increased survival as compared to men, and there were no significant prognostic associations with TAN count in stage III/IV patients, although there were only 12 stage IV patients. Arginase staining did not provide additional information. Stage II colorectal cancer patients with high TAN live nearly 3 times longer than those with low TAN. Women with stage II disease and high TAN counts appear to be driving the survival benefit seen in the stage II patients and have increased overall survival in all stages.</p></div

Example of staining and digital analysis.

<p>(Row A) H&E of representative section, (Row B) Arginase staining, (Row C), Halo^™ digital analysis counting total cells (deep blue) and arginase positive cells (brown).</p

Comparison of clinical and pathologic features by TAN counts (n = 221).

<p>Comparison of clinical and pathologic features by TAN counts (n = 221).</p

Summary of patient characteristics, n = 221.

<p>Summary of patient characteristics, n = 221.</p

Example of low and high TAN count tumor samples.

<p>H&E of representative sections (400X) of a high TAN count tumor (left) and a low TAN count tumor (right) are shown. Examples of TAN that were counted based on morphology are shown in boxes in the high TAN count tumor, with arrows to indicate eosinophils that were not counted. There are no TANs seen in the low TAN count tumor.</p