Readability of Online Patient Educational Resources Found on NCI-Designated Cancer Center Web Sites.

BACKGROUND: The NIH and Department of Health & Human Services recommend online patient information (OPI) be written at a sixth grade level. We used a panel of readability analyses to assess OPI from NCI-Designated Cancer Center (NCIDCC) Web sites. METHODS: Cancer.gov was used to identify 68 NCIDCC Web sites from which we collected both general OPI and OPI specific to breast, prostate, lung, and colon cancers. This text was analyzed by 10 commonly used readability tests: the New Dale-Chall Readability Formula, Flesch Reading Ease scale, Flesch-Kinaid Grade Level, FORCAST scale, Fry Readability Graph, Simple Measure of Gobbledygook test, Gunning Frequency of Gobbledygook index, New Fog Count, Raygor Readability Estimate Graph, and Coleman-Liau Index. We tested the hypothesis that the readability of NCIDCC OPI was written at the sixth grade level. Secondary analyses were performed to compare readability of OPI between comprehensive and noncomprehensive centers, by region, and to OPI produced by the American Cancer Society (ACS). RESULTS: A mean of 30,507 words from 40 comprehensive and 18 noncomprehensive NCIDCCs was analyzed (7 nonclinical and 3 without appropriate OPI were excluded). Using a composite grade level score, the mean readability score of 12.46 (ie, college level: 95% CI, 12.13-12.79) was significantly greater than the target grade level of 6 (middle-school: P<.001). No difference between comprehensive and noncomprehensive centers was identified. Regional differences were identified in 4 of the 10 readability metrics (P<.05). ACS OPI provides easier language, at the seventh to ninth grade level, across all tests (P<.01). CONCLUSIONS: OPI from NCIDCC Web sites is more complex than recommended for the average patient.

Fibroblast Growth Factor Receptors as Targets for Radiosensitization in Head and Neck Squamous Cell Carcinomas.

PURPOSE: We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts. METHODS AND MATERIALS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization expression was assessed in a cohort of HNSCC patient samples, cell lines, and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle, and DNA damage repair were evaluated. Reverse phase protein array was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell lines and PDX models. RESULTS: FGFR1, FGFR2, and FGFR3 RNA in situ hybridization were expressed in 41%, 81%, and 89% of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time-dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appears to be multifactorial, involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared with radiation or drug alone in an FGFR-expressing HNSCC cell line xenograft and PDX. CONCLUSIONS: These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations.

FGFR Inhibition Enhances Sensitivity to Radiation in Non-Small Cell Lung Cancer.

FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect γH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.

National survey: Developing a common approach to grading of practice in pre-registration midwifery.

This paper presents the final phase of a national project exploring grading of practice in programmes leading to registration as a midwife in the United Kingdom. The aim was to develop a generic framework for grading practice, enhancing standardisation while enabling flexibility in application of current and new educational standards. A mixed method on-line survey considered existing practice assessment tools, factors contributing to robust and reliable assessment and perceptions of two assessment tools developed by the research team: a 'Lexicon Framework' and 'Rubric', which were tested through scenarios. Participants included 170 midwifery and nursing academics, clinicians and students, representing 20 universities in the UK. Seven key themes emerged, from which an 'Evidence Based Model for Professional Practice Assessment' was developed. The proposed tools were overall positively evaluated and demonstrated a good level of reliability. A national tool to standardise midwifery practice assessment is recommended, and scope for transferability of our tools to all midwifery programmes and to nursing was identified. Other recommendations include engagement of key stakeholders in development of practice assessment documentation, and maintaining the professional purpose of grading practice as central to the process. A set of key principles for assessing practice is presented.

Biological characterization of a novel in vitro cell irradiator.

To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through γH2AX image cytometry. A high correlation between physical absorbed dose and biologic dose was seen for the production of intracellular reactive oxygen species, physical DNA double strand breaks, and modulation of the cellular double stand break pathway. The results compared favorably to irradiation with a traditional 137Cs source. The rapid, straightforward tests described form a reasonable approach for biologic characterization of novel irradiators. These additional testing metrics go beyond standard physics testing such as Monte Carlo simulation and thermo-luminescent dosimeter evaluation to confirm that a novel irradiator can produce the desired dose effects in vitro. Further, assessment of these biological metrics confirms that the physical handling of the cells during the irradiation process results in biologic effects that scale appropriately with dose.

Cotargeting mTORC and EGFR Signaling as a Therapeutic Strategy in HNSCC.

Head and neck squamous cell carcinomas (HNSCC) are frequently altered along the PI3K/AKT/mTORC signaling axis. Despite excellent preclinical data, the use of compounds targeting this pathway as monotherapy has been underwhelming in initial clinical trials, and identification of predictive biomarkers remains challenging. To investigate mTORC-specific inhibition, we tested catalytic mTORC (AZD8055) and PI3K/mTORC (NVP-BEZ-235) inhibitors ± cetuximab in a panel of HNSCC cell lines and patient-derived xenografts (PDX). Cell lines were assayed for response to all agents and siRNA knockdown of targets by multiple approaches. All cell lines showed similar response to both drug and siRNA inhibition of both PI3K and mTORC pathways, with anti-EGFR combination producing modest additive effect. Five PDX models that presented PIK3CA mutation or intrinsic cetuximab resistance were treated with a combination of cetuximab and AZD8055. In vivo single-agent mTORC inhibition inhibited growth of one PIK3CA-mutant cancer, but had little effect on any PIK3CAWT or a second PIK3CA-mutant model. In all models, the combination therapy showed greater growth delay than monotherapy. The uniform ability of PI3K and mTORC inhibition to suppress the growth of HNSCC cells highlights the pathway's role in driving proliferation. Although single-agent therapy was largely ineffective in vivo, improved response of combination treatment in an array of PDXs suggests the potential for adding a catalytic mTORC inhibitor to cetuximab therapy. Overall, these results add to a growing body of evidence, suggesting that approaches that attempt to match biomarkers to the optimal therapy in HNSCC remain complex and challenging. Mol Cancer Ther; 16(7); 1257-68. ©2017 AACR.