Correction: Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0194809.].

Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma.

BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors. METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling. RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model. CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

EQ-5D Health Utility Scores: Data from a Comprehensive Canadian Cancer Centre.

BACKGROUND: To improve the precision of health economics analyses in oncology, reference datasets of health utility (HU) scores are needed from cancer survivors across different disease sites. These data are particularly sparse amongst Canadian survivors. METHODS: A survey was completed by 1759 ambulatory cancer survivors at the Princess Margaret Cancer Centre which contained demographic questions and the EuroQol-5D (EQ-5D) instrument. Clinical information was abstracted from electronic records and HU scores were calculated using Canadian health state valuations. Construct validity was assessed through correlation of HU and visual analog scale (VAS) scores (Spearman) and by comparing HU scores between performance status groups (effect size). The influence of socio-demographic clinical variables on HU was analyzed by non-parametric between-group comparisons and multiple linear regression. RESULTS: Mean EQ-5D HU scores were derived for 26 cancers. Among all survivors, the mean ± standard error of the mean EQ-5D utility score was 0.81 ± 0.004. Scores varied significantly by performance status (p < 0.0001) and correlated with VAS (Spearman r = 0.61). The cancer sites with the lowest mean HU scores were acute lymphoblastic leukemia (0.70 ± 0.03) and pancreatic cancer (0.76 ± 0.03); testicular cancer (0.89 ± 0.02) and chronic lymphocytic leukemia (0.90 ± 0.05) had the highest mean scores. A multiple regression model showed that scores were influenced by disease site (p < 0.001), education level (p < 0.001), partner status (p < 0.001), disease extent (p = 0.0029), and type of most recent treatment (p = 0.0061). CONCLUSIONS: This work represents the first set of HU scores for numerous cancer sites derived using Canadian preference weights. The dataset demonstrated construct validity and HU scores varied by general socio-demographic and clinical parameters.

Cancer Patients? Willingness to Routinely Complete the EQ-5D Instrument at Clinic Visits.

BACKGROUND: Health utility (HU) scores play an essential role in pharmacoeconomic analyses. Routine clinical administration of the EuroQol-5 Dimensions (EQ-5D) can allow for HU and health related quality of life (HRQOL) assessments in the real-world setting. OBJECTIVES: The primary goals of this study were to evaluate whether patients were willing to complete the EQ-5D instrument on a routine basis and which clinical or demographic factors influence this willingness. METHODS: 618 adult cancer survivors across multiple cancer disease sites at the Princess Margaret Cancer Centre completed an acceptability survey after completing the EQ-5D instrument. RESULTS: The mean (SD) EQ-5D score was 0.81 (0.15). Among those surveyed, 88% reported that the EQ-5D was easy to complete. 91% took under 5 minutes and 88% were satisfied with its length. 85% were satisfied with the types of questions asked on the EQ-5D. Importantly, 92% reported that they would complete the EQ-5D, even if it were used solely for research purposes; 73% agreed with the notion of completing it regularly at their clinic visits. Patients with lower EQ-5D scores (p=0.0006), and non-Caucasians (p=0.0024; 60% willing) were less willing to complete the instrument on a regular basis. Curability of tumour, disease site, age, and gender did not influence willingness. CONCLUSIONS: The majority of cancer patients across disease sites are willing to complete the EQ-5D instrument regularly, even if it were solely for research purposes, but up to 39% declined participation in the first place.

Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

The high morbidity and mortality of patients with esophageal (E) and gastro-esophageal junction (GEJ) cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs) as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR), and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55) in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32). Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04) and older patients (p=0.01). Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment.

There are very few xenograft models available for the study of esophageal (E) and gastro-esophageal junction (GEJ) cancer. Using a NOD/SCID model, we implanted 90 primary E and GEJ tumors resected from patients and six endoscopic biopsy specimens. Of 69 resected tumors with histologically confirmed viable adenocarcinoma or squamous cell carcinoma, 22 (32%) was engrafted. One of 11 tumors, considered to have had a complete pathological response to neo-adjuvant chemo-radiation, also engrafted. Of the 23 patients whose tumors were engrafted, 65% were male; 30% were early stage while 70% were late stage; 22% received neo-adjuvant chemo-radiation; 61% were GEJ cancers. Engraftment occurred in 18/54 (33%) adenocarcinomas and 5/16 (31%) squamous cell carcinomas. Small endoscopic biopsy tissue had a 50% (3/6) engraftment rate. Of the factors analyzed, pretreatment with chemo-radiation and well/moderate differentiation showed significantly lower correlation with engraftment (P<0.05). In the subset of patients who did not receive neo-adjuvant chemo-radiation, 18/41 (44%) engrafted compared with those with pretreatment where 5/29 (17%, P=0.02) engrafted. Primary xenograft lines may be continued through 4-12 passages. Xenografts maintained similar histology and morphological characteristics with only minor variations even after multiple passaging in most instances.