Background:Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer.Method:We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters.Results:We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas.Conclusion:Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology.
Introduction:Survival in small cell lung cancer (SCLC) is limited by the development of chemoresistance. Factors associated with chemoresistance in vitro have been difficult to validate in vivo. Both Bcl-2 and β1-integrin have been identified as in vitro chemoresistance factors in SCLC but their importance in patients remains uncertain. Tissue microarrays (TMAs) are useful to validate biomarkers but no large TMA exists for SCLC. We designed an SCLC TMA to study potential biomarkers of prognosis and then used it to clarify the role of both Bcl-2 and β1-integrin in SCLC.Methods:A TMA was constructed consisting of 184 cases of SCLC and stained for expression of Bcl-2 and β1-integrin. The slides were scored and the role of the proteins in survival was determined using Cox regression analysis. A meta-analysis of the role of Bcl-2 expression in SCLC prognosis was performed based on published results.Results:Both proteins were expressed at high levels in the SCLC cases. For Bcl-2 (n=140), the hazard ratio for death if the staining was weak in intensity was 0.55 (0.33–0.94, P=0.03) and for β1-integrin (n=151) was 0.60 (0.39–0.92, P=0.02). The meta-analysis showed an overall hazard ratio for low expression of Bcl-2 of 0.91(0.74–1.09).Conclusions:Both Bcl-2 and β1-integrin are independent prognostic factors in SCLC in this cohort although further validation is required to confirm their importance. A TMA of SCLC cases is feasible but challenging and an important tool for biomarker validation.
Background: Outgrowth of new blood vessels (neovascularization) allows tumors to supply themselves with oxygen and nutrients, and to rapidly metastasize throughout the body. Triple negative breast cancer (TNBC) is particularly susceptible to neovascularization. However, success with anti-angiogenics is highly variable and often patient-specific. This is particularly true as anti-angiogenics are being combined with immunotherapies. Thus, there is a huge unmet need for clinicians to test and predict clinical efficacy of anti-angiogenics at the individual patient level, prior to treatment. Methods: Here, we characterize a patient-autologous, ex-vivo tumor model, termed CANscript, as a platform to study the intratumor microvascular density (iMVD) of breast cancer samples (N=15). To profile iMVD we used immunohistochemical (IHC) analysis of CD34, an early biomarker of neovascularization. We then introduced anticancer and anti-angiogenic agents (e.g. Avastin) for 72 hours, and subsequently quantified phenotypic response to drugs by testing viability, cell death, proliferation and morphology. These quantitative data were then fed into a machine learning algorithm that provides a clinical response prediction (M-Score). Results: We determined that ex-vivo culture reliably retains baseline heterogeneity of iMVD based on expression of CD34+ nodes per visual field by IHC. Furthermore, we show that anticancer and anti-angiogenic agents will dynamically alter iMVD, ex-vivo, in a patient-specific manner. Finally, we show that prediction of clinical response using the 'M-Score' algorithm associates with diminished expression of CD34 per visual field of IHC after drug pressure. Summary: Neovascularization and iMVD are features of aggressive cancers, such as TNBC. CANscript provides a rapid assessment of clinical response to anticancer drugs, many of which induce their antitumor effect by targeting the tumor vasculature. We show that pharmacodynamics of antiangiogenics can be captured during acute ex-vivo culture under drug pressure, which associate to clinical response prediction. Therefore, we highlight the ability of CANscript as a platform to predict clinical response to anti-angiogenic drugs, and may therefore be a logical 'testing ground' to predict clinical efficacy of antiangiogenic drugs combined with immunotherapies. Citation Format: Smalley M, Alam N, Murmu N, Somashekhar S, Ulaganathan B, Thayakumar A, Maciejko L, Ganesh J, Lawson M, Gertje H, Shanthappa BU, Goldman A. A live tissue platform allows dynamic measurement of neovascularization and prediction of clinical response in human breast cancer samples, ex vivo [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-07-03.
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IntroductionOver several years there has been an ongoing rise in 62-day Lung Cancer pathway referrals initiated by GPs as two-week wait referrals (2WW). This was particularly marked in 2014 and breach rates increased across the East of England SCN. Within the Essex Lung Cancer Network an audit of these breaches was undertaken by three Trusts to look for common themes and to share best practice.MethodsData were collected for all pathways that failed to meet the 62-day target across three NHS Trusts in Essex to identify any predictive factors for breaching the pathway. A standard proforma was used for abstraction. Results were analysed using GraphPad Prism 6 (La Jolla, CA).ResultsIn 2014 a total of 1,419 2WW referrals were received by the three Trusts of which 13–23% were diagnosed with lung cancer. Between 19% and 54% breached the 62-day target (89 of 246 pathways). The median length of the breached pathways varied from 86–88 days by Trust. Trusts did not appear to differ significantly by end treatment after pathway breach. There were generic common themes within the breached pathways of each Trust but for the two worst performing Trusts specific pathway issues were identified. In one Trust it was clear that time delays to perform CT guided lung biopsies with a 2.75 relative risk of breaching if a pathway involved a CT biopsy (95% CI 1.6–4.6, p < 0.0001). At another Trust a high proportion of breached pathways had a bronchoscopy as the first test but went on to have further diagnostic biopsies by other methods.ConclusionMany of the diagnostic delays were due to complex patient pathways needing multiple diagnostic tests. However for two Trusts significant problems were highlighted for targeted quality improvement plans. Selecting the best test to give diagnostic and staging information is vital particularly when services are stretched and capacity is reached.
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