Tyrosine Kinase Growth Factors in Gastric Cancer

In the West of Scotland in the last thirty years there has been a definite decrease in the incidence and mortality from gastric cancer but the survival of patients who develop adenocarcinoma of the stomach remains poor. This thesis is introduced by an audit of gastric cancer in a single centre over a period of twenty years. This aims to describe changes in the presentation, diagnosis and management of the condition during the period of study. Overall, despite improvements in investigation the disease still presents at an advanced stage and rates of curative resection are low. Advances in surgical technique and post-operative care have not improved long term survival with little significant additional benefit from current adjuvent medical therapy. The tyrosine kinase growth factor receptors have been investigated in a number of human cancers including breast, colon, ovarian and squamous carcinoma. In gastric cancer, the level of expression and prognostic value of EGFr and c-erbB-2 have been reported with some considerable variation using standard immunohistochemistry. To assess the use of growth factors as tumour markers or potential therapeutic targets, reliable quantitative and reproducible measurements of expression must be established. This study reports the quantitative expression of EGFr and c-erbB-2 using radioimmunohistochemistry (RIHC) and compares the results with expression using conventional immunohistochemistry (IHC). The correlation of established clinico- pathological factors with EGFr, c-erbB-2 and the gene amplification of c-erbB-2 using fluorescence in situ hybridisation is investigated. In both EGFr and c-erbB-2 expression there is good overall correlation analysis using RIHC and IHC (p<0.0005) but the separation of results is significantly better with RIHC particularly in the higher expressing tumours. In comparing tumour to mucosal samples, 22.4% of tumours expressed c-erbB-2 at a higher level, using RIHC and 43.3% with IHC. EGFr was expressed in 22.4% of cases more than the mucosal range with RIHC and 41. 8% with IHC. There was no correlation of EGFr and c-erb-2 (r2 = 0.004, p = 0.594). In this study there is significant correlation of c-erbB-2 with well and moderately well differentiated tumours (p=0.008) and no serosal involvement (p=0.066). EGFr in this study also appears to correlate with well and moderately well differentiated tumours (p=0.079). There was no correlation between EGFr, c-erbB-2 and patient survival. This thesis has demonstrated IGF-I induced cellular proliferation with a dose dependent inhibition by the tyrophostin RG13022. IGF-I is found to be a less potent stimulator of the MAP kinase pathway than EGF and RG13022 is less able to inhibit this pathway

Variation in the management of elderly patients in two neighboring breast units is due to preferences and attitudes of health professionals

Introduction: Elderly breast cancer patients have been shown to be managed less aggressively than younger patients. There is evidence that their management varies between institutions. We audited the management of elderly patients in two neighboring units in Glasgow and aimed to identify reasons for any differences in practice found. Methods: Patients aged ≥70 years, who were managed for a new diagnosis of breast cancer in the two units between 2009 and 2013, were identified from a prospectively maintained database. Tumor pathology, treatment details, postcode and consultant in charge of care were obtained from the same database. Comorbidities were obtained from each patient’s electronic clinical record. Questionnaires were distributed to members of each multidisciplinary teams. Results: 487 elderly patients in Unit 1 and 467 in Unit 2 were identified. 76.2% patients in Unit 1 were managed surgically compared to 63.7% in Unit 2 (p&lt;0.0001). There was no difference between the two units in patient age, tumor pathology, deprivation or comorbidity. 16.2% patients managed surgically in Unit 1 had a comorbidity score of 6 and above compared to 11% of surgically managed patients in Unit 2 (p=0.036). Responses to questionnaires suggested that staff at Unit 1 were more confident of the safety of general anesthetic in elderly patients and were more willing to consider local anesthetic procedures. Conclusion: A higher proportion of patients aged &gt;70 years with breast cancer were managed surgically in Unit 1 compared to Unit 2. Reasons for variation in practice seem to be related to attitudes of medical professionals toward surgery in the elderly, rather than patient or pathological factors

Research is ‘a step into the unknown’: an exploration of pharmacists’ perceptions of factors impacting on research participation in the NHS

Objective This study explored National Health Service (NHS) pharmacists&rsquo; perceptions and experiences of pharmacist-led research in the workplace.&nbsp; Design Semistructured, face-to-face discussions continued until distinct clusters of opinion characteristics formed. Verbatim transcripts of audio-recordings were subjected to framework analysis.&nbsp; Setting Interviews were carried out with 54 pharmacists with diverse backgrounds and roles from general practices and secondary care in the UK's largest health authority.&nbsp; Results The purpose and potential of health services research (HSR) was understood and acknowledged to be worthwhile by participants, but a combination of individual and system-related themes tended to make participation difficult, except when this was part of formal postgraduate education leading to a qualification. Lack of prioritisation was routinely cited as the greatest barrier, with motivation, confidence and competence as additional impediments. System-related themes included lack of practical support and pharmacy professional issues. A minority of highly motivated individuals managed to embed research participation into routine activity.&nbsp; Conclusions Most pharmacists realised the desirability and necessity of research to underpin pharmacy service expansion, but a combination of individual and professional level changes is needed to increase activity. Our findings provide a starting point for better understanding the mindset of hospital-based and general practice-based pharmacists towards research, as well as their perceived barriers and supports

A roadmap for patient-public involvement and engagement (PPIE) : recounting the untold stories of breast cancer patient experiences

Introduction Breast cancer remains a prevalent disease in women worldwide. Though significant advancements in the standard of care for breast cancer have contributed to improved patient survival and quality of life, a breast cancer diagnosis and subsequent treatment interventions have a long-lasting impact on patients’ lived experiences. A high-quality healthcare system uses a patient-centred approach to healthcare, with patient engagement being a central pillar in the delivery of patient-centred care. However, the disconnect between patients and researchers can translate into research lacking real-world relevance to patient health needs. Here, we report a patient and stakeholder engagement workshop series that was conceptualized with the goal of promoting dialogue between patients with breast cancer, breast cancer researchers and the clinician involved in their care. We present the collaborative learning process and emerging opportunities from this patient engagement workshop series as a community-academic partnership. Method We report on a three-part storytelling workshop, with the scope of the workshops including topics related to raising awareness of the patient lived experience following a breast cancer diagnosis, breast cancer research activities undertaken by researchers, and the approach used by multidisciplinary healthcare teams in the management of breast cancer using storytelling as a tool. We used an iterative approach to cohort trust and relationship building, narrative development, and the use of multiple media formats to capture patient stories. This included the use of object memories, storytelling prompt cards and open-mic audio format to capture patient stories from diagnosis to treatment, and remission. Results 20 patients shared their stories with key themes emerging from the qualitative analysis of audio recordings. For many, this was the first time they had spoken about their breast cancer experience beyond family and friends. Emerging themes included common public misconceptions about a breast cancer diagnosis, the importance of self-advocacy in patient decision making about treatment, and the complex emotional journey experienced by patients diagnosed with breast cancer. The group-based storytelling approach provided collective empowerment to share personal experiences and connect meaningfully across the peer community. Conclusion While a breast cancer diagnosis can be overwhelming from a physical, social, emotional and cognitive perspective, storytelling as a patient engagement approach can build patient trust in researchers, ensuring that as key stakeholders they are involved in the process of research. Understanding the patient perspective of a breast cancer diagnosis and subsequent experiences can support healthcare professionals in developing an empathetic approach to sharing information, and involving patients in shared decision making about their healthcare

The role of KPNA2 mutations in breast cancer prognosis : a survey of publicly available databases

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions. We report a survey of several publicly available databases probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing information available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival. Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents. In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer

Prognostic role of preoperative circulating systemic inflammatory response markers in primary breast cancer: meta-analysis

Background: Circulating markers of the systemic inflammatory response are prognostic in several cancers, but their role in operable breast cancer is unclear. A systematic review and meta-analysis of the literature was carried out. Methods: A search of electronic databases up to August 2020 identified studies that examined the prognostic value of preoperative circulating markers of the systemic inflammatory response in primary operable breast cancer. A meta-analysis was carried out for each marker with more than three studies, reporting a HR and 95 per cent confidence interval for disease-free survival (DFS), breast cancer-specific survival (BCSS) or overall survival (OS). Results: In total, 57 studies were reviewed and 42 were suitable for meta-analysis. Higher neutrophil-to-lymphocyte ratio (NLR) was associated with worse overall survival (OS) (pooled HR 1.75, 95 per cent c.i. 1.52 to 2.00; P &lt; 0.001), disease-free survival (DFS) (HR 1.67, 1.50 to 1.87; P &lt; 0.001), and breast cancer-specific survival (BCSS) (HR 1.89, 1.35 to 2.63; P &lt; 0.001). This effect was also seen with an arithmetically-derived NLR (dNLR). Higher platelet-to-lymphocyte ratio (PLR) was associated with worse OS (HR 1.29, 1.10 to 1.50; P = 0.001) and DFS (HR 1.58, 1.33 to 1.88; P &lt; 0.001). Higher lymphocyte-to-monocyte ratio (LMR) was associated with improved DFS (HR 0.65, 0.51 to 0.82; P &lt; 0.001), and higher C-reactive protein (CRP) level was associated with worse BCSS (HR 1.22, 1.07 to 1.39; P = 0.002) and OS (HR 1.24, 1.14 to 1.35; P = 0.002). Conclusion: Current evidence suggests a role for preoperative NLR, dNLR, LMR, PLR, and CRP as prognostic markers in primary operable breast cancer. Further work should define their role in clinical practice, particularly reproducible thresholds and molecular subtypes for which these may be of most value

Evaluation of the role of KPNA2 mutations in breast cancer prognosis using bioinformatics datasets

Breast cancer, comprising of several sub-phenotypes, is a leading cause of female cancer-related mortality in the UK and accounts for 15% of all cancer cases. Chemoresistant sub phenotypes of breast cancer remain a particular challenge. However, the rapidly-growing availability of clinical datasets, presents the scope to underpin a data-driven precision medicine-based approach exploring new targets for diagnostic and therapeutic interventions. We report the application of a bioinformatics-based approach probing the expression and prognostic role of Karyopherin-2 alpha (KPNA2) in breast cancer prognosis. Aberrant KPNA2 overexpression is directly correlated with aggressive tumour phenotypes and poor patient survival outcomes. We examined the existing clinical data available on a range of commonly occurring mutations of KPNA2 and their correlation with patient survival. Our analysis of clinical gene expression datasets show that KPNA2 is frequently amplified in breast cancer, with differences in expression levels observed as a function of patient age and clinicopathologic parameters. We also found that aberrant KPNA2 overexpression is directly correlated with poor patient prognosis, warranting further investigation of KPNA2 as an actionable target for patient stratification or the design of novel chemotherapy agents. In the era of big data, the wealth of datasets available in the public domain can be used to underpin proof of concept studies evaluating the biomolecular pathways implicated in chemotherapy resistance in breast cancer

Mammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective, single-arm, FH01 study.

BACKGROUND: Evidence supports a reduction in mortality from breast cancer with mammographic screening in the general population of women aged 40-49 years, but the effect of family history is not clear. We aimed to establish whether screening affects the disease stage and projected mortality of women younger than 50 years who have a clinically significant family history of breast cancer. METHODS: In the single-arm FH01 study, women at intermediate familial risk who were younger than 50 years were enrolled from 76 centres in the UK, and received yearly mammography. Women with BRCA mutations were not explicitly excluded, but would be rare in this group. To compare the FH01 cohort with women not receiving screening, two external comparison groups were used: the control group of the UK Age Trial (106,971 women aged 40-42 years at recruitment, from the general population [ie, average risk], followed up for 10 years), and a Dutch study of women with a family history of breast cancer (cancer cases aged 25-77 years, diagnosed 1980-2004). Study endpoints were size, node status, and histological grade of invasive tumours, and estimated mortality calculated from the Nottingham prognostic index (NPI) score, and adjusted for differences in underlying risk between the FH01 cohort and the control group of the UK Age Trial. This study is registered with the National Research Register, number N0484114809. FINDINGS: 6710 women were enrolled between Jan 16, 2003, and Feb 28, 2007, and received yearly mammography for a mean of 4 years (SD 2) up until Nov 30, 2009; surveillance and reporting of cancers is still underway. 136 women were diagnosed with breast cancer: 105 (77%) at screening, 28 (21%) symptomatically in the interval between screening events, and three (2%) symptomatically after failing to attend their latest mammogram. Invasive tumours in the FH01 study were significantly smaller (p=0·0094), less likely to be node positive (p=0·0083), and of more favourable grade (p=0·0072) than were those in the control group of the UK Age Trial, and were significantly less likely to be node positive than were tumours in the Dutch study (p=0·012). Mean NPI score was significantly lower in the FH01 cohort than in the control group of the UK Age Trial (p=0·00079) or the Dutch study (p<0·0001). After adjustment for underlying risk, predicted 10-year mortality was significantly lower in the FH01 cohort (1·10%) than in the control group of the UK Age Trial (1·38%), with relative risk of 0·80 (95% CI 0·66-0·96; p=0·022). INTERPRETATION: Yearly mammography in women with a medium familial risk of breast cancer is likely to be effective in prevention of deaths from breast cancer