BACKGROUND: Pancreatic ductal adenocarcinoma maintains a formidable mortality rate with rising incidence despite extensive research efforts. As of 2021 pancreatic cancer is the third leading cause of cancer-related deaths in the United States despite its incidence representing only 3% of all cancer diagnoses. Given the high mortality rate, research efforts push to improve prognosis by expanding knowledge and tools in the realms of diagnostics, genetics, development of screening modalities, and targeted treatments. Modifications in treatment algorithms have led to only modest improvements in outcome. Current research efforts focus on primary and secondary prevention aimed at modifications of known environmental and hereditary risk factors. Available studies highlight the relationship between relative geography and cancers; however, there is a paucity of research available on the Social Determinants of Health on access to pancreatic cancer care and outcomes. PROPOSED PROJECT: Data will be extracted from the Surveillance, Epidemiology, and End Results (SEER) database and combined with US Census data along with medical record information as relevant over a seven-year period from January 1, 2010, through December 31, 2017. Social Vulnerability Index scores will be derived from the available data as a surrogate for Social Determinant of Health and be assigned to each case of pancreatic cancer from 2010-2017. These scores will be grouped by zip code. Analysis will then be performed to identify the mean stage at time of diagnosis for each zip code. Further analysis will be performed to calculate survival curves for each zip code and cox proportional-hazards will be performed on results to determine statistical significance of SVI with respect to geography. CONCLUSIONS: The proposed study will investigate the impact of geography as a Social Determinant of Health (SDoH) within the United States on the stage at time of diagnosis for pancreatic ductal adenocarcinoma. As a secondary measure, overall survival following diagnosis of pancreatic ductal adenocarcinoma will be examined. SIGNIFICANCE: This study will identify the impact of social determinants of health on geography and correlate the impact on outcomes in pancreatic ductal adenocarcinoma in the United States of America. This study may also identify geographic regions in which the incidence of PDAC is higher than expected which would present a population to investigate for additional screening studies and development of risk prediction models.

Predicting the prognosis of patients with prostate cancer is a clinically important problem. Previous studies have indicated that the expression of haptoglobin-related protein epitopes in samples of breast cancer in early stages was associated with earlier relapses and higher risk for tumor recurrence. Oncogenic antigen 519 (OA-519) is the new marker designation for molecules expressing haptoglobin-related protein epitopes. The objective of this immunohistochemical study was to examine OA-519 expression in prostate cancer samples and its relationship to the established prognostic indicators of tumor grade, tumor volume, and clinical stage. Forty-two consecutive tissue samples of prostate adenocarcinoma were examined using an affinity- purified anti-OA-519 antibody. Twenty specimens (48%) tested positive, whereas 22 (52%) tested negative. No staining was observed in normal or hyperplastic prostate tissue. Staining occurred in 6 of 9 (67%) grade III, 14 of 23 (61%) grade II, and in none of 10 (0%) grade I cases (I vs. II and/or III: Fisher exact test, P < 0.006). Twenty-three of the 42 samples were transurethral resection specimens with cancer; 11 (48%) of these tested positive. The mean percentage of tissue chips with tumor, a measure of tumor volume, was significantly higher in the positive group (57%) than in the negative group (15%) (P = 0.004). The proportion of positively stained cases increased with advancing clinical stage, with 25% of Stage A cases expressing OA-519, and 46%, 67%, and 64% of Stages B, C, and D, respectively, expressing OA-519. OA-519 expression correlates with higher tumor grades, larger tumors, and possibly with advanced stage, and thus, it is potentially of prognostic value in prostate cancer.

Yes / HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the con-text of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overex-pressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum–resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials. / This research was supported by GRACE, a gynaecological charity based in Surrey, UK.

Li Kam-tao, Philip. / "January 2003." / Thesis (M.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 252-281). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web.

[Truncated abstract] Clinical and pathological predictors of survival for stage II and III colon cancer patients treated with or without chemotherapy: a population-based study. Aim: Using a population-based cohort of colorectal cancer (CRC), the major aims of this study were to: 1. Identify clinico-pathological markers that can be used to define a subset of stage II colon cancer patients with excellent prognosis and who therefore do not require referral for adjuvant chemotherapy; 2. Investigate whether there is a survival benefit from the use of adjuvant chemotherapy in a population-based cohort of stage II colon cancer; 3. Investigate stage III colon cancer patients for evidence of predictive markers for response to 5FU chemotherapy; 4. Investigate CRC for age-related differences in clinico-pathological and molecular features. Hypotheses to be tested: 1. A subset of good prognosis stage II colon cancers can be defined using routine pathological markers; 2. Females colon cancer patients gain more survival advantage from 5FU chemotherapy than males; 3. Tumours from young CRC patients have different molecular characteristics to those from older patients; 4. The underlying molecular characteristics of tumour can impact upon the response to 5FU chemotherapy. Methods: The study cohort consisted of 5,971 cases diagnosed between 1993 and 2003 representing over 90% of the CRCs diagnosed in the state of Western Australia. Results: The major findings of this translational research into colon cancer can be summarized as follows: The morphological features of serosal and vascular invasion allow for prognostic stratification of stage II colon cancer into

[Truncated abstract] The treatment of childhood acute lymphoblastic leukaemia (ALL) is one of the great success stories of paediatric oncology, transforming a universally fatal disease into one where 75 to 90% of children are now cured. Although in the past survival for children with T-cell ALL (T-ALL) lagged behind that of children with pre-B ALL, the use of contemporary intensified treatment strategies has significantly diminished this difference, with many investigators reporting similar cure rates for both groups of patients. Despite these marked improvements, numerous challenges still face physicians treating children with T-ALL. Firstly, there have been no additional major improvements in outcome over the last decade, despite additional treatment intensification. Secondly, effective regimens remain elusive for treating children with relapsed T-ALL or patients with resistant disease. Finally, there is a need to identify patients currently potentially overtreated and thus unnecessarily subjected to acute and long term toxicities without benefit. A major challenge therefore, is the identification of novel reliable prognostic markers, in order to identify patients at high risk of relapse and conversely those least likely to relapse, to guide therapy appropriately. Children predicted with a high risk of relapse would be candidates for intensification of therapy and/or novel experimental agents. Conversely, patients predicted to be at low risk of relapse could be offered clinical trials using reduced intensity therapy, thereby minimising toxicity. '...' Crucially, the 3-gene predictor was validated in a completely independent cohort of T-ALL patients, also treated on CCG style therapy. Our 3-gene predictor appears to identify a high risk group of patients which require alternative therapeutic strategies in order to attain a cure. This study has also identified a potential novel agent for the treatment of T-ALL, which may be used as an anthracycline potentiator or anthracycline-sparing agent. We hypothesised that genes associated with a relapse signature provide promising targets for novel therapies. We tested the hypothesis that CFLAR, an inhibitor of the extrinsic apoptotic pathway and a member of the 3-gene predictor may be involved in the development of resistance to chemotherapy. To test our hypothesis we used a novel agent, 2-cyano-3, 12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), previously shown to inhibit CFLAR protein, in two cell lines established in our laboratory from paediatric patients diagnosed with T-ALL. We found that CDDO displayed single agent activity at sub-micromolar concentrations in both cell lines tested. Importantly, minimally lethal doses of CDDO resulted in significant enhancement of doxorubicin mediated cytotoxicity in one of the cell lines assessed. The findings presented as part of this thesis have revealed the value of gene expression analysis of childhood T-ALL for identifying novel prognostic markers. This study has shown that expression profiles may provide better prognostic information than currently available clinical variables. Additionally, genes that constitute a relapse signature may provide rational targets for novel therapies, as demonstrated in this study, which assessed a potential novel agent for the treatment of T-ALL.

[Tuncated abstract] This research thesis consists of five sections. Section one provides the background information (chapter 1) and a description of characteristics of the cohort and the methods of analysis (chapter 2). The Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system is one of commonly used severity of illness scoring systems in many intensive care units (ICUs). Section two of this thesis includes an assessment of the performance of the APACHE II scoring system in an Australian context. First, the performance of the APACHE II scoring system in predicting hospital mortality of critically ill patients in an ICU of a tertiary university teaching hospital in Western Australia was assessed (Chapter 3). Second, a simple modification of the traditional APACHE II scoring system, the 'admission APACHE II scoring system', generated by replacing the worst first 24-hour data by the ICU admission physiological and laboratory data was assessed (Chapter 3). Indigenous and Aboriginal Australians constitute a significant proportion of the population in Western Australia (3.2%) and have marked social disadvantage when compared to other Australians. The difference in the pattern of critical illness between indigenous and non-indigenous Australians and also whether the performance of the APACHE II scoring system was comparable between these two groups of critically ill patients in Western Australia was assessed (Chapter 4). Both discrimination and calibration are important indicators of the performance of a prognostic scoring system. ... The use of the APACHE II scoring system in patients readmitted to ICU during the same hospitalisation was evaluated and also whether incorporating events prior to the ICU readmission to the APACHE II scoring system would improve its ability to predict hospital mortality of ICU readmission was assessed in chapter 10. Whilst there have been a number of studies investigating predictors of post-ICU in-hospital mortality none have investigated whether unresolved or latent inflammation and sepsis may be an important predictor. Section four examines the role of inflammatory markers measured at ICU discharge on predicting ICU re- 4 admission (Chapter 11) and in-hospital mortality during the same hospitalisation (Chapter 12) and whether some of these inflammatory markers were more important than organ failure score and the APACHE II scoring system in predicting these outcomes. Section five describes the development of a new prognostic scoring system that can estimate median survival time and long term survival probabilities for critically ill patients (Chapter 13). An assessment of the effects of other factors such as socioeconomic status and Aboriginality on the long term survival of critically ill patients in an Australian ICU was assessed (Chapter 14). Section six provides the conclusions. Chapter 15 includes a summary and discussion of the findings of this thesis and outlines possible future directions for further research in this important aspect of intensive care medicine.

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Au travers d’études cliniques et biologiques, de méta-analyses et de revues systématiques de la littérature, nous avons étudié les CBNPC de stade III sur le plan thérapeutique et cherché des facteurs pronostiques pour la survie dans le but d’améliorer la classification internationale et, à terme, de permettre une meilleure prise en charge des patients inclus dans ce groupe hétérogène de tumeurs.<p>Dans le cadre d’essais randomisés, nous avons montré qu’un abord multimodal et multidisciplinaire permettait d’améliorer le pronostic des patients atteints d’un CBNPC de stade III. Le traitement des tumeurs non résécables implique une combinaison de chimiothérapie et de radiothérapie, dont l’administration concomitante doit être proposée aux patients aptes à la tolérer. La chimiothérapie doit être incluse dans le schéma thérapeutique des tumeurs potentiellement résécables. Elle permet une résection chirurgicale complète chez des patients sélectionnés dont la tumeur était initialement non résécable.<p>Nous avons déterminé que des caractéristiques cliniques (l’indice de performance et l’âge), biologiques (les taux sanguins de polynucléaires neutrophiles, d’hémoglobine et de plaquettes, la bilirubinémie) et propres à la tumeur (l’extension locale [T3-4] et ganglionnaire [N3]) avaient une valeur pronostique indépendante pour la survie. Ceci nous a permis d’aboutir à une proposition de modification de la classification internationale concernant les CBNPC de stade III.<p>Bien que pris individuellement, les facteurs biologiques que nous avons étudiés (p53, EGF-R, TTF-1, Mdm2) n’aient pas de valeur pronostique pour la survie, nous avons montré que la combinaison EGF-R+/TTF1- était un facteur pronostique indépendant en analyse multivariée pour la survie spécifique au cancer bronchique.<p>Nous avons finalement évalué le rôle pronostique de la tomodensitométrie par émission de positrons et de la mesure semi-quantitative de captation du 18F-FDG (SUV) sur la survie des patients atteints de CBNPC et montré qu’un SUV élevé était un facteur de mauvais pronostic pour la survie. / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

the majority of patients with early breast cancer receive some form of systemic adjuvant therapy (chemo-, endocrine, and/or targeted therapy). Despite the increase in adjuvant therapy prescription, little progress has been made with respect to assisting oncologists to determine which breast cancer patients, particularly those deemed at “lower risk” of relapse, require chemotherapy or other systemic therapy and which women can safely be treated with loco-regional treatment alone. For these reasons, the identification of prognostic and predictive markers that will assist the clinician in selecting the most suitable form of medical therapy has become very high priority as well as a real challenge in translational research. <p>\ / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished