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Introduction: Referral for CS/HIPEC is variable, and barriers encountered by referring physicians are unknown. Identification of such barriers is useful for the creation of tailored knowledge translation (KT) strategies. Methods: Interviews of 20 medical oncologists and surgeons in the New York (NY) area were completed to identify barrier topics, using the Pathman framework of uptake of innovations (awareness, agreement, adoption, adherence) at the various levels of the individual, practice group, and organization. Barriers were used to structure a survey for evaluation of prevalence at the population level of medical oncologists and surgeons in NY State. Results: Barrier topics of awareness included training at a CS/HIPEC center, and availability of multidisciplinary cancer conferences. Agreement barriers centered mainly on quality of published literature, and the paradigm shift of carcinomatosis as a systemic to locoregional disease process. Adoption barriers included knowledge of outcomes of a CS/HIPEC surgeon, and concerns with morbidity/mortality rates. Adherence barriers included the lack of reflection of CS/HIPEC in current CPGs, financial/resource and logistic concerns of referrals, and lack of quality measures for the procedure. For the survey, 119 responded (12% response rate), including 42 medical oncologist and 77 surgeons. The majority were aware of CS/HIPEC (n=113, 95%). Medical oncologists were less likely than surgeons to agree with CS/HIPEC related to published evidence (76% vs 92 %, p = 0.02). Surgeons were more likely to be aware of where to refer patients for the procedure, and were less likely to have concerns regarding morbidity/mortality, compared with medical oncologists (p = 0.05, p = 0.04). Representation of CS/HIPEC in CPGs and quality measures/outcomes data was felt to result in adherence to a regular referral practice. Discussion: This prospective study of stakeholders for CS/HIPEC is the first to evaluate and characterize barriers to referral for this complex and controversial surgical innovation, with prevalence at the population level. / Thesis / Master of Health Sciences (MSc) / This thesis identifies problems encountered with referring patients to a specialist surgeon for a procedure that involves both surgical removal of tumors and treatment of the abdominal cavity with chemotherapy. These problems are evaluated from interviews with specialists in the field, and then evaluated at a higher level of all practicing referring specialists through a survey. The results will be used to improve patient outcomes in the future.

Colorectal tumors are hierarchically organized and governed by populations of self-renewing cancer stem cells, representing one of the deadliest types of cancers worldwide. Emergence of a cancer stem-like phenotype depends on epigenetic reprogramming, associated with profound transcriptional changes. As described for pluripotent reprogramming, epigenetic modifiers play a key role in developing and maintaining cancer stem cells by establishing embryonic stem-like transcriptional programs, thus altering the balance between self-renewal and differentiation. Through my work, I have identified overexpression of histone methyltransferase G9a as a risk factor for colorectal cancer, associated with shorter relapse-free survival. Moreover, using human transformed pluripotent cells as a surrogate model for cancer stem cells, I demonstrate that G9a activity is essential for the maintenance of an embryonic stem-like transcriptional signature that is required to promote self-renewal, tumorigenicity and an undifferentiated state. Such a role was also applicable to colorectal cancer, where inhibitors of G9a histone methyltransferase function induced intestinal differentiation while restricting tumor-initiating activity in patient-derived colorectal tumor samples. By integrating transcriptome profiling with G9a/H3K9me2 loci co-occupancy, the canonical Wnt pathway, epithelial-to-mesenchyme transition and extracellular matrix organization were identified as potential targets of such a chromatin regulation mechanism in colorectal cancer stem cells. Considering such novel insights on the role of G9a as a driver of the cancer stem cell phenotype, as well as a promoter of self-renewal, tumorigenicity and an undifferentiated state, I established and executed a multi-step drug screening pipeline to identify new repurposed drugs that selectively alter G9a functions in human CSCs. This pipeline revealed 3 new drug candidates that inhibit H3K9me2 deposition and impair human CSCs in culture. Future in-depth characterization of those candidates will represent an important step toward the development of novel CSC-targeting therapeutics.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13561号 / 論医博第2290号 / 新制||医||1067(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 今中 雄一, 教授 村川 泰裕 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24798号 / 医博第4990号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 萩原 正敏, 教授 妹尾 浩, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23572号 / 医博第4786号 / 新制||医||1054(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 武藤 学, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Excerpt: The conclusions by Zhang et al. (2015) were notable, but the support for the conclusions was not particularly strong because of two issues. The first weakness is that although some studies have found correlations between self-efficacy and pain, the study did not consider the possibility that it is symptom distress that affects self-efficacy in colorectal cancer patients. Rather, it was assumed only that self-efficacy caused reduced symptom effects instead of a reverse or mutual relationship. The study did not consider the possibility that low self-efficacy in those with high symptom distress was actually caused by the distress itself, which is a plausible explanation. In fact, Chiarotto et al. (2014) found that cancer patients on pain medication have higher rates of self-efficacy, which would appear to show that distress reduces self-efficacy, rather than the other way around, as assumed in the above study.

In 2019, cancer was the second leading cause of death in the United States. Colorectal cancer is the second most common cancer affecting both men and women. Colorectal screenings are an important preventive health service, with approximately half of cases detected through screening, improving life expectancy among those diagnosed. Previous research has noted differences in screening rates between racial or ethnic groups, with whites being screened at a higher rate than other racial and ethnic groups. Additionally, the prevalence of colorectal cancer is becoming more common among persons younger than 50 years old, prompting testing guidelines to be revised in 2018 that call for testing to begin at 45 instead of age 50. The purpose of this analysis is to investigate this issue further by examining differences in colorectal screening among various racial and ethnic groups. A cross-sectional study using the 2021 Behavioral Risk Factor Surveillance System for respondents from West Virginia and Oregon (combined) was used to examine colon cancer screening by various racial and ethnic populations. Individuals responding receipt of a colonoscopy or sigmoidoscopy were the primary outcome of interest. Racial and ethnic groups include whites-only, blacks-only, other races, multi-racial and those of Hispanic ethnicity. Additional covariates of interest were included in the analysis based on Andersen’s behavior model for health service utilization and includes predisposing (gender, age, education, marital status) enabling (insurance, employment status) need (body mass index, other types of cancers) factors. Bivariate and multivariate logistic regression analysis was used to examine these relationships. The study population included 2,831 adults who self-reported being screened for colon cancer. Overall 61% of white populations reported receipt of colon cancer screening compared to 54% of Black, 52% of Other, and 43% of Hispanic populations (p<0.00). Adjusting for additional covariates of interest, there were no significant differences between colon cancer screening among black populations compared to their white counterparts (aOR=.81; 95% CI=0.40-1.64). Age and education independently predicted being screened for colon cancer. Graduating from college increased an individual’s odds of being screened for colon cancer (OR= 2.1, 95% CI: 1.1-4.0). The odds also increased for individuals between the age of 55 to 64 (OR=4.2, 95% CI: 3.2-5.3) and ages 65 to 74 (OR=10.0, 95% CI: 6.8-14.8). Our study did not find significant differences in colon cancer screening by race/ethnicity in these two states. It is possible the racial and ethnic composition of the states contributed to the observed findings. West Virginia and Oregon are predominantly white. Smaller subpopulation groups within the national BRFSS dataset may not be sufficient to detect important differences in screenings. Furthermore, it is possible that several factors associated with screening (age, education) may be associated with race/ethnicity but are stronger predictors than race/ethnicity itself. Regular screening for colorectal cancer can help with detecting and treating colon cancer. Additional efforts to increase the general knowledge of colorectal cancer risks should be encouraged for individuals who did not graduate from college and are between 45 to 55 years old.

Kolorektal cancer är en sjukdom som drabbar individer över 60 års ålder och är den tredje vanligaste cancerformen i Sverige. Syftet med denna litteraturstudie var att redogöra hur individerna upplever livskvalitet efter kolorektal kirurgiskt ingrepp. Litteraturstudien gjordes utifrån ett systematiskt tillvägagångssätt. Litteratursökningen utfördes i databaserna Cinahl, Medline, PsychInfo, PubMed, Samsök samt The Cochrane Library. Kvantitativa studier inkluderades vilka kvalitetsgranskades av båda författarna oberoende av varandra med hjälp av ett modifierat granskningsprotokoll. Resultatet visade en sexuell dysfunktion, förändrad fysisk - social funktion, magtarm - urinblåse dysfunktion, psykiska - emotionella förändringar, förändrad kroppsuppfattning och framtidsperspektiv hos patienter som hade genomgått ett kirurgiskt ingrepp. Fler studier behövs för att slutsatser med hög evidensgrad skall kunna dras. / Colorectal cancer is a disease that affects individuals over age 60 and is the third most common cancer form in Sweden. The aim of this study was to report on how individuals experienced their quality of life after colorectal surgery. The literature review was made in accordance to a systematic procedure. The literature searching was made in the databases CINAHL, Medline, PsychInfo, PubMed, Search, and The Cochrane Library. Quantitative studies were included and the quality was assessed by both authors independently of each other using a modified audit protocol. The results showed a sexual dysfunction, changed physical-social function, gastrointestinal- bladder dysfunction, mental- emotional changes, and changes in body image and future perspectives in patients who had undergone a surgical procedure. Further studies needs to make conclusion with high evidence.