Introduction: This study evaluated long-term outcomes of young survivors of colorectal cancer including survival, development of acute illnesses, and childbirth. Methods: Persons aged 20-44 diagnosed with colorectal cancer and surviving at least five years were identified using the Ontario Cancer Registry and compared to randomly selected controls. Outcomes included death, admission to hospital for acute illness, and childbirth in women, determined by linkage to provincial administrative data. Results: There were 917 cancer survivors in this study. Survivors were more likely to die (HR 8.2, 95%CI [5.8, 11.6]), and require admission to hospital for acute illness (rate ratio 3.4, 95%CI [2.9, 4.1]) than controls. There was no difference in admissions for childbirth in women (HR 0.6, 95%CI [0.3, 1.4]). Conclusions: Five-year survivors of colorectal cancer remain at high risk of long-term death and illness. Aggressive surveillance for recurrent malignant disease is necessary to mitigate risk of death.

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Every year, more than a million people are diagnosed with colorectal cancer (CRC) that develops in the large intestine. It is one of the most studied cancers in the world but still more knowledge about how this cancer develops and acts is needed in order to use more effective ways to treat CRC. Autophagy is a vital mechanism in cells that is also suggested to maintain cancer cell survival. In normal cells, it plays an important role by removing damaged cells and organelles as well as eliminating pathogens. Under metabolic stress this mechanism is induced to provide enough nutrients and energy for the cell to survive. Cancer cells are exposed to greater environmental stress than normal cells and therefore, cancer cells exhibit higher levels of autophagy suggesting it to be a crucial mechanism for their survival. Gaining a deeper understanding of this essential mechanism and its activation might provide new insights and improved treatments for the fight against colorectal cancer. In situ Proximity Ligation Assay (PLA) is a protein detection method that enables sensitive and specific detection of proteins and protein-protein interactions (PPIs) in cell lines and tissue samples. The method uses simultaneous recognition of two independent antigens on a protein or protein complex together with a rolling circle amplification (RCA) to form a rolling circle product (RCP) on top of the target. By using fluorescent oligonucleotides, RCP can be visualized and is seen as a bright spot that enables sensitive detection of the target at single-molecule resolution. The aim of this study was to develop assays to detect endogenous molecular events known to be biomarkers of autophagy in situ in order to study autophagy mechanism in CRC patient samples. We focused our research on two PPIs that were known to interact when autophagy is induced. The first investigated interaction was between microtubule-associated protein 1A/1B- light chain 3 (LC3) and sequestome-1 (SQSTM1), an interaction that occurs during autophagy initiation. The second interaction was between B-cell lymphoma 2 (Bcl-2) and Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) that takes place during hypoxia-induced autophagy. To study whether these PPIs can be used as a detection method to monitor autophagy, we used a well- established cell model based on serum starvation and CoCl2 - an hypoxic mimetic- treatment of the intestinal cancer cell line Caco-2 in comparison to normal culture condition. According to isPLA quantification, detection of both PPIs was distinctly higher in treated cells compared to untreated cells giving promising results and suggesting that they can be potentially used as suitable assays to monitor these biomarkers of autophagy. For development of an improved protein detection method that enables the study of several PPIs simultaneously in a tissue sample (In situ Multiplexing), we conjugated directly a short oligonucleotide strand to the primary antibodies. These formed proximity probes could later be used in in situ for multiplexing.

Colorectal cancer (CRC) is common in Ontario. This study described the processes of care following CRC resection, and identified CRC relapse from administrative data. Methods: CRC patients aged 18-80 from 1996-2001 with a colorectal resection were identified from the Ontario Cancer Registry. Linked discharge abstracts and physician billings were examined for physician visits, body imaging and endoscopy over the 5 year follow-up period. Administrative codes suggesting disease relapse were compared with patient charts. Results: Overall, 12,804 patients were identified and 8,804 had no evidence of relapse. Most (96.2%) patients had general practitioner follow-up, while 49.3% had medical oncology and 80.4% had general surgery follow-up. Greater than 90% of patients received endoscopy, while only 68.7% of patients received body imaging. Detecting disease relapse was 87.5% sensitive and 93.0% specific. Conclusions: There is potential for improving post-resectional follow-up in CRC patients. It is possible to detect relapse through administrative databases.

BACKGROUND: The gold standard treatment for colorectal cancer liver metastases (CRCLM) is surgical resection. Unfortunately, the majority of patients with colorectal hepatic metastases are not candidates for resection. In recent years, several alternatives have emerged for patients whom are not resection candidates including modern systemic chemotherapy, targeted biologic treatments, regional therapies and local tumor ablation options. Microwave ablation (MWA) therapy is one such treatment alternative, based on thermal tissue ablation. This modality in concert with the most recent published literature on its use for patients with CRCLM will be reviewed in this paper. LITERATURE REVIEW FINDINGS: A structured review of the literature on ablative technologies was performed. In recent years, there has been an evolution from radiofrequency ablation (RFA) to microwave ablation therapy for the treatment of CRCLM. RFA has several limitations to its use and MWA theoretically avoids such limitations making it the currently preferable treatment option. There are limited publications comparing the use of RFA to MWA and limited publications on the use of microwave ablation for CRCLM. This paper will focus on the most recent data on MWA for CRCLM. This data can then be compared to the already published data on RFA. PROPOSED METHODS: Given the relative novel status for MWA as a treatment option for CRCLM, a potential disadvantage for its use is the perceived lack of knowledge across the medical professional spectrum. In an effort to expand the knowledge of MWA, the proposed outcomes for this study include creating a curriculum to be offered as a CME course focused for Primary Care Providers (PCPs) to provide a basis of clinical familiarity for its use. This effort will familiarize providers who may have patients diagnosed with CRCLM and also allow them to initiate the conversation about this therapy with their patients who may be candidates for this treatment. CONCLUSIONS: MWA therapy is a safe and effective treatment modality for CRCLM. Due to this new development in treating liver lesions originating from colorectal cancer, it’s imperative for providers to become familiar with these new technologies especially considering the high incidence of CRCLM. Therefore, a curriculum for PCPs will allow for a better understanding of this new technology and foster better provider-patient relationships.

Thesis (M.S.H.P.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / BACKGROUND: Effective colorectal cancer prevention programs should ensure that patients with adenomas receive timely surveillance colonoscopy consistent with guidelines. The aim of our study was to identify patient-, provider-, and system-level predictors of adherence with surveillance colonoscopy in an ethnically diverse safety-net population. METHODS: We performed a retrospective analysis of average-risk patients age 50-75 with adenomas diagnosed at screening colonoscopy at Boston Medical Center and its affiliated community health centers from 1/1/2005 to 12/31/2007. The primary outcome was on-time follow-up defined as attendance at surveillance colonoscopy within 5.5 years of the screening colonoscopy. We compared frequencies of on-time follow-up and performed multivariable analysis, including ethnicity/language and any variable with P value <0.20 in unadjusted analysis. RESULTS: We identified 891 patients, of which 38% were English-speaking Non-Hispanic blacks, 24% Non-Hispanic white, and 10% Spanish-speaking Hispanics. Overall, 38.2% attended on-time surveillance colonoscopy. In unadjusted analyses, having ≥3 PCP visits in year 3-5 after baseline colonoscopy (OR 3.6 [2.6-5.1]), having “adenoma” on the electronic medical record problem list (OR 2.2 [1.6-2.9]), age (OR 0.98 [0.96-1.0]), and Charlson Index ≥1 (OR 1.3 [1.0-1.8]) were positively associated with adherence. In multivariate analysis, having “adenoma” on the problem list remained significant (adjusted OR (aOR) 1.8 [1.3-2.5]). Significant interactions were observed for ethnicity/language and PCP visits (P=0.008). CONCLUSION: A substantial proportion of adenoma-bearing patients fail to attend surveillance colonoscopy even in a safety net setting. Adding “adenomas” to the EMR problem list improved attendance, suggesting that system-level interventions may increase adherence to surveillance colonoscopy. / 2031-01-01

The anticancer drug Camptothecin (CPT) specifically targets topoisomerase I (topoI). While this class of drug is used to treat various solid tumors, CPT is only effective in 13-30 percent of the patient population. Although the mechanism of the CPT resistance pathway is not fully understood, we found cancer cells degrade topoisomerase I (topoI) in response to CPT. The observed relationship between higher basal DNA-PKcs mediated phosphorylation of topoI, rapid degradation of topoI, and resistance to CPT suggested that DNA-PKcs is a critical regulator of the phosphorylation status of topoI and the rate of topoI degradation in response to CPT. The data shows CTDSP1 (a dual phosphatase) acts as a negative regulator of DNA-PKcs. Because CTDSP1 functionality plays a role in maintaining higher basal phosphorylation levels of topoI, CTDSP1 impairment contributes to greater CPT resistance. This renders the CPT chemotherapy treatment ineffective. We hypothesized inducing the catalytically inactive form of CTDPS1 via both knockdown and inhibition experiments would increase cancer cell resistance to CPT as a result of an overactive topoI degradation pathway. The function of CTDSP1 was impaired in the two colon cancer cell lines, HCT15 and HCT116, by silencing with siRNA and using Rabeprazole (a pharmacological agent known to inhibit CTDSP1). Inhibition of CTDSP1 phosphatase activity resulted in greater phosphorylation of DNA-PKcs and increased the rate of topoI degradation in the cells in response to CPT. Cellular resistance was also more notable in the sensitive HCT116 cell lines. HCT15 cells degrade topoI rapidly and are resistant to CPT. Thus, the effect of CPT is not as pronounced in this cell line. CTDSP1 knock down cells showed the greatest DNA-PKcs phosphorylation and topoI degradation when treated with CPT. In addition, the present study includes a clonogenic assay that shows a larger cell survival fraction in Rabeprazole treated HCT116 cells in comparison to controls after exposure to CPT. A higher survival fraction after CPT exposure is reflective of greater CPT resistance. This suggests that cell viability is enhanced during CPT chemotherapy treatment in CTDSP1 null colorectal cancer cells. Lastly, An EGFP read out experiment of topoI tagged to EGFP demonstrated CTDSP1 inhibition results in reduced topoI levels in colorectal cancer cells. The present study showed the potential link between lower topoI levels and greater resistance to CPT by showing that both effects are outcomes of silencing CTDSP1. / 2018-07-11T00:00:00Z

Colorectal cancer is a common disease, representing the third and second most common cause of cancer death in the United States in women and men, respectively. [Ahnen et al.: Mayo Clin Proc 2014;89:216-224; Siegel et al.: CA Cancer J Clin 2016;66:7]. It is estimated that 20% of patients have distant metastatic disease at time of diagnosis [Ahnen et al.: Mayo Clin Proc 2014;89:216-224; Siegel et al.: CA Cancer J Clin 2016;66:7]. The most common metastatic sites include regional lymph nodes, liver, lungs, and peritoneum via lymphatic/hematogenous dissemination as well as contiguous and transperitoneal routes [Ahnen et al.: Mayo Clin Proc 2014;89:216-224; Siegel et al.: CA Cancer J Clin 2016;66:7]. Upon review of the literature, we found that metastatic colon cancer to the scrotum is rare. The following case report proved to be a unique example of this type of metastasis. This rare regional metastasis is theorized to have resulted from a colo-urethro-scrotal fistula that precipitated from the patient's prior traumatic event. (C) 2017 The Author(s) Published by S. Karger AG, Basel

Although there is consistent evidence of an inverse association between physical activity and colorectal cancer (CRC), it is unclear whether physical activity has to be lifelong in order to protect against CRC, or whether there are critical time periods in which physical activity is most protective. This thesis investigated the association between recreational physical activities in specific age periods and across the lifetime and CRC risk in data from a population-based case control study (n=1395) in Newfoundland and Labrador. There were no significant associations between recreational physical activity at any age period or across the lifetime. Lack of association with activity in early adulthood is consistent with other studies in which this has been investigated. Lack of association in later life and across the lifetime may in part be explained by low levels of recreational physical activity, with only 30% of participants meeting World Cancer Research Fund cancer prevention recommendations.

Objective: To determine the clinical validity of family history (FH) in colorectal cancer (CRC) risk classification. Methods: The Assessment of Risk of Colon Tumors In Canada case-control dataset was used to develop regression models associating risk factors with CRC in Ontario adults. Two regression models (‘clinically-driven’ based on a previously published tool, and data-driven) examined discrimination between CRC cases and controls, with and without the inclusion of FH as a risk variable. Discrimination was assessed using the area under the receiver operator characteristics curve. Results: For males, with the addition of FH, there were statistically significant yet quantitatively modest improvements in both models (3.7% clinically-driven, 6.8% data-driven). For females, while FH was a statistically significant predictor of CRC status in the data-driven model, the improvement in discrimination was not significant in either model. Conclusion: FH provides very small improvement in model discrimination beyond other standard CRC risk factors.