Metastatic carcinomas to the thyroid are quite rare in daily cytology practice. However, when present they may produce a diagnostic dilemma, particularly when they share some morphologic similarities with primary thyroid lesions and when occurring in patients with occult malignant history. Herein, we report a case of metastatic gastric signet ring cell carcinoma to the thyroid. Our patient presented with an isolated right thyroid nodule, which was clinically considered to be a primary thyroid neoplasm. Fine-needle aspiration (FNA) cytology of the nodule revealed a cellular specimen with cohesive fragments and scattered individual neoplastic cells. The neoplastic cells had enlarged nuclei, fine chromatin, and inconspicuous nucleoli. Nuclear crowding, molding, and grooving were prominent. Intranuclear inclusion-like clearance was identified. Some tumor cells also had eccentric nuclei, creating a signet ring cell appearance. The colloid was scant. These cytological features may be seen in cases of papillary thyroid carcinoma or signet ring cell follicular adenoma; however, the presence of the signet ring cells is unusual in primary thyroid lesions and raises the possibility of a metastatic lesion to the thyroid. In our case, the tumor cells were positive for AE1/AE3, mucicarmine, and periodic acid-Schiff, but negative for thyroglobulin and thyroid transcription factor-1. The patient was also found to have a 3.7-cm mass in the distal esophagus/proximal stomach. Biopsy of this mass showed an invasive signet ring cell carcinoma. The purpose of our study is to discuss the cytological features and the differential diagnosis of this unusual thyroid FNA case.

In the past several years, cancer treatments using FDA approved immune checkpoint inhibitors have become more popular than common chemotherapeutic agents. However, the costs, risks, and benefits associated with these treatments are still being assessed. Currently, new therapies are being tested that utilize oncolytic viruses to treat solid tumor and metastatic cancers. Reovirus is a non-enveloped virus with a double capsid structure and a genome consisting of 10 segments of double-stranded RNA encoding eleven proteins, which has been shown to have effective oncolytic activity. There are various different strains of reoviruses that can produce cytopathic effects in mammalian host cells. Moreover, several studies have shown that reovirus can be administered in multiple ways and that administration may depend on the cancer type. This investigation examined the type 3 dearing strain of reovirus and whether different types of tumors would benefit from having a specific administration appropriate to their type such as intratumoral injections for solid tumors and intravenous administration for blood/metastatic cancers. Various clinical trials were assessed in which reovirus was administered intratumorally, intravenously at a maximum dose of 3x1010 TCID50, and in combinations with other cancer therapeutics. Reovirus was shown to be safe and well-tolerated across a variety of administrations and cancer morphologies. Moreover, along with its cytopathic effects, reovirus was shown to have potent immune system stimulating effects. Overall, intratumoral administration was preferred effective for solid tumor cancers while intravenous administration was preferred for blood and metastatic cancers.

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No / Metastatic melanoma is the leading cause of skin‑cancer related deaths and while in recent years some progress has been made with targeted therapies, there remains an urgent unmet need for novel therapeutic treatments and reliable diagnostic, prognostic and predictive biomarkers. The emergence of next generation sequencing (NGS) has seen a growing appreciation for the role played by non‑coding genomic transcripts in regulating gene expression and by extension impacting on disease progression. The long non‑coding RNAs (lncRNAs) represent the most enigmatic of these new regulatory molecules. Our understanding of how lncRNAs regulate biological functions and their importance to disease aetiology, while still limited, is rapidly improving, in particular with regards to their role in cancer. Herein we review the identification of several lncRNAs shown to impact on melanoma disease progression and discuss how these molecules are operating at the molecular level.

Current treatments for prostate cancer (PCa) are marred with high relapse frequency and development of progressively aggressive cancers; developing new treatment options for PCa remains crucial. In this project, a series of synthetic compounds based on natural products will be screened to identify inhibitors for Aurora-A kinase (Aur-A). Aur-A facilitates centrosome separation and bipolar spindle formation during mitosis. Aur-A is overexpressed in metastatic PCa cells, and is a good candidate for targeted therapies. Compound libraries are designed using natural compounds that contain simple structural elements as starting points for developing drug like libraries. High-throughput screening of these libraries will be used to identify potent antimitotic agents that selectively affect cancer cells but not normal cells. A combination of in vitro protein assays – quantifying protein activity – cell-based assays – measuring cell growth and proliferation – and cell-reporter assays – to determine which metabolic pathway the compound affects – were used to identify potential inhibitors. Through these methods, we have identified several compounds, with special consideration to thiazole piperazine compounds, to successfully inhibit proliferation of metastatic PCa cells.

No description available.

No description available.

This dissertation explores how language has evolved as metastatic breast cancer (MBC) has shifted from an imminent death sentence to a potentially chronic disease. War rhetoric, of which the survivor trope is a part, has been the primary mechanism by which healthcare defines the cancer experience. Using Celeste Condit's framework of rhetorical formations, I question if a new rhetoric of breast cancer is indeed emerging as new developments in medicine allow women with terminal disease to live longer. My data reveals that this new rhetorical formation, of which metavivor rhetoric is the anchor point, contains its own key metaphors and rhetorical appeals. In metavivor rhetoric, the focus becomes living with cancer, in which simply existing through a sense of homeostasis develops as the central part of the rhetoric. In this homeostasis as the key part of metavivor rhetoric, a cure is not the focus, as it is in survivor rhetoric. I explore how this emerging rhetoric supersedes the war rhetoric that is deeply entrenched in medical discourse--especially breast cancer--for decades, and how metavivor rhetoric builds upon and repudiates the war rhetoric. Through my qualitative rhetorical analysis of a popular breast cancer message board for patients with metastatic disease, I coded 589 posts to see how women use language to discuss living with MBC, and Condit's concept of rhetorical formations allows me to argue more specifically for the changes I see in patient discourse. My analysis revealed that women living with MBC argue against war/survivor rhetoric and prefer metavivor rhetoric and its ancillary terms, allowing them to transition to an acceptance of their own mortality. I conclude that a new rhetorical formation has taken shape within MBC patient discourse, with implications for women's mortality as they live with a chronic disease, and as I look to the future of this research, my goal is to promote rhetorical changes that will help to enfranchise women with MBC into the broader breast cancer discourse in the United States. / Doctor of Philosophy / Metastatic breast cancer has become a disease that some women can live with for many years, as treatments have advanced for this specific type of cancer. As this disease has become a chronic condition for many women, the language that women use to discuss living with chronic cancer has also shifted. Using the framework of Celeste Condit's rhetorical formations, which encompasses uses of metaphors, topics, and values, among other rhetorical features, I examine how language has shifted from one of war and survivor rhetoric to that of metavivor rhetoric. In metavivor rhetoric, the focus becomes living with cancer, through a sense of homeostasis and of simply existing with cancer. Within homeostasis as the key part of metavivor rhetoric, a cure is not the focus, as it is in survivor rhetoric. By examining how women talk about living with cancer on a popular online breast cancer support group, I analyze the shifts that take place in their language and argue that women have moved from the dominant war and survivor rhetorical formation to one that is grounded in metavivor rhetoric and the idea of homeostasis. Within this evolution comes a transition to their own mortality as they come to better understand what it means to live with a chronic, yet ultimately, terminal, illness and an acknowledgment of the impact that their lives' perceived time has on these language choices.

In most randomised controlled trials (RCTs), a large number of patients need to be followed over many years, for the clinical benefit of the drug to be accurately quantified (1). Using an early proxy, or a surrogate endpoint, in place of the direct endpoint of overall survival (OS) could theoretically shorten the duration of RCTs and minimise the exposure of patients to ineffective or toxic treatments (2, 3). This thesis examined the relationship between surrogate endpoints and OS in metastatic colorectal cancer (CRC), advanced non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). A review of the literature identified 144 RCTs in metastatic CRC, 189 in advanced NSCLC and 133 in MBC. The publications were generally of poor quality with incomplete reporting on many key variables, making comparisons between studies difficult. The introduction of the CONSORT statement was associated with improvements in the quality of reporting. For CRC (337 arms), NSCLC (429 arms) and MBC (290 arms) there were strong relationships between OS and progression free survival (PFS), time to progression (TTP), disease control rate (DCR), response rate (RR) and partial response (PR). Correlation was also demonstrated between OS and complete response (CR) in CRC and duration of response (DOR) in MBC. However, while strong relationships were found, the proportion of variance explained by the models was small. Prediction bands constructed to determine the surrogate threshold effect size indicated that large improvements in the surrogate endpoints were needed to predict overall survival gains. PFS and TTP showed the most promise as surrogates. The gain in PFS and TTP required to predict a significant gain in overall survival was between 1.2 and 7.0 months and 1.8 and 7.7 months respectively, depending on trial size and tumour type. DCR was a better potential predictor of OS than RR. The results of this study could be used to design future clinical trials with particular reference to the selection of surrogate endpoint and trial size.

In most randomised controlled trials (RCTs), a large number of patients need to be followed over many years, for the clinical benefit of the drug to be accurately quantified (1). Using an early proxy, or a surrogate endpoint, in place of the direct endpoint of overall survival (OS) could theoretically shorten the duration of RCTs and minimise the exposure of patients to ineffective or toxic treatments (2, 3). This thesis examined the relationship between surrogate endpoints and OS in metastatic colorectal cancer (CRC), advanced non-small cell lung cancer (NSCLC) and metastatic breast cancer (MBC). A review of the literature identified 144 RCTs in metastatic CRC, 189 in advanced NSCLC and 133 in MBC. The publications were generally of poor quality with incomplete reporting on many key variables, making comparisons between studies difficult. The introduction of the CONSORT statement was associated with improvements in the quality of reporting. For CRC (337 arms), NSCLC (429 arms) and MBC (290 arms) there were strong relationships between OS and progression free survival (PFS), time to progression (TTP), disease control rate (DCR), response rate (RR) and partial response (PR). Correlation was also demonstrated between OS and complete response (CR) in CRC and duration of response (DOR) in MBC. However, while strong relationships were found, the proportion of variance explained by the models was small. Prediction bands constructed to determine the surrogate threshold effect size indicated that large improvements in the surrogate endpoints were needed to predict overall survival gains. PFS and TTP showed the most promise as surrogates. The gain in PFS and TTP required to predict a significant gain in overall survival was between 1.2 and 7.0 months and 1.8 and 7.7 months respectively, depending on trial size and tumour type. DCR was a better potential predictor of OS than RR. The results of this study could be used to design future clinical trials with particular reference to the selection of surrogate endpoint and trial size.