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In order to facilitate targeted outreach, we sought to identify patient populations with a lower likelihood of returning for breast cancer screening after COVID-19-related imaging center closures. Methods Weekly total screening mammograms performed throughout 2019 (baseline year) and 2020 (COVID-19-impacted year) were compared. Demographic and clinical characteristics, including age, race, ethnicity, breast density, breast cancer history, insurance status, imaging facility type used, and need for interpreter, were compared between patients imaged from March 16 to October 31 in 2019 (baseline cohort) and 2020 (COVID-19-impacted cohort). Census data and an online map service were used to impute socioeconomic variables and calculate travel times for each patient. Logistic regression was used to identify patient characteristics associated with a lower likelihood of returning for screening after COVID-19-related closures. Results The year-over-year cumulative difference in screening mammogram volumes peaked in week 21, with 2962 fewer exams in the COVID-19-impacted year. By week 47, this deficit had reduced by 49.4% to 1498. A lower likelihood of returning for screening after COVID-19-related closures was independently associated with younger age (odds ratio (OR) 0.78, p < 0.001), residence in a higher poverty area (OR 0.991, p = 0.014), lack of health insurance (OR 0.65, p = 0.007), need for an interpreter (OR 0.68, p = 0.029), longer travel time (OR 0.998, p < 0.001), and utilization of mobile mammography services (OR 0.27, p < 0.001). Conclusion Several patient factors are associated with a lower likelihood of returning for screening mammography after COVID-19-related closures. Knowledge of these factors can guide targeted outreach to vulnerable patients to facilitate breast cancer screening.

Thymidylate synthase is a target of 5-fluoruracil, a pyrimidine analog used to treat gastrointestinal and other cancers. The 5-fluorouracil metabolite, fluoro-deoxyuridine monophosphate, forms a ternary complex with thymidylate synthase and 5,10-methylene tetrahydrofolate. The purpose of this study was to evaluate the time-honored connection between thymidylate synthase and 5-fluorouracil. From our literature search spanning reports from 1995 to 2007 published in journals having an impact factor greater than two, we stratified the tumors within each article, according to low versus high thymidylate synthase expression. These groups were subdivided into responders, stable disease or disease progression. The relationship between thymidylate synthase expression and 5-fluorouracil response was analyzed for the overall group, as well as for subsets. Overall, the literature supported an approximately two-fold inverse relationship between thymidylate synthase expression and response to 5-fluoruracil. We found no change in the trend for a relationship between thymidylate synthase and 5-fluorouracil when the literature was stratified by date of publication, impact factor of the journal in which the report was published, or substrate (mRNA versus protein) for measuring thymidylate synthase expression. Of note, there is no significant change in the trend when comparing 5-fluorouracil treatment alone or in combination with leucovorin. We found a decline of this trend when certain chemotherapeutics were used in combination with 5-fluorouracil. In sum, the connection between thymidylate synthase expression and patient response to 5-fluorouracil does not satisfy expectations for an effective drug-target relationship; and thus, studies of the thymidylate synthase tandem repeat status might only be clinically valuable in regards to patient toxicity. Thus, we question the reliability of thymidylate synthase expression as a clinical predictor of 5-fluorouracil response. Future research could perhaps be directed towards alternate targets and metabolites of 5-fluorouracil, in an effort to find a clinically relevant biomarker panel for response and to optimize fluoropyrimidine-based therapy.

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Pancreatic cancer is the fourth leading cause of cancer-related deaths in this country, and there is currently no effective targeted treatment for this deadly disease. A dire need exists to rapidly translate our molecular understanding of this devastating disease into effective, novel therapeutic options. Mesothelin is a candidate target protein shown by a number of laboratories to be specifically overexpressed in pancreatic cancers and not in the adjacent normal tissue. Translational investigations have shown promising results using this molecule as a therapeutic target (e.g., vaccine strategies). In addition, the mesothelin promoter has been cloned and dissected and can therefore be used as a vehicle for regulating expression of DNA sequences. Using a novel, proven, biodegradable nanoparticulate system, we sought to target mesothelin-expressing pancreatic cancer cells with a potent suicide gene, diphtheria toxin-A (DT-A). We first confirmed reports that a majority of pancreatic cancer cell lines and resected pancreatic ductal adenocarcinoma specimens overexpressed mesothelin at the mRNA and protein levels. High mesothelin-expressing pancreatic cancer cell lines produced more luciferase than cell lines with undetectable mesothelin expression when transfected with a luciferase sequence under the regulation of the mesothelin promoter. We achieved dramatic inhibition of protein translation (>95%) in mesothelin-expressing pancreatic cancer cell lines when DT-A DNA, driven by the mesothelin promoter, was delivered to pancreatic cancer cells. We show that this inhibition effectively targets the death of pancreatic cancer cells that overexpress mesothelin. The work presented here provides evidence that this strategy will work in pre-clinical mouse pancreatic cancer models, and suggests that such a strategy will work in the clinical setting against the majority of pancreatic tumors, most of which overexpress mesothelin.