Su1554 DOSE PERTURBATION OF ESOPHAGEAL AND BILIARY STENTS IN PROTON RADIATION

Abstract Background The COVID-2019 pandemic continues to restrict access to endoscopy, resulting in delays or cancellation of non-urgent endoscopic procedures. A delay in the removal or exchange of plastic biliary stents may lead to stent occlusion with consensus recommendation of stent removal or exchange at three-month intervals [1–4]. We postulated that delayed plastic biliary stent removal (DPBSR) would increase complication rates. Aims We aim to report our single-centre experience with complications arising from DPBSR. Methods This was a retrospective, single-center, observational cohort study. All subjects who had ERCP-guided plastic biliary stent placement in Halifax, Nova Scotia between Dec 2019 and June 2020 were included in the study. DPBSR was defined as stent removal >=90 days from insertion. Four endpoints were assigned to patients: 1. Stent removed endoscopically, 2. Died with stent in-situ (measured from stent placement to documented date of death/last clinical encounter before death), 3. Pending removal (subjects clinically well, no liver enzyme elevation, not expired, endpoint 1 Nov 2020), and 4. Complication requiring urgent reintervention. Kaplan-Meier survival analysis was used to represent duration of stent patency (Fig.1). Results 102 (47.2%) had plastic biliary stents placed between 2/12/2019 and 29/6/2020. 49 (48%) were female, and the median age was 68 (R 16–91). Median follow-up was 167.5 days, 60 (58.8%) subjects had stent removal, 12 (11.8%) died before replacement, 21 (20.6%) were awaiting stent removal with no complications (median 230d, R 30–332), 9 (8.8%) had complications requiring urgent ERCP. Based on death reports, no deaths were related to stent-related complications. 72(70.6%) of patients had stents in-situ for >= 90 days. In this population, median time to removal was 211.5d (R 91-441d). 3 (4.2%) subjects had stent-related complications requiring urgent ERCP, mean time to complication was 218.3d (R 94–441). Stent removal >=90 days was not associated with complications such as occlusion, cholangitis, and migration (p=1.0). Days of stent in-situ was not associated with occlusion, cholangitis, and migration (p=0.57). Sex (p=0.275), cholecystectomy (p=1.0), cholangiocarcinoma (p=1.0), cholangitis (p=0.68) or pancreatitis (p=1.0) six weeks prior to ERCP, benign vs. malignant etiology (p=1.0) were not significantly associated with stent-related complications. Conclusions Plastic biliary stent longevity may have been previously underestimated. The findings of this study agree with CAG framework recommendations [5] that stent removal be prioritized as elective (P3). Limitations include small sample size that could affect Kaplan-Meier survival analysis. Despite prolonged indwelling stent time as a result of COVID-19, we did not observe an increased incidence of stent occlusion or other complications. Funding Agencies None

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Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

Scientific Reports ◽

10.1038/s41598-021-83142-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tara Al Zubaidi ◽

O. H. Fiete Gehrisch ◽

Marie-Michelle Genois ◽

Qi Liu ◽

Shan Lu ◽

...

Keyword(s):

Dna Replication ◽

Single Molecule ◽

Replication Stress ◽

Proton Radiation ◽

Wild Type ◽

Cellular Effects ◽

Proton Treatment ◽

Dna Replication Stress ◽

Fork Stalling ◽

Mutant Cells

AbstractMutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

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