Faculty Bibliography

BACKGROUND:Mucinous rectal cancer is associated with a higher incidence of microsatellite instability, and a poorer response to neoadjuvant chemoradiotherapy compared to other subtypes of rectal adenocarcinoma. Immune checkpoint inhibitors are an emerging family of anti-cancer therapeutics associated with highly variable outcomes in colorectal cancer. Though the immune landscape of mucinous rectal cancer has not been fully explored, the presence of mucin is thought to act as a barrier preventing immune cell infiltration. OBJECTIVE:The aim of this study was to determine the immune properties of mucinous rectal cancer and investigate the degree of lymphocyte infiltration in this cohort. DESIGN/METHODS:This is a retrospective cohort study which involved, multiplexed immunofluorescence staining of tumor microarrays. SETTINGS/METHODS:Samples originated from a single university teaching hospital. PATIENTS/METHODS:Our cohort included 15 cases of mucinous and 43 cases of non-mucinous rectal cancer. MAIN OUTCOME MEASURES/METHODS:Immune cells were classified and quantified. Immune cell counts were compared between mucinous and non-mucinous cohorts. Immune marker expression within tumor epithelial tissue was evaluated to determine degree of lymphocyte infiltration. RESULTS:Cytotoxic ( p = 0.022), and regulatory T-cells ( p = 0.010) were found to be overrepresented in the mucinous cohort compared to the non-mucinous group. PD-1 expression was also found to be significantly greater in the mucinous group ( p = 0.001). CD3 ( p = 0.001) and CD8 ( p = 0.054) expression within tumor epithelium was also higher in the mucinous group, suggesting adequate immune infiltration despite the presence of mucin. Microsatellite instability status was not found to be a predictor of immune marker expression in our analysis. LIMITATIONS/CONCLUSIONS:The relatively small size of the cohort. CONCLUSION/CONCLUSIONS:Mucinous rectal cancer is associated with an immune rich tumor microenvironment, which was not associated with microsatellite instability status. See Video Abstract at http://links.lww.com/DCR/C65 .

Alternative splicing is implicated in each of the hallmarks of cancer, and is mechanised by various splicing factors. Serine-Arginine Protein Kinase 1 (SRPK1) is an enzyme which moderates the activity of splicing factors rich in serine/arginine domains. Here we review SRPK1's relationship with various cancers by performing a systematic review of all relevant published data. Elevated SRPK1 expression correlates with advanced disease stage and poor survival in many epithelial derived cancers. Numerous pre-clinical studies investigating a host of different tumour types; have found increased SRPK1 expression to be associated with proliferation, invasion, migration and apoptosis in vitro as well as tumour growth, tumourigenicity and metastasis in vivo. Aberrant SRPK1 expression is implicated in various signalling pathways associated with oncogenesis, a number of which, such as the PI3K/AKT, NF-КB and TGF-Beta pathway, are implicated in multiple different cancers. SRPK1-targeting micro RNAs have been identified in a number of studies and shown to have an important role in regulating SRPK1 activity. SRPK1 expression is also closely related to the response of various tumours to platinum-based chemotherapeutic agents. Future clinical applications will likely focus on the role of SRPK1 as a biomarker of treatment resistance and the potential role of its inhibition.

BACKGROUND:Emergency laparotomy is associated with high morbidity and mortality. The early identification of high-risk patients allows for timely perioperative care and appropriate resource allocation. The aim of this study was to develop a nationwide surgical trainee-led quality improvement (QI) programme to increase the use of perioperative risk scoring in emergency laparotomy. METHODS:The programme was structured using the active implementation framework in 15 state-funded Irish hospitals to guide the staged implementation of perioperative risk scoring. The primary outcome was a recorded preoperative risk score for patients undergoing an emergency laparotomy at each site. RESULTS:The rate of patients undergoing emergency laparotomy receiving a perioperative risk score increased from 0-11 per cent during the exploratory phase to 35-100 per cent during the full implementation phase. Crucial factors for implementing changes included an experienced central team providing implementation support, collaborator engagement, and effective communication and social relationships. CONCLUSIONS:A trainee-led QI programme increased the use of perioperative risk assessment in patients undergoing emergency laparotomy, with the potential to improve patient outcomes and care delivery.

OBJECTIVES:To evaluate the potential for long distance airborne transmission of SARS-CoV-2 in indoor community settings and to investigate factors that might influence transmission. DESIGN:Rapid systematic review and narrative synthesis. DATA SOURCES:Medline, Embase, medRxiv, Arxiv, and WHO COVID-19 Research Database for studies published from 27 July 2020 to 19 January 2022; existing relevant rapid systematic review for studies published from 1 January 2020 to 27 July 2020; and citation analysis in Web of Science and Cocites. ELIGIBILITY CRITERIA FOR STUDY SELECTION:Observational studies reporting on transmission events in indoor community (non-healthcare) settings in which long distance airborne transmission of SARS-CoV-2 was the most likely route. Studies such as those of household transmission where the main transmission route was likely to be close contact or fomite transmission were excluded. DATA EXTRACTION AND SYNTHESIS:Data extraction was done by one reviewer and independently checked by a second reviewer. Primary outcomes were SARS-CoV-2 infections through long distance airborne transmission (>2 m) and any modifying factors. Methodological quality of included studies was rated using the quality criteria checklist, and certainty of primary outcomes was determined using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Narrative synthesis was themed by setting. RESULTS:22 reports relating to 18 studies were identified (methodological quality was high in three, medium in five, and low in 10); all the studies were outbreak investigations. Long distance airborne transmission was likely to have occurred for some or all transmission events in 16 studies and was unclear in two studies (GRADE: very low certainty). In the 16 studies, one or more factors plausibly increased the likelihood of long distance airborne transmission, particularly insufficient air replacement (very low certainty), directional air flow (very low certainty), and activities associated with increased emission of aerosols, such as singing or speaking loudly (very low certainty). In 13 studies, the primary cases were reported as being asymptomatic, presymptomatic, or around symptom onset at the time of transmission. Although some of the included studies were well conducted outbreak investigations, they remain at risk of bias owing to study design and do not always provide the level of detail needed to fully assess transmission routes. CONCLUSION:This rapid systematic review found evidence suggesting that long distance airborne transmission of SARS-CoV-2 might occur in indoor settings such as restaurants, workplaces, and venues for choirs, and identified factors such as insufficient air replacement that probably contributed to transmission. These results strengthen the need for mitigation measures in indoor settings, particularly the use of adequate ventilation. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42021236762.

High ambient temperatures pose a significant risk to health. This study investigates the heatwave mortality in the summer of 2020 during the SARS-CoV-2 coronavirus (COVID-19) pandemic and related countermeasures. The heatwaves in 2020 caused more deaths than have been reported since the Heatwave Plan for England was introduced in 2004. The total and cause-specific mortality in 2020 was compared to previous heatwave events in England. The findings will help inform summer preparedness and planning in future years as society learns to live with COVID-19. Heatwave excess mortality in 2020 was similar to deaths occurring at home, in hospitals, and in care homes in the 65+ years group, and was comparable to the increases in previous years (2016-2018). The third heatwave in 2020 caused significant mortality in the younger age group (0-64) which has not been observed in previous years. Significant excess mortality was observed for cardiovascular disease, respiratory disease, and Alzheimer's and Dementia across all three heatwaves in persons aged 65+ years. There was no evidence that the heatwaves affected the proportional increase of people dying at home and not seeking heat-related health care. The most significant spike in daily mortality in August 2020 was associated with a period of high night-time temperatures. The results provide additional evidence that contextual factors are important for managing heatwave risks, particularly the importance of overheating in dwellings. The findings also suggest more action is also needed to address the vulnerability in the community and in health care settings during the acute response phase of a heatwave.

BACKGROUND:Centralisation of rectal cancer surgery to designated centres was a key objective of the Irish national cancer control program. A national audit of rectal cancer surgery indicated centralisation was associated with improved early surgical outcomes. This study aimed to determine the impact of implementation of the national cancer strategy on survival from rectal cancer. MATERIALS AND METHODS:Data were collected from the National Cancer Registry of Ireland to include all patients with Stage I-III rectal cancer undergoing rectal cancer surgery with curative intent between 2003 and 2012. Five-year overall survival and cancer-specific survival was compared between patients in the pre-centralisation (2003-2007) and post-centralisation period (2008-2012) and between patients receiving surgery in designated cancer centres and non-cancer centres. RESULTS:The proportion of rectal cancer surgery performed in a designated cancer centre increased from 42% during 2003-2007 to 58% during 2008-2012. Five-year overall survival increased from 66.1% in 2003-2007 to 73.5% in 2008-2012 (p < 0.001). Five-year cancer-specific survival increased from 75.3% in 2003-2007 to 81.9% in 2008-2012 (p < 0.001). Surgery in a cancer centre and surgery post-centralisation were significantly associated with overall and cancer specific survival using Cox proportional hazards regression. CONCLUSION:Survival following resection of rectal cancer was significantly improved following implementation of a national cancer strategy incorporating centralisation of rectal cancer surgery.

Cancer cells' ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells, and quantification of 18 cell lineage and apoptosis proteins. We identified an enrichment for BCL2 in immune, and BAK, SMAC, and XIAP in cancer cells. Ordinary differential equation-based modeling of apoptosis sensitivity at single-cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. Systems modeling at single-cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, but showed significant inter- and intra-tumor heterogeneity.

Heatwaves are a serious threat to human life. Public health agencies that are responsible for delivering heat-health action plans need to assess and reduce the mortality impacts of heat. Statistical models developed in epidemiology have previously been used to attribute past observed deaths to high temperatures and project future heat-related deaths. Here, we investigate the novel use of summer temperature-mortality associations established by these models for monitoring heat-related deaths in regions in England in near real time. For four summers in the period 2011-2020, we find that coupling these associations with observed daily mean temperatures results in England-wide heatwave mortality estimates that are consistent with the excess deaths estimated by UK Health Security Agency. However, our results for 2013, 2018 and 2020 highlight that the lagged effects of heat and characteristics of individual summers contribute to disagreement between the two methods. We suggest that our method can be used for heatwave mortality monitoring in England because it has the advantages of including lagged effects and controlling for other risk factors. It could also be employed by health agencies elsewhere for reliably estimating the health burden of heat in near real time and near-term forecasts.

BACKGROUND/UNASSIGNED:Mucinous colorectal cancer (CRC) represents 10% of all CRC and is associated with chemotherapy resistance. This study aimed to determine expression of apoptosis and necroptosis mediators in mucinous CRC. METHODS/UNASSIGNED:RNA gene expression data were extracted from TCGA. Protein levels in 14 mucinous and 39 non-mucinous tumors were measured by multiplexed immunofluorescence. Levels of apoptosis and necroptosis signalling proteins were analysed in SW1463 (mucinous rectal), SW837 (non-mucinous rectal), LS174T (mucinous colon) and HCT116 (non-mucinous colon) cell lines by western blot. Cell death was investigated by flow cytometry measurement of propidium iodide stained cells. RESULTS/UNASSIGNED:High cleaved-Caspase 3 expression was noted in resected mucinous tumors. Western blot identified alterations in apoptosis proteins in mucinous CRC, most prominently downregulation of Bcl-xL protein levels (p=0.029) which was also observed at the mRNA level in patients by analysis of TCGA gene expression data (p<0.001). Treatment with 5-FU did not significantly elevate cell death in mucinous cells, while non-mucinous cells showed robust cell death responses. However, 5-FU-induced phosphorylation of MLKL in mucinous cancer cells, suggestive of a switch to necroptotic cell death signaling. CONCLUSION/UNASSIGNED:Apoptotic and necroptotic mediators are differentially expressed in mucinous and non-mucinous colorectal cancers and represent targets for investigation of cell death mechanisms in the mucinous subtype.

BACKGROUND:Immune checkpoint inhibition has demonstrated success in overcoming tumor-mediated immune suppression in several types of cancer. However, its clinical use is limited to a small subset of colorectal cancer (CRC) patients, and response is highly variable between CRC subtypes. This study aimed to determine the profile of immune checkpoints and factors associated with immune checkpoint inhibitor response in mucinous CRC. METHODS:Gene expression data from CRC was extracted from the TCGA PanCanAtlas data-freeze release. Gene expression data were reported as batch-corrected and normalized RNA expression derived from RNA-Seq quantification. Clinical, pathologic, and transcriptomic data were compared between mucinous and non-mucinous CRC cohorts. RESULTS:The 557 cases of CRC eligible for inclusion in this study comprised 486 cases of non-mucinous CRC (87.3 %) and 71 cases of mucinous CRC (12.7 %). High correlation was observed in the expression of the included immune checkpoints. Significantly higher expression of programmed cell death protein 1 ligand (PD-L1) and T cell immunoglobulin and mucin domain 3 (TIM-3) was observed in mucinous CRC than in non-mucinous CRC. In a multiple regression model, significant contributors to the prediction of TIM-3 gene expression were microsatellite instability (MSI) (unstandardized regression coefficient [B] = 1.223; p < 0.001), stage (American Joint Committee on Cancer [AJCC] 2; B = 0.423; p < 0.05), and mucinous status (B = 0.591; p < 0.01). CONCLUSION/CONCLUSIONS:Expression of TIM-3, an emerging immune checkpoint inhibition target, was significantly higher in mucinous CRC, and expression was predicted by mucinous status independently of MSI. These findings should prompt investigation of immune checkpoint signaling in the mucinous tumor microenvironment to clarify the potential for immune checkpoint inhibition in mucinous CRC.