CCC publication: Reduction in the resident intestinal myelomonocytic cell population occurs during Apc Min/+ mouse intestinal tumorigenesis

Citation: Oncology letters. 2021, 21(4), 263
Author: Olusola O Faluyi, Mark A Hull, Alexander F Markham, Constanze Bonifer, P Louise Coletta
Abstract: With its significant contribution to cancer mortality globally, advanced colorectal cancer (CRC) requires new treatment strategies. However, despite recent good results for mismatch repair (MMR)-deficient CRC and other malignancies, such as melanoma, the vast majority of MMR-proficient CRCs are resistant to checkpoint inhibitor (CKI) therapy. MMR-proficient CRCs commonly develop from precursor adenomas with enhanced Wnt-signalling due to adenomatous polyposis coli (APC) mutations. In melanomas with enhanced Wnt signalling due to stabilized β-catenin, immune anergy and resistance to CKI therapy has been observed, which is dependent on micro-environmental myelomonocytic (MM) cell depletion in melanoma models. However, MM populations of colorectal adenomas or CRC have not been studied. To characterize resident intestinal MM cell populations during the early stages of tumorigenesis, the present study utilized the ApcMin/+ mouse as a model of MMR-proficient CRC, using enhanced green fluorescent protein (EGFP) expression in the mouse lysozyme (M-lys) lys-EGFP/+ mouse as a pan-myelomonocytic cell marker and a panel of murine macrophage surface markers. Total intestinal lamina propria mononuclear cell (LPMNC) numbers significantly decreased with age (2.32±1.39×107 [n=4] at 33 days of age vs. 1.06±0.24×107 [n=8] at 109 days of age) during intestinal adenoma development in ApcMin/+ mice (P=0.05; unpaired Student's t-test), but not in wild-type littermates (P=0.35). Decreased total LPMNC numbers were associated with atrophy of intestinal lymphoid follicles and the absence of MM/lymphoid cell aggregates in ApcMin/+ mouse intestine, but not spleen, compared with wild-type mice. Furthermore, during the early stage of intestinal adenoma development, there was a two-fold reduction of M-lys expressing cells (P=0.05) and four-fold reduction of ER-HR3 (macrophage sub-set) expressing cells (P=0.05; two tailed Mann-Whitney U test) in mice with reduced total intestinal LPMNCs (n=3). Further studies are necessary to determine the relevance of these findings to immune-surveillance of colorectal adenomas or MMR-proficient CRC CKI therapy resistance.
Keywords: Apc; ApcMin/+ mouse; intestine; mouse lysozyme; myelomonocytic; tumorigenesis.

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CCC publication: The Enzyme-Modified Neutral Comet (EMNC) Assay for Complex DNA Damage Detection

Citation: Methods and protocols. 2021, 4(1), 14
Author: Maria Rita Fabbrizi, Jonathan R Hughes, Jason L Parsons
Abstract: The comet assay is a versatile, simple, and sensitive gel electrophoresis-based method that can be used to measure and accurately quantify DNA damage, particularly single and double DNA strand breaks, in single cells. While generally this is used to measure variation in DNA strand break levels and repair capacity within a population of cells, the technique has more recently been adapted and evolved into more complex analysis and detection of specific DNA lesions, such as oxidized purines and pyrimidines, achieved through the utilization of damage-specific DNA repair enzymes following cell lysis. Here, we detail a version of the enzyme-modified neutral comet (EMNC) assay for the specific detection of complex DNA damage (CDD), defined as two or more DNA damage lesions within 1-2 helical turns of the DNA. CDD induction is specifically relevant to ionizing radiation (IR), particularly of increasing linear energy transfer (LET), and is known to contribute to the cell-killing effects of IR due to the difficult nature of its repair. Consequently, the EMNC assay reveals important details regarding the extent and complexity of DNA damage induced by IR, but also has potential for the study of other genotoxic agents that may induce CDD.
Keywords: DNA damage; DNA repair; comet assay; complex DNA damage; ionising radiation; protons.

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CCC publication: FP04.02 Feasibility of Radiotherapy Planning in the First 50 Patients Recruited to the ADSCaN Clinical Trial,

Citation: Journal of Thoracic Oncology. 2021, 16(3 Sup), S197. Conference Abstract
Author: R. Mir, C. Faivre-Finn, C. Lawless, E. Mccartney, C. Peedell, T. Pope, A. Shaw, R. Simoes, M. Hatton,

CCC publication: P03.02 Neoadjuvant Osimertinib with/without Chemotherapy vs Chemotherapy for EGFR Mutated Resectable NSCLC: NeoADAURA

Citation: Journal of Thoracic Oncology. 2021, 16(3), S258. Conference Abstract
Author: M. Tsuboi, W. Weder, C. Escriu, C. Blakely, J. He, S. Dacic, Y. Yatabe, L. Zeng, A. Walding, J. Chaft,

CCC publication: 203MO Changes in management for patients with lung cancer treated with radical radiotherapy during the first wave of the COVID-19 pandemic in the UK (COVID-RT Lung),

Citation: Journal of Thoracic Oncology. 2021, 16(4 Sup), S808
Author: K. Banfill, G. Price, K. Wicks, A. Britten, C. Carson, M. Hatton, K. Thippu Jayaprakash, A. Jegannathen, C.L. Lee, N. Panakis, C. Peedell, C. Stilwell, T. Pope, C. Powell, V. Wood, S. Zhou, C. Faivre-Finn,

CCC publication: Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial

Citation: The Lancet. Oncology. 2021, 22(5), 690-701. 2021, S1470-2045(21), 00027-9. Online ahead of print.
Author: Angela Lamarca, Daniel H Palmer, Harpreet Singh Wasan, Paul J Ross, Yuk Ting Ma, Arvind Arora, Stephen Falk, Roopinder Gillmore, Jonathan Wadsley, Kinnari Patel, Alan Anthoney, Anthony Maraveyas, Tim Iveson, Justin S Waters, Claire Hobbs, Safia Barber, W David Ryder, John Ramage, Linda M Davies, John A Bridgewater, Juan W Valle,
Abstract: Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer.
Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30.
Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients).
Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.
Funding: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.

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WUTH publication: Collaborative Overview of coronaVIrus impact on ORTHopaedic training in the UK (COVI - ORTH UK)

Citation: The Surgeon. 2021, S1479-666X(21), 00057-3. Online ahead of print
Author: Malwattage Lara Tania Jayatilaka, Mohammed As-Sultany, Ayman Gabr, Luke Thornton, Simon Graham, Lyndon Mason, Nicholas Greville Farrar, COVI-ORTH UK
Abstract: Introduction: COVID-19 was declared a pandemic by the World Health Organization on the 11th of March 2020 with the NHS deferring all non-urgent activity from the 15th of April 2020. The aim of our study was to assess the impact of COVID-19 on Trauma and Orthopaedic trainees nationally.
Methods: Trauma and Orthopaedic (T&O) specialty trainees nationally were asked to complete an electronic survey specifically on the impact of COVID-19 on their training. This UK based survey was conducted between May 2020 and July 2020.
Results: A total of 185 out of 975 (19%) T&O specialty trainees completed the survey. Redeployment was experienced by 25% of trainees. 84% of respondents had experienced a fall in total operating numbers in comparison with the same time period in 2019. 89% experienced a fall in elective operating and 63% experienced a fall in trauma operating. The pandemic has also had an effect on the delivery of teaching, with face to face teaching being replaced by webinar-based teaching. 63% of training programmes delivered regular weekly teaching, whilst 19% provided infrequent sessions and 11% provided no teaching.
Conclusion: This study has objectively demonstrated the significant impact of the COVID-19 pandemic on all aspects of T&O training.
Keywords: COVID–19; Coronavirus; Education; Pandemic; Training; Trauma & orthopaedics.

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WUTH publication: COVID-19 Vaccine Prioritisation for Medical Students: The Forgotten Cohort?

Citation: Clinical Oncology. 2021, S0936-6555(21), 00084-4. Online ahead of print.
Author: J S Lim, T P T Au Yong, C S Boon, I S Boon

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WUTH publication: Functional outcomes & metal ion levels following ceramic on metal total hip arthroplasty: 9 Year follow-up

Citation: Journal of orthopaedics. 2021, 24, 131-34
Author: Nisarg Mehta, Dhawal Patel, Justin Leong, Phil Brown, Fintan Adrian Carroll
Abstract: In this study, we evaluate the mid-term functional and radiological outcomes of Ceramic on Metal Total Hip Arthroplasty (CoM THA) THA. 66 CoM THAs were performed between 2008 and 2010. These were evaluated and followed up in 2017-18, at a mean follow-up of 9 years to record the Oxford Hip Score [OHS] and whole blood Cobalt and Chrome levels. Our all cause revision rate was 4.5% (3 out of 66). At mid-term follow up, patients with CoM THAs are mostly asymptomatic with reasonable functional outcomes, we have reported similar revision rates in conjunction with raised blood metal ion levels and frequency of radiolucent lines.
Keywords: Arthroplasty; Ceramic on metal; Chromium levels; Cobalt levels.

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WUTH publication: Theatre ventilation

Citation: Annals of the Royal College of Surgeons of England. 2021, 103(3), 151-54
Author: C Theodorou, G S Simpson, C J Walsh
Abstract: Introduction: Owing to the COVID-19 pandemic, there has been significant disruption to all surgical specialties. In the UK, units have cancelled elective surgery and a decrease in aerosol generating procedures (AGPs) was favoured. Centres around the world advocate the use of negative pressure environments for AGPs in reducing the spread of infectious airborne particles. We present an overview of operating theatre ventilation systems and the respective evidence with relation to surgical site infection (SSI) and airborne pathogen transmission in light of COVID-19.
Methods: A literature search was conducted using the PubMed, Cochrane Library and MEDLINE databases. Search terms included "COVID-19", "theatre ventilation", "laminar", "turbulent" and "negative pressure".
Findings: Evidence for laminar flow ventilation in reducing the rate of SSI in orthopaedic surgery is widely documented. There is little evidence to support its use in general surgery. Following previous viral outbreaks, some centres have introduced negative pressure ventilation in an attempt to decrease exposure of airborne pathogens to staff and surrounding areas. This has again been suggested during the COVID-19 pandemic. A limited number of studies show some positive results for the use of negative pressure ventilation systems and reduction in spread of pathogens; however, cost, accessibility and duration of conversion remain an unexplored issue. Overall, there is insufficient evidence to advocate large scale conversion at this time. Nevertheless, it may be useful for each centre to have its own negative pressure room available for AGPs and high risk patients.
Keywords: COVID-19; Coronavirus; General surgery; Laminar flow; Operating room; SARS.

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