Royal Marsden NHS Foundation Trust Research Articles

The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

A CT-based radiomics classification model for the prediction of histological type and tumour grade in retroperitoneal sarcoma (RADSARC-R): a retrospective multicohort analysis

Retroperitoneal sarcomas are tumours with a poor prognosis. Upfront characterisation of the tumour is difficult, and under-grading is common. Radiomics has the potential to non-invasively characterise the so-called radiological phenotype of tumours. We aimed to develop and independently validate a CT-based radiomics classification model for the prediction of histological type and grade in retroperitoneal leiomyosarcoma and liposarcoma. A retrospective discovery cohort was collated at our centre (Royal Marsden Hospital, London, UK) and an independent validation cohort comprising patients recruited in the phase 3 STRASS study of neoadjuvant radiotherapy in retroperitoneal sarcoma. Patients aged older than 18 years with confirmed primary leiomyosarcoma or liposarcoma proceeding to surgical resection with available contrast-enhanced CT scans were included. Using the discovery dataset, a CT-based radiomics workflow was developed, including manual delineation, sub-segmentation, feature extraction, and predictive model building. Separate probabilistic classifiers for the prediction of histological type and low versus intermediate or high grade tumour types were built and tested. Independent validation was then performed. The primary objective of the study was to develop radiomic classification models for the prediction of retroperitoneal leiomyosarcoma and liposarcoma type and histological grade. 170 patients recruited between Oct 30, 2016, and Dec 23, 2020, were eligible in the discovery cohort and 89 patients recruited between Jan 18, 2012, and April 10, 2017, were eligible in the validation cohort. In the discovery cohort, the median age was 63 years (range 27-89), with 83 (49%) female and 87 (51%) male patients. In the validation cohort, median age was 59 years (range 33-77), with 46 (52%) female and 43 (48%) male patients. The highest performing model for the prediction of histological type had an area under the receiver operator curve (AUROC) of 0·928 on validation, based on a feature set of radiomics and approximate radiomic volume fraction. The highest performing model for the prediction of histological grade had an AUROC of 0·882 on validation, based on a radiomics feature set. Our validated radiomics model can predict the histological type and grade of retroperitoneal sarcomas with excellent performance. This could have important implications for improving diagnosis and risk stratification in retroperitoneal sarcomas. Wellcome Trust, European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group, the National Institutes for Health, and the National Institute for Health and Care Research Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.

Statistical methods and data visualisation of patient-reported outcomes in early phase dose-finding oncology trials: a methodological review

Traditionally, within dose-finding clinical trials, treatment toxicity and tolerability are assessed by clinicians. Research has shown that clinician reporting may have inadequate inter-rater reliability, poor correlation with patient reported outcomes, and under capture the true toxicity burden. The introduction of patient-reported outcomes (PROs), where the patient can assess their own symptomatic adverse events or quality of life, has potential to complement current practice to aid dose optimisation. There are no international recommendations offering guidance for the inclusion of PROs in dose-finding trial design and analysis. Our review aimed to identify and describe current statistical methods and data visualisation techniques employed to analyse and visualise PRO data in published early phase dose-finding oncology trials (DFOTs). DFOTs published from June 2016-December 2022, which presented PRO analysis methods, were included in this methodological review. We extracted 35 eligible papers indexed in PubMed. Study characteristics extracted included: PRO objectives, PRO measures, statistical analysis and visualisation techniques, and whether the PRO was involved in interim and final dose selection decisions. Most papers (30, 85.7%) did not include clear PRO objectives. 20 (57.1%) papers used inferential statistical techniques to analyse PROs, including survival analysis and mixed-effect models. One trial used PROs to classify a clinicians' assessed dose-limiting toxicities (DLTs). Three (8.6%) trials used PROs to confirm the tolerability of the recommended dose. 25 trial reports visually presented PRO data within a figure or table within their publication, of which 12 papers presented PRO score longitudinally. This review highlighted that the statistical methods and reporting of PRO analysis in DFOTs are often poorly described and inconsistent. Many trials had PRO objectives which were not clearly described, making it challenging to evaluate the appropriateness of the statistical techniques used. Drawing conclusions based on DFOTs which are not powered for PROs may be misleading. With no guidance and standardisation of analysis methods for PROs in early phase DFOTs, it is challenging to compare study findings across trials. Therefore, there is a crucial need to establish international guidance to enhance statistical methods and graphical presentation for PRO analysis in the dose-finding setting. EA has been supported to undertake this work as part of a PhD studentship from the Institute of Cancer Research within the MRC/NIHR Trials Methodology Research Partnership. AM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust, the Institute of Cancer Research and Imperial College.

Pseudoprogression in patients with uterine leiomyosarcoma treated with first-line single-agent doxorubicin

AimTo evaluate the incidence of pseudoprogression in patients with metastatic or inoperable uterine leiomyosarcoma (LMS) treated with first-line single-agent doxorubicin. MethodsThe Royal Marsden NHS Foundation Trust Sarcoma Unit database was searched to identify all patients with metastatic or inoperable LMS treated with first-line doxorubicin from January 2006 to January 2022. Patients with available computed tomography scans performed at baseline and during doxorubicin therapy were included. Response evaluation criteria in solid tumours v1.1 and Choi criteria were applied. Any increase in the sum of the longest diameter that decreased on the subsequent scan was labelled as pseudoprogression. ResultsThe total number of patients evaluated was 52. In total, 19% (n = 10) of patients treated with doxorubicin showed pseudoprogression. However, pseudoprogression at the time of the second scan was not associated with time to doxorubicin failure. Choi criteria identified 30% (n = 3) of pseudoprogressors as responding. ConclusionDespite the use of doxorubicin as first-line therapy for soft-tissue sarcomas for over 40 years, pseudoprogression has not been described. This retrospective study shows that pseudoprogression occurs in 19% of patients with metastatic/inoperable uterine LMS treated with first-line doxorubicin. Choi criteria were not consistently able to differentiate pseudoprogression from true progression. It is imperative that oncologists and radiologists are aware of this as symptomatically stable/improving patients may benefit from continued treatment despite initial radiological growth in tumour size.

Editorial introductions.

Editorial introductions.

Assessing the collection and reporting of patient-reported outcome data in interventional cancer trials: a single institution, retrospective systematic evaluation

BackgroundTo understand our performance with respect to the collection and reporting of patient-reported outcome (PRO) measure (PROM) data, we examined the protocol content, data completeness and publication of PROs from interventional trials conducted at the Royal Marsden NHS Foundation Trust (RM) and explored factors associated with data missingness and PRO publication.DesignFrom local records, we identified closed, intervention trials sponsored by RM that opened after 1995 and collected PROMs as primary, secondary or exploratory outcomes. Protocol data were extracted by two researchers and scored against the SPIRIT-PRO (PRO protocol content checklist; score 0–100, higher scores indicate better completeness). For studies with locally held datasets, the information team summarized for each study, PRO completion defined as the number of expected (as per protocol) PRO measurements versus the number of actual (i.e. completed) PRO measurements captured in the study data set. Relevant publications were identified by searching three online databases and chief investigator request. Data were extracted and each publication scored against the CONSORT-PRO (PRO manuscript content checklist; scored as SPIRIT-PRO above). Descriptive statistics are presented with exploratory comparisons of point estimates and 95% confidence intervals.ResultsTwenty-six of 65 studies were included in the review. Nineteen studies had accessible datasets and 18 studies published at least one article. Fourteen studies published PRO results. Most studies had a clinical (rather than PRO) primary outcome (16/26). Across all studies, responses in respect of 35 of 69 PROMs were published. Trial protocols scored on average 46.7 (range 7.1–92.9) on the SPIRIT-PRO. Among studies with accessible data, half (10/19) had less than 25% missing measurements. Publications scored on average 80.9 (range 36–100%) on the CONSORT-PRO. Studies that published PRO results had somewhat fewer missing measurements (19% [7–32%] vs 60% [− 26 to 146%]). For individual PROMs within studies, missing measurements were lower for those that were published (17% [10–24%] vs 41% [18–63%]). Studies with higher SPIRIT-PRO scores and PROs as primary endpoints (13% [4–22%] vs 39% [10–58%]) had fewer missing measurements.ConclusionsMissing data may affect publication of PROs. Extent of inclusion of SPIRIT-PRO protocol items and PROs as primary endpoints may improve data completeness. Preliminary evidence from the study suggests a future larger study examining the relationship between PRO completion and publication is warranted.

OGC O02 The prognostic effect of pathological lymph node regression after neoadjuvant chemotherapy for oesophageal adenocarcinoma – a multicentre study

Abstract Background The prognostic benefits of primary tumour and lymph node (LN) downstaging after neoadjuvant chemotherapy for oesophageal adenocarcinoma are well described. Pathological primary tumour regression grading (TRG) is widely used in the assessment of response to chemotherapy and has been shown to have prognostic value in this patient group. However, there is a lack of robust evidence regarding the prognostic effect of pathological response in LN despite emerging evidence of a discrepancy, up to 25% of patients in some studies, between TRG in the primary tumour and response in regional LNs. Although primary tumour regression is routinely documented as part of the standard pathological reporting of oesophagectomy specimens, LN regression is generally overlooked despite it's potential prognostic value. The aim of this study was to investigate the relationship between pathological response in LN, tumour recurrence and survival. Methods Multicentre cohort study including 763 patients with oesophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgery at Guy's and St Thomas’ NHS Foundation Trust (NHS-FT), The Royal Marsden NHS-FT, University Hospitals Birmingham NHS-FT, University Hospital Southampton NHS-FT and Belfast Health and Social Care Trust. Tumour regression was assessed in the primary tumour (as described by Mandard) and, retrospectively, in LNs retrieved from oesophagectomy specimens. LN were graded according to the proportion of fibrosis and residual tumour providing a LN regression score (LNRS). LNRS 1, complete response; LNRS 2, &amp;lt; 10% remaining tumour; LNRS 3, 10–50% remaining tumour; LNRS 4, &amp;gt; 50% viable tumour; LNRS 5, no evidence of response. Regression was defined as a LNRS of 1–3. Patients were classified as LN negative (no evidence of tumour or regression in any LN), complete LN-responders (evidence of regression ≥1 LN, no residual tumour in any LN), partial LN-responders (evidence of regression ≥1 LN with residual tumour ≥1 LN) and LN non-responders (no or minimal regression in any LN). Survival analysis was performed using multivariable Cox regression providing hazard ratios (HR) with 95% confidence intervals (CI) adjusting for age, gender, chemotherapy regimen, clinical stage, tumour grade, lympho-vascular invasion and primary tumour response. Results Mean age was 63 years with the majority male (86.2%). In total, 17,930 LN from 763 patients were analysed for evidence of response to chemotherapy. Overall, 243 (31.8%) patients were classified as LN negative, 62 (8.1%) as complete LN-responders, 155 (20.3%) as partial LN-responders and 303 (39.7%) as LN non-responders. Less than half (322/763, 42.2%) of patients demonstrated a pathological response in the primary tumour (Mandard score 1–3). Some patients had a LN response in the absence of a response in the primary tumour (97/431, 22.5%). Multivariable Cox regression survival analysis demonstrated improved overall survival in complete LN-responders (HR 0.37 95% CI 0.24–0.58), partial LN-responders (HR 0.70 95% CI 0.55–0.89) and LN negative patients (HR 0.34 95% CI 0.26–0.44) compared to LN non-responders. Similar results were observed for disease-free survival (complete LN-responders, HR 0.34 95% CI 0.22–0.53; partial LN-responders, HR 0.74 95% CI 0.58–0.93; LN negative, HR 0.33 95% CI 0.25–0.42). Rates of tumour recurrence were lower in patients who demonstrated a LN response or had negative LN (LN negative 23.0% vs complete LN-responders 19.4% vs partial LN-responders 50.3% vs LN non-responders 66.7%, p&amp;lt;0.001). Conclusions In this cohort of patients with oeosphageal adenocarcinoma treated with neoadjuvant chemotherapy prior to surgical resection, LN regression was a strong predictive factor for better survival. This relationship was independent of primary tumour response, which was discordant in a significant number of patients. Complete LN-responders had equivalent survival to those with negative LN. Complete and partial LN-responders had better survival than LN non-responders. Evaluation and documentation of LN regression should be considered during the standard pathological reporting of oesophagectomy specimens.

A radiomics-based decision support tool improves lung cancer diagnosis in combination with the Herder score in large lung nodules.

Large lung nodules (≥15mm) have the highest risk of malignancy, and may exhibit important differences in phenotypic or clinical characteristics to their smaller counterparts. Existing risk models do not stratify large nodules well. We aimed to develop and validate an integrated segmentation and classification pipeline, incorporating deep-learning and traditional radiomics, to classify large lung nodules according to cancer risk. 502 patients from five U.K. centres were recruited to the large-nodule arm of the retrospective LIBRA study between July 2020 and April 2022. 838 CT scans were used for model development, split into training and test sets (70% and 30% respectively). An nnUNet model was trained to automate lung nodule segmentation. A radiomics signature was developed to classify nodules according to malignancy risk. Performance of the radiomics model, termed the large-nodule radiomics predictive vector (LN-RPV), was compared to three radiologists and the Brock and Herder scores. 499 patients had technically evaluable scans (mean age 69±11, 257 men, 242 women). In the test set of 252 scans, the nnUNet achieved a DICE score of 0.86, and the LN-RPV achieved an AUC of 0.83 (95% CI 0.77-0.88) for malignancy classification. Performance was higher than the median radiologist (AUC 0.75 [95% CI 0.70-0.81], DeLong p=0.03). LN-RPV was robust to auto-segmentation (ICC 0.94). For baseline solid nodules in the test set (117 patients), LN-RPV had an AUC of 0.87 (95% CI 0.80-0.93) compared to 0.67 (95% CI 0.55-0.76, DeLong p=0.002) for the Brock score and 0.83 (95% CI 0.75-0.90, DeLong p=0.4) for the Herder score. In the international external test set (n=151), LN-RPV maintained an AUC of 0.75 (95% CI 0.63-0.85). 18 out of 22 (82%) malignant nodules in the Herder 10-70% category in the test set were identified as high risk by the decision-support tool, and may have been referred for earlier intervention. The model accurately segments and classifies large lung nodules, and may improve upon existing clinical models. This project represents independent research funded by: 1) Royal Marsden Partners Cancer Alliance, 2) the Royal Marsden Cancer Charity, 3) the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London, 5) Cancer Research UK (C309/A31316).

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Molecular subtypes of leiomyosarcoma: Moving toward a consensus

Editorial introductions.

Editorial introductions.

Knowing to Ask and Feeling Safe to Tell - Understanding the Influences of HCP-Patient Interactions in Cancer Care for LGBTQ+ Children and Young People.

BackgroundLesbian, gay, bisexual, transgender, queer or questioning (LGBTQ+) people experience healthcare inequalities in cancer care. Previous studies have focused on knowledge, attitudes and behaviours of healthcare professionals (HCPs) treating adults with cancer and how these contribute to inequalities. To date, no research has focused on HCPs treating LGBTQ+ children and adolescents with cancer in the UK. This is important given that this group may be at a critical time for exploring their gender identity and sexual orientation, whilst also facing a cancer diagnosis. We aimed to explore the knowledge, attitudes and behaviours of paediatric, teenage and young adult oncology HCPs treating LGBTQ+ patients in the UK.MethodsWe carried out semi-structured interviews with 8 HCPs in paediatric, teenage and young adult (TYA) oncology from the Royal Marsden NHS Foundation Trust. Eight questions were asked, which centred around participants’ knowledge, attitudes and behaviours regarding management of LGBTQ+ patients in oncology. Interview transcripts were analysed by inductive thematic analysis.ResultsWe identified 10 themes, including novel themes (how HCPs acquire knowledge and expectations of a ‘third party’ to be the expert) which may underlie previously observed trends in knowledge, attitudes and behaviours of HCPs. We highlight other themes and HCP concerns specific to care of LGBTQ+ patients in paediatrics (influence of the parental-carer dynamic, concerns around patient age and development as a barrier to disclosure) which require further research. We found evidence of the interrelatedness of HCP knowledge, attitudes and behaviours and the ability of these elements to positively influence each other. We mapped our themes across these elements to form a new suggested framework for improving HCP-patient interactions in LGBTQ+ Cancer Care. We found a need both for individual HCP education and organisational change, with creation of a culture of psychological safety to improve patient care.ConclusionKnowledge, attitudes and behaviours of HCPs are closely interdependent when providing care to young LGBTQ+ patients with cancer. The authors suggest that future efforts to improve care of these patients address this complexity by spanning the domains of our suggested framework. Whilst HCP education is essential, change must also occur at an organisational level.

MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING

You have accessJournal of UrologyCME1 May 2022MP09-17 PREDICTING INCIDENCE VERSUS MORTALITY FOR CANCERS ASSOCIATED WITH OVERDIAGNOSIS: AN OVERLOOKED ISSUE FOR POLYGENIC RISK SCORES AND CANCER SCREENING Andrew Vickers, Amit Sud, Jonine Bernstein, and Richard Houlston Andrew VickersAndrew Vickers More articles by this author , Amit SudAmit Sud More articles by this author , Jonine BernsteinJonine Bernstein More articles by this author , and Richard HoulstonRichard Houlston More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002531.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Population-based cancer screening programs, including prostate-specific antigen (PSA) screening for prostate cancer, are generally directed at all healthy individuals in a given age stratum. It has recently been proposed that PSA screening could be risk-stratified using polygenic risk scores (PRSs) based on panels of single-nucleotide polymorphisms (SNPs): those with high PRS would be screened whereas those with low PRS would be exempted. However, prostate cancer PRSs were generated using the endpoint of cancer incidence rather than cancer-specific mortality, and it has been demonstrated that the PRSs do not differentially predict lethal vs. indolent disease. As such, use of PRSs to risk-stratify screening will not address overdiagnosis, the major problem associated with PSA screening. METHODS: We developed a simple net benefit formulation to comparing different screening strategies, given as: deaths prevented – number screened / NWS – number diagnosed / (NWD -1), where NWS and NWD are the number of individuals we would be willing to, respectively, screen and diagnose, to prevent one death. We applied the formula to empirical data on PSA screening and varied NWS and NWD to assess the effects on our findings. RESULTS: Risk-stratifying PSA screening using a PRS that does not differentially discriminate between incident and lethal cancer did not improve screening outcomes in our model. Net benefit was 4 per 1000 for screening all eligible men. For a PRS with a C-index of 0.75 (higher than is typically found) but which did not discriminate between incidence and mortality, net benefit was 3.80, 3.36 and 1.78 for restricting screening to those with the highest 50%, 25% and 10% PRS. Net benefit was far lower for a concordance index of 0.65, closer to what is often reported. Results were robust for different choices of NWS and NWD. In contrast, risk stratifying screening based on PSA, which does predict mortality better than incidence, was associated with a net benefit up to 5.64, higher than that for screening all men. CONCLUSIONS: Using PSA levels to determine which men should continue screening will improve screening outcomes; using PRS to risk-stratify screening will do more harm than good. If PRS-based cancer screening is to be effective, research needs to focus on identifying PRSs associated with cancer mortality. Source of Funding: This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H. Scher [P50-CA92629], the Sidney Kimmel Center for Prostate and Urologic Cancers. R.H. acknowledges grant support from Cancer Research UK (C1298/A8362) and the Wellcome Trust (214388). A.S. is in receipt of a National Institute for Health Research (NIHR) Academic Clinical Lectureship and funding from the Royal Marsden Biomedical Research Centre. This is a summary of independent research supported by the NIHR Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e143 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Vickers More articles by this author Amit Sud More articles by this author Jonine Bernstein More articles by this author Richard Houlston More articles by this author Expand All Advertisement PDF DownloadLoading ...

New drug slows development of most common type of breast cancer, trial shows

A phase III trial of a new drug for the treatment of advanced breast cancer has shown that adding it to hormone therapy can lengthen time to disease progression and increase the chance of a tumour shrinking. Researchers at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research (ICR) enrolled 708 people […]

Active marsden - development of a physical activity strategy

Purpose: This project formed part of the Darzi Fellowship supporting complex change in healthcare. Its purpose was to co-produce a physical activity strategy for the Royal Marsden NHS Foundation Trust.

Approach to screening for Familial Adenomatous Polyposis (FAP) in a cohort of 226 patients with Desmoid-type Fibromatosis (DF): experience of a specialist center in the UK.

Desmoid-type fibromatosis (DF) are locally infiltrative, non-metastasizing tumours associated with significant morbidity and mortality if located intra-abdominally, retroperitoneally or in head and neck localisation. They are mostly sporadic, due to somatic CTNNB1 mutations. Alternatively, they can be associated with germline pathogenic variants in APC causing Familial Adenomatous Polyposis (FAP). Germline APC variants and somatic CTNNB1 mutations are mutually exclusive. We conducted a retrospective descriptive analysis of patients with DF seen at the Royal Marsden NHS Foundation Trust Sarcoma Unit in London. We aimed to describe the methods of screening for FAP in patients with DF from a specialist unit. Patients diagnosed between 1992 and 2020 were selected from the prospectively maintained Sarcoma Unit database. 226 patients were identified and 67% (n = 152) were female. Median age at diagnosis was 37.5 (range 2-81) years. Tumour localisation was limbs/pelvis in 30.9% (N = 70), intra-abdominal 16.8% (N = 38), abdominal wall 23.5% (N = 53), thorax 18.6% (N = 42), head and neck 3.1% (N = 7) and vertebral/paravertebral 7.1% (N = 16). Colonoscopy was requested in 65 patients (28.8% of all cases) and was completed in forty-six (20.4%). Molecular testing of CTNNB1 testing was requested in 35 cases (15.5%). APC germline test was requested in 12 cases. Four patients in our cohort had an FAP-associated DF. CTNNB1 ± APC testing and colonoscopy are useful tools for the screening of patients with DF. CTNNB1 molecular testing should be performed in all cases of newly diagnosed DF. Negative CTNNB1 results, alongside clinical assessment, should prompt APC testing and/or colonoscopy.

Multimodal Testing Reveals Subclinical Neurovascular Dysfunction in Prediabetes, Challenging the Diagnostic Threshold of Diabetes

Background: There is growing evidence that small nerve fibre and retinal neurovascular damage occur in prediabetes before the onset of type 2 diabetes. Methods: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent corneal confocal microscopy (CCM), electrochemical skin conductance (ESC), optical coherence tomography angiography (OCT-A), and handheld electroretinography (ERG) measurements. Findings: Seventy-five participants with normoglycaemia (n=20), prediabetes (n=29) and type 2 diabetes (n=26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16 Td·s: 4·05 µV, 95% confidence interval (CI) 0·96-7·13) and high (32 Td·s: 5·20 µV, 95% CI 1·54-8·86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2, 95% CI 0·005-0·095) and deep (0·048 pixels/mm2, 95% CI 0·003-0·093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32 Td·s (r=-0.256, p=0·028), implicit time at 32 Td·s (r=0·422, p=0·0002) and 16 Td·s (r=0·327, p=0·005), OCT parafoveal vessel density in the superficial (r=-0·238, p=0·049) and deep (r=-0·3, p=0·017) retinal layers, corneal nerve fibre length (CNFL) (r=-0·293, p=0·017), and hand ESC (r=-0·244, p=0·035) were observed. HOMA-IR was a predictor of CNFD (β=-0·94, 95% CI -1·66 to -0·21, p=0·012) and CNBD (β=-5·02, 95% CI -10·01 to -0·05, p=0·048). Interpretation: The diagnosis of diabetes is based on historical data showing emergent retinopathy on fundus examination; newer tests reveal abnormal retinal neurovascular structure (OCT-A) and function (ERG) occurring before retinopathy. Funding: This research received no funding support. Declaration of Interests: None of the authors have any relevant financial disclosures to declare. LKC Technologies Inc. and Impeto Medical Inc. provided free use of the RETeval and SUDOSCAN devices, respectively, for this study. CB is part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Ethics Approval Statement: This study adhered to the Declaration of Helsinki (2008) and was approved by an independent National Health Service Research Ethics Committee in November 2018 (REC ID: 18/LO/2126). Written informed consent was obtained from all participants.

Providing holistic care to patients undergoing surgery in the COVID-19 pandemic

Filipe Carvalho, Advanced Nurse Practitioner in Colorectal Surgery at Royal Marsden NHS Foundation Trust, describes the value of holistic nursing practice during a pandemic

Editorial introductions

Editorial introductions

Collateral Damage: The Impact on Cancer Outcomes of the COVID-19 Pandemic

Background: Cancer diagnostics and surgery have been disrupted by the response of healthcare services to the COVID-19 pandemic. Progression of cancers during delay will impact on patient long-term survival. Methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of three months and six months and periods of disruption of one year and two years. Using healthcare resource costing, we contextualise attributable lives saved and life years gained from cancer surgery to equivalent volumes of COVID-19 hospitalisations. Findings: Per year, 94,912 resections for major cancers result in 80,406 long-term survivors and 1,717,051 life years gained. Per-patient delay of six months would cause attributable death of 10,555 of these individuals with loss of 205,024 life years. For cancer surgery, average life years gained (LYGs) per patient are 18·1 under standard conditions and 15·9 with a delay of six months (a loss of 2·3 LYG per patient). Taking into account units of healthcare resource (HCRU), surgery results on average per patient in 2·25 resource-adjusted life years gained (RALYGs) under standard conditions and 1·98 RALYGs following delay of six months. For 94,912 hospital COVID-19 admissions, there are 474,505 LYGs requiring of 1,097,937 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5·0 LYG and 0·43 RALYGs. Interpretation: Delay of six months in surgery for incident cancers would mitigate 43% of life years gained by hospitalisation of an equivalent volume of admissions for community acquired COVID-19. This rises to 62% when considering resource-adjusted life-years gained. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued. Funding Statement: MEJ additionally received funding from Breast Cancer Now.GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award [C18081/A18180] and is Associate Director of the multi-institutional CanTest Collaborative funded by Cancer Research UK [C8640/A23385]. B.T and A.G. are supported by Cancer Research UK award C61296/A27223. R.S.H. is supported by Cancer Research UK (C1298/A8362) and Bobby Moore Fund for Cancer Research UK). A.S. is in receipt of an Academic Clinical Lectureship from National Institute for Health Research (NIHR) and Biomedical Research Centre (BRC) post-doctoral support. This is a summary of independent research supported by the NIHR BRC at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research. Declaration of Interests: The authors declare no competing interests.

Quantifying and Mitigating the Impact of the COVID-19 Pandemic on Outcomes in Colorectal Cancer

Background: The COVID-19 pandemic has caused disruption across cancer pathways for diagnosis and treatment. In England, 32% of colorectal cancer (CRC) is diagnosed via urgent symptomatic referral from primary care, the “2-week-wait” (2WW) pathway. Access to routine endoscopy is likely to be a critical bottleneck causing delays in CRC management due to chronic limitation in capacity, acute competition for physician time, and safety concerns. Methods: We used age-specific, stage-specific 10 year CRC survival for England 2007-2017 and 2WW CRC cases volumes. We used per-day hazard ratios of CRC survival generated from observational studies of CRC diagnosis-to-treatment interval to model the effect of different durations of per-patient delay. We utilised data from a large London observational study of faecal immunochemical testing (FIT) in symptomatic patients to model FIT-triage to mitigate delay to colonoscopy. Findings: Modest delays result in significant reduction in survival from CRC with a 4-month delay resulting across age groups in ≥20% reduction in survival in Stage 3 disease and in total over a year, 1,419 attributable deaths across the 11,266 CRC patients diagnosed via the 2WW pathway. FIT triage of >10 ug Hb/g would salvage 1,292/1,419 of the attributable deaths and reduce colonoscopy requirements by >80%. Diagnostic colonoscopy offers net survival in all age groups, providing nosocomial COVID-19 infection rates are kept low (<2·5%). Interpretation: To avoid significant numbers of avoidable deaths from CRC, normal diagnostic and surgical throughput must be maintained. An accrued backlog of cases will present to primary care following release of lockdown, supranormal endoscopy capacity will be required to manage this without undue delays. FIT-triage of symptomatic cases provides a rational approach by which to avoid patient delay and mitigate pressure on capacity in endoscopy. This would also reduce exposure to nosocomial COVID-19 infection, relevant in particular to older patient groups. Funding Statement: MEJ additionally received funding from Breast Cancer Now. B.T and A.G. are supported by Cancer Research UK award C61296/A27223. C.L. and C.T. receive support from the Movember foundation. R.S.H. is supported by Cancer Research UK (C1298/A8362) and Bobby Moore Fund for Cancer. GL is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship Award [C18081/A18180] and is Associate Director of the multi-institutional CanTest Collaborative funded by Cancer Research UK [C8640/A23385]. Research UK). D.C.M is supported by Cancer Research UK (C57955/A24390. A.S. is in receipt of an Academic Clinical Lectureship from National Institute for Health Research (NIHR) and Biomedical Research Centre (BRC) post-doctoral support. This is a summary of independent research supported by the NIHR BRC at the Royal Marsden NHS Foundation Trust and Institute of Cancer Research. Declaration of Interests: The authors declare no competing interests.