Imperial College London

Dr Mark P. Lythgoe

Faculty of MedicineDepartment of Surgery & Cancer

Clinical Research Fellow
 
 
 
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m.lythgoe

 
 
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Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

34 results found

Lythgoe MP, Prasad V, 2021, How the US Food and Drug Administration’s approval of aducanumab for Alzheimer's disease has implication for oncology and beyond, European Journal of Cancer, Vol: 157, Pages: 68-70, ISSN: 0959-8049

Journal article

Lythgoe MP, Prasad V, 2021, The FDA’s latest move to expand eligibility for oncology trials — a double-edged sword?, Nature Reviews Clinical Oncology, ISSN: 1759-4774

Journal article

Lythgoe MP, Liu DSK, Annels NE, Krell J, Frampton AEet al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3)., J Clin Pathol, Vol: 74, Pages: 543-547

Lymphocyte-activation gene 3 (LAG-3) is a coreceptor found on activated T-lymphocytes activated B-lymphocytes and natural killer (NK) cells. It is closely related to CD4 where it shares multiple common and divergent features. It contains specific binding sites with high affinity to major histocompatibility complex (MHC) Class II and functions as an inhibitor of T-cell signalling. Tumour-infiltrating lymphocytes with high LAG-3 expression have been found in many solid tumours including ovarian cancer, melanoma, colorectal cancer and haematological malignancies including Hodgkin and diffuse large B-cell lymphoma. LAG-3 antagonism has been demonstrated to restore the anti-tumourigenic function of T-cells in vivo, however, mechanistic knowledge remains relatively poorly defined. As other immune checkpoint inhibitors have transformed the management of difficult to treat cancers, such as melanoma, it is hoped that LAG-3 might have the same potential. This review will explore LAG-3 modulation as an anticancer therapy, highlighting recent clinical developments.

Journal article

Sharma R, Lythgoe MP, Slaich B, Patel Net al., 2021, Exploring the epigenome in gastroenteropancreatic neuroendocrine neoplasias, Cancers, Vol: 13, Pages: 1-18, ISSN: 2072-6694

Gastroenteropancreatic neuroendocrine neoplasias are a diverse group of neoplasms with different characteristics in terms of site, biological behaviour and metastatic potential. In comparison to other cancers, they are genetically quiet, harbouring relatively few somatic mutations. It is increasingly becoming evident that epigenetic changes are as relevant, if not more so, as somatic mutations in promoting oncogenesis. Despite significant tumour heterogeneity, it is obvious that DNA methylation, histone and chromatin modifications and microRNA expression profiles are distinctive for GEP-NEN subtypes and may correlate with clinical outcome. This review summarises existing knowledge on epigenetic changes, identifying potential contributions to pathogenesis and oncogenesis. In particular, we focus on epigenetic changes pertaining to well-differentiated neuroendocrine tumours, which make up the bulk of NENs. We also highlight both similarities and differences within the subtypes of GEP-NETs and how these relate and compare to other types of cancers. We relate epigenetic understanding to existing treatments and explore how this knowledge may be exploited in the development of novel treatment approaches, such as in theranostics and combining conventional treatment modalities. We consider potential barriers to epigenetic research in GEP-NENs and discuss strategies to optimise research and development of new therapies.

Journal article

Abdelmalak R, Lythgoe MP, Evans J, Flynn M, Waters J, Webb A, Pinato DJ, Sharma Ret al., 2021, Exploration of Novel Prognostic Markers in Grade 3 Neuroendocrine Neoplasia, CANCERS, Vol: 13

Journal article

Lythgoe MP, Krell J, McNeish IA, Tookman Let al., 2021, Safe administration of chemotherapy in mast cell activation syndrome, Journal of Oncology Pharmacy Practice, Vol: 27, Pages: 1005-1010, ISSN: 1078-1552

IntroductionMast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.Case reportWe present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.

Journal article

Lythgoe M, Krell J, Warner JL, Desai A, Khaki ARet al., 2021, Time intervals between U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) new cancer therapy approvals., Journal of Clinical Oncology, Vol: 39, Pages: 1575-1575, ISSN: 0732-183X

Background: Novel therapies are transforming cancer care. Regulatory review and approval are essential to deliver safe and efficacious innovations to patients. Studies prior to 2010 describe quicker approval decisions for new oncology drug registrations with the FDA compared to the EMA (median delay 238 days). Both regulatory agencies have subsequently improved procedures to expedite approval times. We compared regulatory market authorisation dates at the FDA and EMA for new oncology therapies from 2010-2020. Methods: New oncology therapeutic approvals between 2010-2020 were identified from the FDA and EMA regulatory databases. We analysed only initial approvals (not supplementary licenses) for active anti-cancer therapies (excluding biosimilars and supportive drugs). The delay in regulatory approval between the FDA and EMA was calculated in calendar days. We further analysed therapies by therapeutic class, evaluating for significant differences. Results: We identified 108 new therapy registrations during the study period. 104 (96.3%) therapies were approved by the FDA and 90 (83.3%) had EMA market authorisation. 4 (3.7%) drugs were not FDA registered, including 3 unsuccessful applications and 1 which sought licensing in a different indication. 18 (16.5%) drugs were not EMA registered, including 9 (8.8%) which did not pursue EMA licensing, 3 (2.9%) withdrawn licensing applications, 3 (2.9%) sought licensing in different tumour group/indication, 1 (0.9%) rejected application and 2 (1.9%) with applications under review at submission date. Of the 86 drugs approved by both agencies, 80 were approved first by the FDA and 6 by the EMA. The median delay in approval between the FDA and EMA was 227 days (IQR:124-354 days). Table shows approvals by therapeutic class. The shortest median time difference for approval was for monoclonal antibodies (171 days) with the longest for kinase inhibitors (281 days). Conclusions: This study shows more new oncology therapies are approved

Journal article

Lythgoe MP, Krell J, Kenny L, Khaki ARet al., 2021, 157P Racial diversity and reporting in FDA registration trials for breast cancer from 2006 to 2021, Annals of Oncology, Vol: 32, Pages: S88-S88, ISSN: 0923-7534

BackgroundIn the USA, there are >250,000 diagnoses of breast cancer (BC) annually, with significant racial disparities in incidence, subtype and outcomes. FDA clinical trials guidance recommend 5 categories of race reporting (White, Black, Asian, American Indian/Alaskan Native [AIAN] & Native Hawaiian/Pacific Islander [NHPI]). Furthermore, International Committee of Medical Journal Editors (ICMJE) guidance recommend authors, as a minimum, provide descriptive data for race. We analysed racial diversity in BC drug registration trials and compliance with FDA/ICMJE guidance.MethodsWe performed a retrospective review of BC FDA market authorisations from 2006 to 2021. Clinical trial publications cited on the licensing label were identified and analysed. If race was under-reported (<3 groups), the study report on clinicaltrials.gov was analysed. The total proportion of racial group participation and number of registration trials with adequate reporting was determined.Results38 new licensing indications were identified, involving 41 trials and 23 drugs. Overall, 36,081 patients participated: 19,495 (54.0%) White, 4194 (11.6%) Asian, 748 (2.1%) Black, 228 (0.6%) AIAN, 8 (0.1%) NHPI, 840 (2.3%) other and 10568 (29.3%) unknown. The table shows breakdown by BC subtype. Race was reported in 29 (70%) licensing trial publications, of which 7 provided only limited data. For licensing trials where no race data was reported, a further 6 (14%) had information within the study report. In the 10 years prior to the introduction of new FDA guidance in 2016 only 50% of registration studies met FDA/ICJME race reporting requirements. Since 2016 this has improved to 85%

Journal article

Lythgoe MP, Krell J, Savage P, Prasad Vet al., 2021, Race reporting and diversity in US food and drug administration (FDA) registration trials for prostate cancer; 2006-2020., Prostate Cancer and Prostatic Diseases, ISSN: 1365-7852

BACKGROUND: There is significant racial disparity in prostate cancer (PCa) in terms of incidence, treatment, and outcomes. Racial diversity and compliance with FDA race reporting guidelines in PCa drug registration trials are unknown. We analyzed racial diversity and race reporting in drug licensing trials for PCa. METHODS: New drug authorizations for PCa from 2006 to 2020 were identified. The corresponding licensing trial publications were analyzed to check compliance with current FDA recommendations for race reporting. If race was unreported, the clinical trial report was analyzed to determine participant recruitment by race and lead the recruiting country. RESULTS: During the study period, 17 new drug registrations for the management of PCa involving ten unique drugs were identified. In total, 18,455 participants were included in FDA registration trials, of which 76.3% were white or Caucasian, 7.9% Asian, 2.9% Black or African American, 0.5% American Indian or Alaskan Native, 0.1% Native Hawaiian or other Pacific Islander, 1.8% other or multiple races and 10.5% unknown. 53% of trials reported race in the licensing publication, however of this only 55% met current FDA recommendations. When the race was unreported in the licensing publication, 88% of studies had further information in the clinical study report. CONCLUSION: We found a significant under-representation of non-white participants in FDA drug registration trials for PCa. Race reporting in licensing publication is inconsistent and both FDA and International Committee of Medical Journal Editors guidelines are not being universally followed. Given the disproportionality of the disease burden of PCa, recruitment of Black and other minority participants to trials should be a research priority.

Journal article

Lythgoe MP, Cheng VWT, McKenzie HS, Kwan A, Konstantis A, Ma R, Teo PJ, Fitzpatrick A, Lythgoe MPet al., 2021, V6 PRIMROSE: A national trainee collaborative-led, multicentre prospective audit on the care of breast cancer patients with central nervous system disease in the UK, BJS Open, Vol: 5, Pages: 1-1, ISSN: 2474-9842

PRIMROSEA national trainee collaborative-led, multicentre prospective audit on the care of breast cancer patients with central nervous system disease in the UKMark P Lythgoe1, Vinton WT Cheng2, Hayley S McKenzie3, Amy Kwan4, Apostolos Konstantis5, Ruichong Ma6, Pei J Teo7, Amanda Fitzpatrick8, Laura Woodhouse9 & Carlo Palmieri10 on behalf of the BNTRC† and PRIMROSE study group1Imperial College Healthcare NHS Trust, London, 2Leeds Cancer Centre, Leeds, 3University of Southampton, Southampton, 4University of Sheffield, Sheffield, 5The Princess Alexandra NHS Trust, Harlow 6Oxford University Hospitals NHS Trust, Oxford, 7Worcestershire Acute Hospitals NHS Trust, Worcester, 8Institute of Cancer Research, London, 9The Christie NHS Foundation Trust, Manchester, 10University of Liverpool, Liverpool, †British Neurosurgical Trainee Research CollaborativeIntroductionBreast cancer is the commonest cancer in the UK and the 4th leading cause of cancer-related death. Breast cancer brain metastases (BCBM) are a poor prognostic indicator and associated with very poor survival and only a minority of patients survive >1 year despite oncological treatment. The rising prevalence of patients with BCBM represent an increasing unmet healthcare need. However, in the UK there is a paucity of data about prevalence, survival and management. Guidance on managing brain metastases is improving, however it is unclear how this has been applied in the context of BCBM and whether recommended standards are uniformly applied across the UKMethodsPRIMROSE is a trainee collaborative-led initiative to estimate BCBM prevalence, assess current practice (comparing national/international standards) and determine long term outcomes/sequalae. Anonymised data is being pooled via secure REDCap database collating demographics, clinico-pathological information, prior treatment, BCBM treatment and other key variables. All UK hospitals can register, with recruitment driven by trainees via the UK B

Journal article

Lythgoe M, Julve M, Krell J, Savage P, Grivas P, Khaki ARet al., 2021, Racial diversity and reporting in FDA registration trials for genitourinary (GU) cancers from 2006-20, Journal of Clinical Oncology, Vol: 39, Pages: 22-22, ISSN: 0732-183X

Background: GU cancers account for 1 in 5 of new cancer diagnoses in the USA. Significant racial disparities exist in terms of incidence, treatment and outcomes. Current FDA clinical trial guidance advises race reporting as a minimum of 5 categories (White/Caucasian, Black, Asian, American Indian or Alaskan Native [AIAN] and Native Hawaiian or Pacific Islander [NHPI]). Guidelines from the International Committee of Medical Journal Editors (ICMJE) recommend that authors should as a minimum, provide descriptive data for variables such as race and ethnicity. We analysed racial diversity in GU registration trials and compliance with FDA/ICMJE guidance in reporting. Methods: A retrospective review of new market authorisations in GU cancers from Jan 2006 to Oct 2020 was conducted utilizing the FDA website. Clinical trials cited on the licensing label for market authorization were recorded and corresponding registration trial publication identified. If race was unreported or partially reported (defined ≤3 groups), then the trial report on clinicaltrials.gov or FDA website was analysed. Total proportion of racial group participation and the proportion of registration trials with adequate reporting was determined. Results: We identified 42 new licensing indications, involving 33 unique drugs. Overall 30,316 patients participated in GU cancer registration trials; 21,068 (69.5%) White or Caucasian, 2516 (8.3%) Asian, 621(2%) Black or African American, 92 (0.3%) AIAN, 17 (0.1%) NHPI, 558 (1.8%) other or multiple races and 5463 (18%) unknown. Table shows breakdown by tumour group. Race reporting occurred in 23 (55%) registration trial publications, of which 5 provided only limited information (e.g. Caucasian only). For studies where no race information was reported, a further 10 (24%) had information within the trial report. In the 5 years prior to the introduction of FDA guidance in 2016 only 30% of registration studies met FDA/ICJME requirements. Since 2016 this has improve

Journal article

Esagian SM, Khaki AR, Diamantopoulos LN, Carril-Ajuria L, Castellano D, De Kouchkovsky I, Park JJ, Alva A, Bilen MA, Stewart TF, McKay RR, Santos VS, Agarwal N, Jain J, Zakharia Y, Morales-Barrera R, Devitt ME, Nelson A, Hoimes CJ, Shreck E, Gartrell BA, Sankin A, Tripathi A, Zakopoulou R, Bamias A, Rodriguez-Vida A, Drakaki A, Liu S, Kumar V, Lythgoe MP, Pinato DJ, Murgic J, Frobe A, Joshi M, Isaacsson Velho P, Hahn N, Alonso Buznego L, Duran I, Moses M, Barata P, Galsky MD, Sonpavde G, Yu EY, Msaouel P, Koshkin VS, Grivas Pet al., 2021, Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes, BJU International, Vol: 128, Pages: 196-205, ISSN: 1464-4096

ObjectivesTo compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs).Patients and MethodsWe performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression‐free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni‐ and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line).ResultsOut of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43–1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73–1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81–1.27). Patients with mixed‐histology UTUC had a significantly lower ORR and shorter PFS vs mixed‐histology LTUC (aOR 0.20, 95% CI 0.05–0.91 and aHR 1.66, 95% CI 1.06–2.59), respectively).ConclusionOverall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed‐histology UTUC had a lower ORR and shorter PFS compared to mixed‐histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.

Journal article

Lythgoe MP, Krell J, Mahmoud S, Mills E, Vasudevan A, Savage Pet al., 2021, Development and economic trends in anticancer drugs licensed in the UK from 2015 to 2019, Drug Discovery Today, Vol: 26, Pages: 301-307, ISSN: 1359-6446

Analysis of new anticancer drugs licensed in the UK found that 44 new therapies were approved from 2015 to 2019. No other 5-year period has produced as many new therapies. Most new drugs are kinase inhibitors (KIs, N = 18) and monoclonal antibodies (mAbs, N = 16) with only one classical cytotoxic chemotherapy (CC) licensed. The average median treatment duration has risen by 55 days to 318 days (263 days in 2010–2014). Drug costs have escalated; an average treatment course now costs £62 343, compared to £35 383 in 2010–2014. New drugs are delivering significant clinical benefits with longer treatment durations. However, the financial burden is greater, heralding economic challenges for healthcare providers.

Journal article

Khaki AR, Li A, Diamantopoulos LN, Miller NJ, Carril-Ajuria L, Castellano D, De Kouchkovsky I, Koshkin V, Park J, Alva A, Bilen MA, Stewart T, Santos V, Agarwal N, Jain J, Zakharia Y, Morales-Barrera R, Devitt M, Nelson A, Hoimes CJ, Shreck E, Gartrell BA, Sankin A, Tripathi A, Zakopoulou R, Bamias A, Rodriguez-Vida A, Drakaki A, Liu S, Kumar V, Lythgoe MP, Pinato DJ, Murgic J, Fröbe A, Joshi M, Isaacsson Velho P, Hahn N, Alonso Buznego L, Duran I, Moses M, Barata P, Galsky MD, Sonpavde G, Yu EY, Shankaran V, Lyman GH, Grivas Pet al., 2021, A new prognostic model in patients with advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors, European Urology Oncology, ISSN: 2588-9311

BACKGROUND: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1). OBJECTIVE: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study. DESIGN, SETTING, AND PARTICIPANTS: Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated. RESULTS AND LIMITATIONS: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation. CONCLUSIONS: We developed a new 1L ICI

Journal article

Powell K, Lythgoe MP, Prasad V, 2021, The Oncologic Drugs Advisory Committee Votes of April 2021 - Implications for the Fate of Accelerated Approval, JAMA Oncology, ISSN: 2374-2437

Journal article

Julve M, Lythgoe M, Clark J, 2021, Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma, Expert Opinion on Pharmacotherapy, Vol: 22, Pages: 351-361, ISSN: 1465-6566

Despite the recent advances in the treatment of malignant melanoma with immunotherapy and BRAF/MEK targeted agents, advanced disease still beholds a poor prognosis for a significant proportion of patients. Cyclin dependent kinase (CDK) inhibitors have been investigated as novel melanoma therapeutics throughout a range of phase 1 and 2 trials, as single agents and in combination with established treatments.Areas covered: This article summarises the rationale for, and development of CDK inhibitors in melanoma, with their evolution from pan-CDK inhibitors to highly specific agents, throughout clinical trials and finally their potential future use.Expert opinion: Whilst CDK inhibitors have been practice changing in breast cancer management, their efficacy is yet to be proven in melanoma. Combination with BRAF/MEK inhibitors has been hindered by dose limiting toxicities, but their role may yet to be found within the spectrum of biomarker derived personalised melanoma management. The effect that CDK inhibitors can have as an adjunct to immunotherapy also remains to be seen.

Journal article

Lythgoe M, Stebbing J, Pickford E, Glasmacher A, Adriani M, Fyvie G, Frampton A, Stevenson A, Krell Jet al., 2020, 805 Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumours, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: A481-A482, ISSN: 2051-1426

Background The gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).Methods Treatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.Results In part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression pan

Journal article

Janiaud P, Axfors C, van't Hooft J, Saccilotto R, Agarwal A, Appenzeller-Herzog C, Contopoulos-Ioannidis DG, Danchev V, Dirnagl U, Ewald H, Gartlehner G, Goodman SN, Haber NA, Ioannidis AD, Ioannidis JPA, Lythgoe MP, Ma W, Macleod M, Malički M, Meerpohl JJ, Min Y, Moher D, Nagavci B, Naudet F, Pauli-Magnus C, O'Sullivan JW, Riedel N, Roth JA, Sauermann M, Schandelmaier S, Schmitt AM, Speich B, Williamson PR, Hemkens LGet al., 2020, The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days, F1000Research, Vol: 9, Pages: 1-19, ISSN: 2046-1402

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic.Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020.Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]).Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global

Journal article

Lythgoe M, Julve M, Pinato D, Sharma Ret al., 2020, "Regorafenib therapy for hepatocellular carcinoma in a HIV-1 infected patient: a case report", Liver Cancer International, Vol: 1, Pages: 51-54, ISSN: 2642-3561

Journal article

Miller NJ, Khaki AR, Diamantopoulos LN, Bilen MA, Santos V, Agarwal N, Morales-Barrera R, Devitt M, Nelson A, Hoimes CJ, Shreck E, Assi H, Gartrell BA, Sankin A, Rodriguez-Vida A, Lythgoe M, Pinato DJ, Drakaki A, Joshi M, Velho PI, Hahn N, Liu S, Buznego LA, Duran I, Moses M, Jain J, Murgic J, Barata P, Tripathi A, Zakharia Y, Galsky MD, Sonpavde G, Yu EY, Lyman GH, Grivas Pet al., 2020, Histological Subtypes and Response to PD-1/PD-L1 Blockade in Advanced Urothelial Cancer: A Retrospective Study, JOURNAL OF UROLOGY, Vol: 204, Pages: 63-69, ISSN: 0022-5347

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Lythgoe MP, Middleton P, 2020, Ongoing clinical trials for the management of the COVID-19 pandemic, Trends in Pharmacological Sciences, Vol: 41, Pages: 363-382, ISSN: 0165-6147

COVID-19 has rapidly developed into a worldwide pandemic with a significant health and economic burden. There are currently no approved treatments or preventative therapeutic strategies. Hundreds of clinical studies have been registered with the intention of discovering effective treatments. Here, we review currently registered interventional clinical trials for the treatment and prevention of COVID-19 to provide an overall summary and insight into the global response.

Journal article

Rumford M, Lythgoe M, McNeish I, Gabra H, Tookman L, Rahman N, George A, Krell Jet al., 2020, Oncologist-led BRCA ‘mainstreaming’ in the ovarian cancer clinic: A study of 255 patients and its impact on their management, Scientific Reports, Vol: 10, ISSN: 2045-2322

Although guidelines recommend BRCA testing for all women with non-mucinous epithelial ovarian cancer, there is significant variability in access to testing across the UK. A germline BRCA mutation (BRCAm) in ovarian cancer patients provides prognostic and predictive information and influences clinical management, such as the use of PARP inhibitors, which have demonstrated a progression-free survival benefit in the BRCAm cohort. Additionally, the finding of a BRCAm has significant implications for patients and their families in terms of cancer risk and prevention. We studied the impact of a newly-formed, oncologist-led ‘mainstreaming’ germline BRCA testing pathway in 255 ovarian cancer patients at Imperial College NHS Trust. Prior to the establishment of ‘mainstreaming’, uptake of germline BRCA testing was 14% with a mean turnaround time of 148.2 calendar days. The ‘mainstreaming’ approach led to a 95% uptake of germline BRCA testing and a mean turnaround time of 20.6 days. Thirty-four (13.33%) BRCAm patients were identified. At the time of data collection nine BRCAm patients had received a PARP inhibitor off-trial, three had entered a PARP inhibitor trial and 5 were receiving platinum-based chemotherapy with a plan to receive PARP inhibitor maintenance. This study provides further evidence of the impact of oncologist-led ‘mainstreaming’ programs.

Journal article

Bhimani J, Philipps L, Simpson L, Lythgoe M, Soultati A, Webb A, Savage Pet al., 2020, The impact of new cancer drug therapies on site specialised cancer treatment activity in a UK cancer network 2014-2018, Journal of Oncology Pharmacy Practice, Vol: 26, Pages: 93-98, ISSN: 1078-1552

IntroductionDrug treatment for cancer has changed dramatically over the past decade with many new drugs often with multiple applications. More recently, the detailed pathway for approval from the National Institute for Health and Care Excellence (NICE) in the UK has been simplified. To explore how these changes have impacted on systemic anti-cancer therapy tumour site-specific prescribing and workload activities, we have reviewed the prescribing records for 2014–2018 in a UK cancer network.MethodsInformation about the numbers of new systemic anti-cancer therapy drugs and NICE approvals were obtained from print editions of the British National Formulary (BNF) and the NICE website. Data on the numbers of new chemotherapy courses and individual treatment-related attendances were obtained from the cancer network Chemocare electronic prescribing system.ResultsDuring the five-year study period, there were 49 new systemic anti-cancer therapy drugs for all tumour types, and a total of 65 NICE technology approvals for solid tumour indications. Overall numbers of treatment courses increased by 40.7% and total treatment-related visits by 80.6%. There was a wide variation across tumour types with the highest number of increased visits seen for melanoma (349.3%) and prostate cancer (242.3%), but in contrast, no appreciable increases were seen for lower gastrointestinal cancers or small cell lung cancer.ConclusionThe study confirms the major impact of the arrival of new drug technology and positive NICE appraisals on increasing systemic anti-cancer therapy prescribing and chemotherapy unit activity. The data in this study may be of help in planning for future service delivery planning and workforce configurations.

Journal article

Khaki AR, Li A, Diamantopoulos LN, Bilen MA, Santos V, Esther J, Morales-Barrera R, Devitt M, Nelson A, Hoimes CJ, Shreck E, Assi H, Gartrell BA, Sankin A, Rodriguez-Vida A, Lythgoe M, Pinato DJ, Drakaki A, Joshi M, Isaacsson Velho P, Hahn N, Liu S, Alonso Buznego L, Duran I, Moses M, Jain J, Murgic J, Baratam P, Barata P, Tripathi A, Zakharia Y, Galsky MD, Sonpavde G, Yu EY, Shankaran V, Lyman GH, Grivas Pet al., 2019, Impact of performance status on treatment outcomes: A real-world study of advanced urothelial cancer treated with checkpoint inhibitors, CANCER, Vol: 126, Pages: 1208-1216, ISSN: 0008-543X

Journal article

Abu-Sbeih H, Faleck D, Ricciuti B, Mendelsohn R, Naqash AR, Cohen J, Sellars M, Balaji A, Ben-betzalel G, Hajir I, Zhang J, Awad M, Leonardi G, Johnson D, Pinato D, Owen D, Weiss S, Lamberti G, Lythgoe M, Manuzzi L, Arnold C, Qiao W, Naidoo J, Markel G, Powell N, Yeung S-C, Sharon E, Dougan M, Wang Yet al., 2019, Immune checkpoint inhibitor therapy in patients with preexisting inflammatory bowel disease, Journal for ImmunoTherapy of Cancer, Vol: 7, Pages: 1-12, ISSN: 2051-1426

PURPOSEThe risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors.PATIENTS AND METHODSWe performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events.RESULTSOf the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively).CONCLUSIONPreexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

Journal article

Malik SS, Lythgoe MP, McPhail M, Monahan KJet al., 2018, Metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a systematic review and meta-analysis, Familial Cancer, Vol: 17, Pages: 557-564, ISSN: 1389-9600

Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with early onset of colorectal cancer at a mean age of 45 years. The mainstay of surgical management is either a segmental or extensive colectomy. Currently there is no unified agreement as to which management strategy is superior due to limited conclusive empirical evidence available. A systematic review and meta- analysis to evaluate the risk of metachronous colorectal cancer (MCC) and mortality in LS following segmental and extensive colectomy. A systematic review of the PubMed database was conducted. Studies were included/ excluded based on pre-specified criteria. To assess the risk of MCC and mortality attributed to segmental or extensive colectomies, relative risks (RR) were calculated and corresponding 95% confidence intervals (CI). Publication bias was investigated using funnel plots. Data about mortality, as well as patient ascertainment [Amsterdam criteria (AC), germline mutation (GM)] were also extracted. Statistical analysis was conducted using the R program (version 3.2.3). The literature search identified 85 studies. After further analysis ten studies were eligible for inclusion in data synthesis. Pooled data identified 1389 patients followed up for a mean of 100.7 months with a mean age of onset of 45.5 years of age. A total 1119 patients underwent segmental colectomies with an absolute risk of MCC in this group of 22.4% at the end of follow-up. The 270 patients who had extensive colectomies had a MCC absolute risk of 4.7% (0% in those with a panproctocolecomy). Segmental colectomy was significantly associated with an increased relative risk of MCC (RR = 5.12; 95% CI 2.88–9.11; Fig. 1), although no significant association with mortality was identified (RR = 1.65; 95% CI 0.90–3.02). There was no statistically significant difference in the risk of MCC betwe

Journal article

Lythgoe MP, Abraham S, 2016, Good practice in shared care for inflammatory arthritis, British Journal of General Practice, Vol: 66, Pages: 275-277, ISSN: 1478-5242

Journal article

Lythgoe MP, Rhodes CJ, Ghataorhe P, Attard M, Wharton J, Wilkins MRet al., 2016, Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future, Pharmacology & Therapeutics, Vol: 164, Pages: 195-203, ISSN: 0163-7258

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.

Journal article

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