Imperial College London

DrJonathanKrell

Faculty of MedicineDepartment of Surgery & Cancer

Clinical SL in Medical Oncology (Gynaecological Oncology)
 
 
 
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j.krell

 
 
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Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

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178 results found

McNeish I, Ennis D, Giannone G, Krell J, Mirza H, McDermott Jet al., 2022, A Randomised, Multi-centre Phase II Trial of Weekly Paclitaxel and Vistusertib in Platinum-Resistant Ovarian High-Grade Serous Carcinoma: OCTOPUS Arm 1, JAMA Oncology, ISSN: 2374-2445

Journal article

Correia JS, Miron Barroso S, Hutchings C, Ottaviani S, Somuncuoğlu B, Castellano L, Porter AE, Krell J, Georgiou TKet al., 2022, How does the polymer architecture and position of cationic charges affect cell viability?, Polymer Chemistry, ISSN: 1759-9954

Polymer chemistry, composition and molar mass are factors that are known to affect cytotoxicity however the influence of polymer architecture has not been investigated systematically. In this study the influence of the position of the cationic charges along the polymer chain on cytotoxicity was investigated while keeping constant the other polymer characteristics. Specifically, copolymers of various architectures, based on a cationic pH responsive monomer, 2-(dimethylamino)ethyl methacrylate (DMAEMA) and a non-ionic hydrophilic monomer, oligo(ethylene glycol)methyl ether methacrylate (OEGMA) were engineered and their toxicity towards a panel of cell lines investigated. Of the seven different polymer architectures examined, the block-like structures were less cytotoxic than statistical or gradient/tapered architectures. These findings will assist in developing future vectors for nucleic acid delivery.

Journal article

Lythgoe MP, Mullish BH, Frampton A, Krell Jet al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, Vol: 30, Pages: 1131-1134, ISSN: 0966-842X

Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and key effectors in determining anti-cancer therapy efficacy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.

Journal article

Lythgoe M, Bower M, Krell J, 2022, From the European Medicines Agency to Project Orbis: New activities and challenges to facilitate UK Oncology Drug Approval following Brexit, The Lancet Oncology, ISSN: 1213-9432

Journal article

Rizwan N, Khaki AR, Desai A, Warner J, Krell J, Lythgoe Met al., 2022, 427 Approval timings and review speed of immune checkpoint inhibitors (ICIs) in cancer therapy between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) from 2010-2022, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd

Conference paper

Lythgoe M, Mullish B, Frampton A, Dama P, Pickford E, Tookman L, Cunnea P, Fotopoulou C, Jeffery I, Fyvie G, Stevenson A, Krell Jet al., 2022, 627 Oral administration of MRx0518 in treatment-naïve cancer patients is associated with compositional taxonomic and metabolomic changes indicative of anti-tumorigenic efficacy, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd

Conference paper

Mirón-Barroso S, Correia JS, Frampton AE, Lythgoe MP, Clark J, Tookman L, Ottaviani S, Castellano L, Porter AE, Georgiou TK, Krell Jet al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X

As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.

Journal article

Montero-Macias R, Rigolet P, Mikhael E, Krell J, Villefranque V, Lecuru F, Fotopoulou Cet al., 2022, Traditional systemic treatment options in advanced low-grade serous ovarian cancer after successful cytoreduction: a systematic review and meta-analysis, Cancers, Vol: 14, Pages: 1-13, ISSN: 2072-6694

Objective: We performed a systematic literature review and a subsequent meta-analysis to compare traditional treatment options, i.e., antihormonal and cytotoxic, in LGSOC. Methods: We conducted a systematic literature review in MEDBASE and MEDLINE between September 2000 and June 2021 for women who received cytotoxic chemotherapy and/or antihormonal treatment after primary cytoreduction due to stage II–IV LGSOC and also at relapse. PFS and OS were calculated depending on the type of their adjuvant treatment. For each endpoint in the meta-analysis, pooled HR was calculated using the random effect model with the inverse variance weighted method. Only primary patients were included in the subsequent meta-analysis due to the small number of studies in the relapsed setting. Results: Five eligible first-line studies were included. Systemic chemotherapy failed to provide a significant OS benefit when compared to no systemic treatment (pooled HR = 1.01, 95% CI [0.79, 1.29]) after successful cytoreduction. Moreover, systemic chemotherapy followed by antihormonal treatment also did not result to a significant PFS or OS benefit when compared to systemic chemotherapy alone (for PSF: pooled HR = 0.59, 95% CI [0.33, 1.04]; for OS: pooled HR = 0.83, 95% CI [0.50, 1.39]). There were insufficient data from studies in the recurrent setting to allow their inclusion in the meta-analysis. Conclusions: In this meta-analysis, we failed to identify a traditional cytotoxic or antihormonal systemic treatment option that was associated with a significant OS or PFS benefit when administered following successful cytoreduction for advanced LGSOC. Prospective randomized studies are urgently warranted to define optimal adjuvant options in this challenging disease.

Journal article

Lythgoe M, Desai A, Gyawali B, Savage P, Warner JL, Krell J, Khaki ARet al., 2022, Cancer therapy approval timings, review speed and publication of pivotal registration trials in the US and Europe from 2010-2019, Jama Network Open, Vol: 5, ISSN: 2574-3805

Importance: Ensuring patients have access to safe and efficacious medicines in a timely manner is an essential goal for regulatory agencies, which has particular significance in oncology due to the significant unmet need for new therapies. The two largest regulatory agencies, the FDA and EMA have pivotal global roles, and their recommendations and approvals are frequently followed by other national regulators.Objective: To compare market authorization dates for new oncology therapies approved in the US and Europe over the past decade and to examine and contrast the regulatory activities of the FDA and EMA in the approval of new cancer medicines.Design, Setting and Participants: A review of the FDA and EMA regulatory databases to identify new oncology therapies approved in both the US and Europe from 2010 to 2019, and characterization of the timings of regulatory activities. Main Outcome Measures: Regulatory approval date, review time, submission of market authorization application, accelerated approval or conditional marketing authorisation status and proportion of approvals prior to peer-reviewed publication of pivotal trial results. Results: In total, 89 new concomitant oncology therapies were approved in the US and Europe from 2010 to 2019. The FDA approved 85 (95%) oncology therapies before European authorization and 4 (5%) therapies after. The median delay in market authorization for new oncology therapies in Europe was 241 days compared to the US. The median review time was 200 days and 426 days for the FDA and EMA, respectively. 60 (67%) new licensing applications were submitted to the FDA first, compared to 25 (28%) to the EMA. 35 (39%) oncology therapies were approved by the FDA prior to pivotal study publication, whereas only 8 (9%) by the EMA.Conclusion and Relevance: In this study we demonstrate that new oncology therapies are approved earlier in the US than Europe. The FDA receives licensing applications sooner and has shorter review times. However, mor

Journal article

Giannone G, Ennis D, Mirza HB, Cheng Z, McDermott J, Lewsley L-A, Clamp AR, Herbertson RA, Glasspool RM, Krell J, Hinsley S, Banerji U, Riisnaes R, Banerjee S, McNeish Iet al., 2022, Targeting PI3K/AKT/mTOR pathway in platinum-resistant ovarian high-grade serous carcinoma: Translational analysis from the randomized phase II OCTOPUS trial, ESMO, Publisher: ELSEVIER, Pages: S384-S384, ISSN: 0923-7534

Conference paper

Cheng Z, Mirza H, Ennis DP, Smith P, Morrill Gavarro L, Sokota C, Giannone G, Goranova T, Bradley T, Piskorz A, Lockley M, for the BriTROC-1 Investigators, Kaur B, Singh N, Tookman L, Krell J, McDermott J, Macintyre G, Markowetz F, Brenton JD, McNeish Iet al., 2022, The genomic landscape of early-stage ovarian high grade serous carcinoma, Clinical Cancer Research, Vol: 28, Pages: 2911-2922, ISSN: 1078-0432

Purpose: Ovarian high grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of volutionary advantage compared to early-stage tumours.Experimental Design: We performed targeted next generation sequencing and shallow whole genome sequencing (sWGS) on pre-treatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy number alterations (SCNA). We comparedresults to pre-treatment samples from 52 stage IIIC/IV HGSC patients from the BriTROC-1 study.Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs 62.3 years respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behaviour. However, ploidy was higher in late-stage (median 3.0) than early-stage (median 1.9) samples. Copy number (CN) signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clustersthat were prognostic.Conclusions: Early stage and late stage HGSC have highly similar patterns of mutation and focal SCNA. However, copy number signature analysis showed that late-stage disease has distinct signature exposures consistent with whole genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early and late-stage or simply time-related markers of evolutionary fitness.

Journal article

Fiorentino F, Krell J, de la Rosa CN, Webber Let al., 2022, DICE: Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian cancer resistant to standard treatment-a study protocol for a randomised trial investigating a novel therapy called TAK228, Trials, Vol: 23, Pages: 1-15, ISSN: 1745-6215

BackgroundThe standard initial treatment for ovarian cancer is surgery and platinum-based chemotherapy and potentially maintenance therapy with avastin or inhibitors of poly-ADP ribose polymerase (PARP). While a proportion of women are cured by this approach, the vast majority will relapse and become resistant to platinum chemotherapy either initially or on subsequent treatment. There is an unmet need to improve response to treatment and quality of life in these women. TAK228 is a novel therapy that can be added to standard treatment in the participant population and the aim of the DICE trial is to assess its effectiveness. Laboratory and clinical research has shown that these ovarian cancers may respond to the molecular target of a drug such as TAK228, and there have been studies using it in other advanced solid tumours including endometrial cancer.MethodsOne hundred twenty-four eligible women will be recruited from participating research sites in the United Kingdom (UK) and Germany. Randomised participants will receive either weekly paclitaxel alone (standard treatment, n = 62) or TAK228 plus weekly paclitaxel (n = 62) until the cancer significantly worsens; there are significant adverse events or any other protocol-defined stopping criteria. Participants will be monitored for response to treatment (using radiological imaging), adverse events and quality of life during both randomised treatment and subsequent follow-up.DiscussionThe primary objective/endpoint of the study is to compare the two treatments in terms of progression-free survival, or the length of time that each participant is alive without the cancer significantly worsening according to defined assessment criteria. If the addition of TAK228 to weekly paclitaxel chemotherapy is shown to significantly improve this statistically, and adverse events and quality of life are not significantly worse than standard treatment, then TAK228 plus weekly paclitaxel could potentially be taken forward within the cont

Journal article

Liu D, Yang QZC, Asim M, Krell J, Frampton Aet al., 2022, The clinical significance of transfer RNAs present in extracellular vesicles, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067

Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organ-isms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs pre-sent within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1st January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included the most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging be-tween 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.

Journal article

Clark J, Fotopoulou C, Cunnea P, Krell Jet al., 2022, Novel ex vivo models of epithelial ovarian cancer: the future of biomarker and therapeutic research, Frontiers in Oncology, Vol: 12, Pages: 1-17, ISSN: 2234-943X

Epithelial ovarian cancer (EOC) is a heterogenous disease associated with variations in presentation, pathology and prognosis. Advanced EOC is typified by frequent relapse and a historical 5-year survival of less than 30% despite improvements in surgical and systemic treatment. The advent of next generation sequencing has led to notable advances in the field of personalised medicine for many cancer types. Success in achieving cure in advanced EOC has however been limited, although significant prolongation of survival has been demonstrated. Development of novel research platforms is therefore necessary to address the rapidly advancing field of early diagnostics and therapeutics, whilst also acknowledging the significant tumour heterogeneity associated with EOC. Within available tumour models, patient-derived organoids (PDO) and explant tumour slices have demonstrated particular promise as novel ex vivo systems to model different cancer types including ovarian cancer. PDOs are organ specific 3D tumour cultures that can accurately represent the histology and genomics of their native tumour, as well as offer the possibility as models for pharmaceutical drug testing platforms, offering timing advantages and potential use as prospective personalised models to guide clinical decision-making. Such applications could maximise the benefit of drug treatments to patients on an individual level whilst minimising use of less effective, yet toxic, therapies. PDOs are likely to play a greater role in both academic research and drug development in the future and have the potential to revolutionise future patient treatment and clinical trial pathways. Similarly, ex vivo tumour slices or explants have also shown recent renewed promise in their ability to provide a fast, specific, platform for drug testing that accurately represents in vivo tumour response. Tumour explants retain tissue architecture, and thus incorporate the majority of tumour microenvironment making them an attractive

Journal article

Ma C, Pai RK, Schaeffer DF, Krell J, Guizzetti L, McFarlane SC, MacDonald JK, Choi W-T, Feakins RM, Kirsch R, Lauwers GY, Pai RK, Rosty C, Srivastava A, Walsh JC, Feagan BG, Jairath Vet al., 2022, Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis, JOURNAL FOR IMMUNOTHERAPY OF CANCER, Vol: 10

Journal article

Merali N, Chouari T, Kayani K, Rayner C, Jimenez Zarco J, Giovannetti E, Krell J, Bagwan I, Relph K, Rockall T, Dhillon T, Pandha H, Annels N, Frampton Aet al., 2022, A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma, Cancers, Vol: 14, Pages: 1-34, ISSN: 2072-6694

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.

Journal article

Constantinou AP, Nele V, Doutch JJ, S Correia J, Moiseev RV, Cihova M, Gaboriau DCA, Krell J, Khutoryanskiy VV, Stevens MM, Georgiou TKet al., 2022, Investigation of the thermogelation of a promising biocompatible ABC triblock terpolymer and its comparison with pluronic F127, Macromolecules, Vol: 55, Pages: 1783-1799, ISSN: 0024-9297

Thermoresponsive polymers with the appropriate structure form physical networks upon changes in temperature, and they find utility in formulation science, tissue engineering, and drug delivery. Here, we report a cost-effective biocompatible alternative, namely OEGMA30015-b-BuMA26-b-DEGMA13, which forms gels at low concentrations (as low as 2% w/w); OEGMA300, BuMA, and DEGMA stand for oligo(ethylene glycol) methyl ether methacrylate (MM = 300 g mol–1), n-butyl methacrylate, and di(ethylene glycol) methyl ether methacrylate, respectively. This polymer is investigated in depth and is compared to its commercially available counterpart, Poloxamer P407 (Pluronic F127). To elucidate the differences in their macroscale gelling behavior, we investigate their nanoscale self-assembly by means of small-angle neutron scattering and simultaneously recording their rheological properties. Two different gelation mechanisms are revealed. The triblock copolymer inherently forms elongated micelles, whose length increases by temperature to form worm-like micelles, thus promoting gelation. In contrast, Pluronic F127’s micellization is temperature-driven, and its gelation is attributed to the close packing of the micelles. The gel structure is analyzed through cryogenic scanning and transmission electron microscopy. Ex vivo gelation study upon intracameral injections demonstrates excellent potential for its application to improve drug residence in the eye.

Journal article

Glover M, Hui G, Chiang R, Savage P, Krell J, Julve M, Grivas P, Lythgoe M, Khaki ARet al., 2022, Disparity of race reporting in US Food and Drug Administration drug approvals for urinary system cancers from 2006 to 2021, BJU International, Vol: 129, Pages: 168-170, ISSN: 1464-4096

Journal article

Samani A, Bennett R, Eremeishvili K, Kalofonou F, Whear S, Montes A, Kristeleit R, Krell J, McNeish I, Ghosh S, Tookman Let al., 2022, Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers, ESMO Open, Vol: 7, ISSN: 2059-7029

Background:Carboplatin remains integral for treatment of gynaecological malignancies and dosing is based on glomerular filtration rate (GFR). Measurement via radiotracer decay (nmGFR) is ideal. However, this may be unavailable. Therefore, GFR is often estimated using formulae that have not been validated in patients with cancer and/or specifically for gynaecological malignancies, leading to debate over optimal estimation. Suboptimal GFR estimation may affect efficacy or toxicity. Methods:We surveyed several UK National Health Service Trusts to assess carboplatin dosing practise. We then explored single-centre accuracy, bias and precision of various formulae for GFR estimation, relative to nmGFR, before validating our findings in an external cohort. Results:Across 18 Trusts, there was considerable heterogeneity in GFR estimation, including the formulae used (Cockcroft-Gault (CG) vs Wright), weight-adjustment and area under the curve (5 vs 6). We analysed 274 and 192 patients in two centres. Overall, CamGFR v2 (a novel formula for GFR estimation developed at Cambridge University Hospitals NHS Foundation Trust) excelled, showing the highest accuracy and precision. This translated into accuracy of hypothetical carboplatin dosing; nmGFR-derived carboplatin dose fell within 20% of the Cam GFR v2-derived dose in 86.5% and 87% of patients across the cohorts. Amongst the CG formula and its derivatives, using adjusted body weight in those with BMI ≥25 kg/m2 (CG-AdBW) was optimal. The Wright and unadjusted CG estimators performed most poorly. Conclusions:When compared with nmGFR assessment, accuracy, bias and precision varied widely between GFR estimators, with the newly developed Cam GFR v2 and CG-AdBW perfoming best. In general, weight (or body surface area)-adjusted formulae performed best, while the unadjusted CG and Wright formulae or the use of AUC6 (vs. nmGFR AUC5) produced risk of significant overdose. Thus, individual centres should validate their GFR estimation me

Journal article

de la Rosa CN, Krell J, Day E, Clarke A, Reddi M, Webber L, Fiorentino Fet al., 2022, Statistical analysis plan for the Dual mTorc Inhibition in advanCed/recurrent Epithelial ovarian, fallopian tube or primary peritoneal cancer (of clear cell, endometrioid and high-grade serous type, and carcinosarcoma) trial (DICE), Trials, Vol: 23, Pages: 1-8, ISSN: 1745-6215

BackgroundTreatment for ovarian cancer includes platinum-based chemotherapy, but many women become resistant to chemotherapy, becoming platinum-resistant. Standard of care for these women is weekly paclitaxel chemotherapy, but cancers can often become paclitaxel resistant. TAK228, an investigational dual TORC1/2 inhibitor, is an oral therapy that can be added to standard treatment. The DICE trial is a phase II international multicentre, parallel-group, superiority clinical trial with 1:1, open label randomisation which has the aim of investigating the effectiveness of TAK228 plus weekly paclitaxel. The planned sample size is 124 women (62 per treatment arm) with platinum-resistant ovarian cancer.ObjectiveTo outline the planned analyses for DICE in a statistical analysis plan (SAP) before database hard lock and the start of analysis. This ensures that bias is minimised during the analysis phase.ResultsThis SAP provides detailed descriptions of the analysis principles and statistical procedures for analysing primary and secondary outcomes of the trial. The primary outcome is overall progression-free survival (PFS). Secondary outcomes include progression-free survival (PFS) at 24 weeks, overall response rate (ORR), duration of response (DoR), time to progression (TTP), clinical benefit rate (CBR) at 4 months, Cancer Antigen 125 (CA125) response according to Gynaecological Cancer Intergroup (GCIG) criteria, overall survival (OS), safety and tolerability as assessed by adverse events and the quality-of-life questionnaires (EORTC QLQ-C30 and EORTC QLQ-OV28). This detailed description includes significance levels, sensitivity analyses and compliance analysis.DiscussionThe DICE trial will determine whether the addition of TAK228 to weekly paclitaxel chemotherapy shows a statistically significant improvement to participant’s progression free and overall survival and that the adverse events (AEs) and quality of life (QoL) are not significantly worse than t

Journal article

Armbrust R, Chekerov R, Sander S, Biebl M, Chopra S, Krell J, Rinne N, Nixon K, Fotopoulou C, Sehouli Jet al., 2021, Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients (Oct, 10.1007/s00404-021-06237-x, 2021), Archives of Gynecology and Obstetrics, Vol: 306, Pages: 291-292, ISSN: 0932-0067

Journal article

Lythgoe MP, Ghani R, Mullish BH, Marchesi JR, Krell Jet al., 2021, The Potential of Faecal Microbiota Transplantation in Oncology, Trends in Microbiology, ISSN: 0966-842X

Journal article

Armbrust R, Chekerov R, Sander S, Biebl M, Chopra S, Krell J, Rinne N, Nixon K, Fotopoulou C, Sehouli Jet al., 2021, Surgery due to mechanical bowel obstruction in relapsed ovarian cancer: clinical and surgical results of a bicentric analysis of 87 patients, Archives of Gynecology and Obstetrics, Vol: 305, Pages: 963-968, ISSN: 0932-0067

IntroductionMechanical bowel obstruction is a frequent acute and life-threatening event in relapsed ovarian cancer. Salvage surgery after failure of all conservative approaches, resulting in short bowel syndrome (SBS) constitutes a therapeutic dilemma. Our aim was to evaluate patients’ surgical and clinical outcome in these highly palliative situations. Previous, limited, data reported a high morbidity and mortality. However, recent surgical and therapeutical improvements in relapsed ovarian cancer (ROC) offer better identification of patients who might benefit from surgery in an effort to extend the window of opportunity to subsequently offer these patients novel systemic therapeutic approaches.Material and methodsAll subsequent ROC patients between 2012 and 2017 with acute mechanical bowel obstruction who underwent salvage extraperitoneal en bloc intestinal resection were retrospectively identified. Data were collected from two ESGO certified Ovarian Cancer Centers of Excellence (Charité Berlin and Imperial College London) and systematically evaluated regarding surgical and clinical outcomes.ResultsOverall, 87 ROC patients were included in the analysis (median age 56 years, range 24–88), 47% were platinum resistant. High grade serous was the most common histology (76%) while most of the patients (67%) had at least two previous lines of treatment. Mean observed OS was 7.8 months. After salvage surgery, 46% of the patients had a residual small bowel length < 180 cm and 18% > 180 cm resulting in 41% in need of total parental nutrition. In 80% of the patients a permanent stoma was necessary. 30d morbidity and mortality was 74% and 10%, respectively. More than half of the patients were able to receive further courses of chemotherapy after surgery.DiscussionSalvage surgery for bowel obstruction in ROC patients needs careful consideration and identification of optimal surgical candidates to have the maximal therapeutic

Journal article

McGrane J, Shaw D, Anand A, Madhuri TK, Krell J, Saunders L, Hawkes C, Schilder JM, York W, Astrom Jet al., 2021, Ovarian Cancer Retrospective European (O'CaRE) observational study to assess burden of disease and time to next treatment in real-world clinical practice: Results from the United Kingdom (UK), Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S741-S741, ISSN: 0923-7534

Conference paper

Lythgoe MP, Liu DSK, Annels NE, Krell J, Frampton AEet al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3), JOURNAL OF CLINICAL PATHOLOGY, Vol: 74, Pages: 543-547, ISSN: 0021-9746

Journal article

Lythgoe M, Cleary S, Kalofonou F, Grunewald T, Miller R, Cartwright D, Glasspool RM, Jones R, Rossides S, Ratnakumaran R, Michael A, McNeish I, Tookman L, Krell Jet al., 2021, 747P Real-world experience of rucaparib in patients with ovarian cancer: A multicentre United Kingdom study, Annals of Oncology, Vol: 32, Pages: S742-S742, ISSN: 0923-7534

BackgroundEpithelial Ovarian Cancer (EOC) is the 5th leading cause of female cancer deaths. Despite high responses to first-line therapy, 5-year survival remains poor at 29%. Rucaparib is a small molecule PARP inhibitor (PARPi) approved as monotherapy for maintenance treatment of recurrent EOC with prior complete/partial response to platinum-based chemotherapy, on the basis of the ARIEL3 trial. Despite the validity of clinical trial evidence, applicability to routine practice is limited and real-world evidence (RWE) is mandated.MethodsWe performed a multi-center retrospective study of patients with advanced EOC receiving rucaparib in the UK from June 2018, via an early access program.Results119 patients were included, with a median age of 66 years (range 26-89). Median ECOG at commencement was 1 (0-3). 91% (n=108) had high grade serous carcinoma and 24% (n=29) germline/somatic BRCA1/2mutation (BRCAm). Prior to rucaparib, patients had a median of 3 therapies (range 1-9) with 8% (n=10) receiving an alternate PARPi. Overall progression free survival (PFS) was 7.5 months (1.1-37.4), with a higher PFS of 9.1 months (1.1-35.5) in BRCAm patients. This is lower than observed in ARIEL3. However, if similar inclusion/exclusion criteria are applied to our RWE population, findings are analogous, with PFS of 10.2 and 16.6 months in the overall and BRCAm groups respectively. Treatment-related toxicity (any grade) was reported in 88% (n=105) of patients, most prevalent being nausea, fatigue, anaemia and other blood dyscrasias. 26% (n=32) of patients experienced a CTCAE grade 3/4 toxicity and 58% (n=69) required dose interruption/reduction. 13% (n=16) of patients discontinued therapy due to a treatment related adverse effect: most frequently fatigue, nausea or thrombocytopenia. No haematological malignancies were observed.ConclusionsOverall we found a lower incidence of any grade and grade 3/4 toxicity, and furthermore equivalent discontinuation rates to ARIEL3. A lower overall PFS

Journal article

Lythgoe M, Adriani M, Stebbing J, Clark J, Pickford E, Frampton A, Liu D, Kyrgiou M, Rees E, Fyvie G, Stevenson A, Krell Jet al., 2021, 543P Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours, Annals of Oncology, Vol: 32, Pages: S607-S607, ISSN: 0923-7534

BackgroundMRx0518 is an oral live biotherapeutic with potent immunostimulatory activity and anti-tumorigenic efficacy in murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer. Previous reports have demonstrated a favourable safety profile in neoadjuvant and metastatic clinical settings, with emerging evidence of immune modulation. We performed a comprehensive analysis of the gene and metagene signature in cancer patients treated with MRx0518 monotherapy.MethodsTreatment-naïve patients with a histologically confirmed diagnosis of cancer scheduled for surgical resection were recruited from April 2019 to February 2020. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011CFU) twice daily from inclusion until the day preceding surgery. Safety and tolerability (CTCAE v4.03) were the primary endpoints of this study. Comprehensive biomarker analysis was also performed in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples using the NanoString IO 360 panel to explore gene and metagene signatures.Results31 samples were collected across tumour groups including breast (n=13) prostate (n=8), uterine (n=6), melanoma (n=2) and bladder (n=2). Differential expression analysis showed significant (p<0.05) increases in genes and metagenes associated with anti-tumour activity, including antigen presentation (AXL & CXCL12), innate immune processes (CHUK, RELA, PPARG & HRAS), interferon response (IFNGR1 & IFNGR2), Th1 cells and CD8+ cells following MRx0518 therapy, echoing preclinical findings. Novel changes, not previously detected in murine models, involving endothelial, mast cells, inflammatory myeloid and inflammatory chemokines were also observed, suggesting MRx0518 may have additional in vivo anti-tumorigenic effects. These changes were more pronounced in the breast cancer cohort.ConclusionsThis analysis, mirrors previous immunostimulatory activity and anti-tumorigenic efficacy observations seen in pre-clini

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

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