Imperial College London

DrAdamFrampton

Faculty of MedicineDepartment of Surgery & Cancer

Honorary Clinical Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2125a.frampton

 
 
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Location

 

4005Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

155 results found

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

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

Bolm L, Petruch N, Sivakumar S, Annels NE, Frampton AEet al., 2022, Gene of the month: T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), JOURNAL OF CLINICAL PATHOLOGY, Vol: 75, Pages: 217-221, ISSN: 0021-9746

Journal article

Frampton AE, Sivakumar S, 2022, A New Combination Immunotherapy in Advanced Melanoma, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 386, Pages: 91-92, ISSN: 0028-4793

Journal article

McKay SC, Pathak S, Wilkin RJW, Kamarajah SK, Wigmore SJ, Rees J, Dunne DFJ, Garcea G, Ahmad J, Carino NDL, Sultana A, Silva M, Lykoudis P, Nasralla D, Milburn J, Shah N, Kocher HM, Bhogal R, Baron RD, Navarro A, Halle-Smith J, Al-Sarireh B, Sen G, Jamieson NB, Briggs C, Stell D, Aroori S, Bowles M, Kanwar A, Harper S, Menon K, Prachalias A, Srinivasan P, Frampton AE, Jones C, Arshad A, Tait I, Spalding D, Young AL, Durkin D, Ghods-Ghorbani M, Sutcliffe RP, Roberts KJet al., 2021, Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience, HPB, Vol: 23, Pages: 1656-1665, ISSN: 1365-182X

Journal article

McLean KA, Kamarajah SK, Chaudhry D, Gujjuri RR, Raubenheimer K, Trout I, AlAmeer E, Creagh-Brown B, Harrison EM, Nepogodiev D, Roslani AC, Li E, Pata F, Ramos-De La Medina A, van Ramshorst GH, Sayyed R, Simoes J, Valente DCA, Smart N, Bhangu A, Glasbey JC, Khaw RA, Ahmed W, Akhbari M, Baker D, Borakati A, Mills E, Murray V, Thavayogan R, Yasin I, Glasbey J, Ridley W, Sarrami M, Zhang G, Egoroff N, Pockney P, Richards T, Edwards M, Lee M, Pinkney T, Pearse R, Vohra R, Sohrabi C, Jamieson A, Nguyen M, Rahman A, English C, Tincknell L, Kakodkar P, Kwek I, Punjabi N, Burns J, Varghese S, Erotocritou M, McGuckin S, Vayalapra S, Dominguez E, Moneim J, Bhatia S, Kouli O, Salehi M, Tan HL, Yoong A, Zhu L, Seale B, Nowinka Z, Patel N, Chrisp B, Harris J, Maleyko I, Muneeb F, Gough M, James CE, Skan O, Chowdhury A, Rebuffa N, Khan H, Down B, Fatimah HQ, Siaw-Acheampong K, Benson RA, Bywater E, Dawson BE, Evans JP, Heritage E, Jones CS, Khatri C, Keatley JM, Knight A, Lawday S, Mann HS, Marson EJ, Mckay SC, Mills EC, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JF, Trout IM, Venn ML, Wilkin RJW, Smart NJ, Minaya-Bravo A, Gallo G, Moug S, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Biel JR, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung E, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Rajkumar STS, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath J, Bromage S, Baroet al., 2021, Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 1448-1464, ISSN: 0007-1323

Journal article

Glasbey J, Ademuyiwa A, Adisa A, AlAmeer E, Arnaud AP, Ayasra F, Azevedo J, Minaya-Bravo A, Costas-Chavarri A, Edwards J, Elhadi M, Fiore M, Fotopoulou C, Gallo G, Ghosh D, Griffiths EA, Harrison E, Hutchinson P, Lawani I, Lawday S, Lederhuber H, Leventoglu S, Li E, Gomes GMA, Mann H, Marson EJ, Martin J, Mazingi D, McLean K, Modolo M, Moore R, Morton D, Ntirenganya F, Pata F, Picciochi M, Pockney P, Ramos-De la Medina A, Roberts K, Roslani AC, Kottayasamy Seenivasagam R, Shaw R, Simões JFF, Smart N, Stewart GD, Sullivan R, Sundar S, Tabiri S, Taylor EH, Vidya R, Nepogodiev D, Bhangu A, Glasbey JC, McLean K, Nepogodiev D, Harrison E, Bhangu AA, Nepogodiev D, Siaw-Acheampong K, Benson RA, Bywater E, Chaudhry D, Dawson BE, Evans JP, Glasbey JC, Gujjuri RR, Heritage E, Jones CS, Kamarajah SK, Khatri C, Khaw RA, Keatley JM, Knight A, Lawday S, Li E, Mann HS, Marson EJ, McLean KA, Mckay SC, Mills EC, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JFF, Trout IM, Venn ML, Wilkin RJW, Bhangu A, Glasbey JC, Smart NJ, Minaya-Bravo A, Evans JP, Gallo G, Moug S, Pata F, Pockney P, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Kamarajah SK, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Rey Biel J, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung EYL, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Shylasree TS, Kottayasamy Seenivasagam R, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath JS, Bromage S, Barod R, Kasivisvaet al., 2021, Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study, The Lancet Oncology, Vol: 22, Pages: 1507-1517, ISSN: 1470-2045

BackgroundSurgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction.MethodsThis international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926.FindingsOf eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notif

Journal article

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, 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

RICOCHET Study Group on behalf of the West Midlands Research Collaborative, 2021, Pancreatic enzyme replacement therapy in patients with pancreatic cancer: A national prospective study., Pancreatology, Vol: 21, Pages: 1127-1134, ISSN: 1424-3903

OBJECTIVE: UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates. DESIGN: RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing. RESULTS: Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5-7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028). CONCLUSION: Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.

Journal article

Malczewska A, Frampton AE, Mato Prado M, Ameri S, Dabrowska AF, Zagorac S, Clift AK, Kos-Kudła B, Faiz O, Stebbing J, Castellano L, Frilling Aet al., 2021, Circulating microRNAs in small-bowel neuroendocrine tumors: a potential tool for diagnosis and assessment of effectiveness of surgical resection, Annals of Surgery, Vol: 274, Pages: e1-e9, ISSN: 0003-4932

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Journal article

Blacker S, Lahiri RP, Phillips M, Pinn G, Pencavel TD, Kumar R, Riga AT, Worthington TR, Karanjia ND, Frampton AEet al., 2021, Which patients benefit from preoperative biliary drainage in resectable pancreatic cancer?, EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY, Vol: 15, Pages: 855-863, ISSN: 1747-4124

Journal article

Patel BY, White L, Gavriilidis P, Satyadas T, Frampton AE, Pai Met al., 2021, A systematic review into patient reported outcomes following pancreaticoduodenectomy for malignancy., Eur J Surg Oncol, Vol: 47, Pages: 970-978

BACKGROUND: Pancreaticoduodenectomy is associated with high rates of morbidity. This combined with the psychological burden of cancer, may impact on a patient's quality of life (QoL), which can be measured by using patient-reported outcomes (PRO). OBJECTIVE: To perform a systematic review to evaluate the measurement of PRO after pancreaticoduodenectomy for cancer. METHODS: 7 different databases were searched using 2 groups of search terms, one relating to pancreaticoduodenectomy, and one to PRO. Three authors screened the search results independently in a systematic manner based on predefined inclusion and exclusion criteria. RESULTS: 27 studies, with 2173 eligible patients were included in the final analysis. Most of the included studies used validated instruments. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was most popular and used in 12 studies. The methodology of all included studies was also scrutinised. 12 studies were deemed to have high quality methodology according to pre-defined criteria. CONCLUSION: The instruments and methods used to measure PRO are variable. The quality of PRO within the available literature has improved over time, as has the number of studies measuring PRO. PRO should be measured with uniformity in future trials so that patients can be provided with more comprehensive information regarding post-operative recovery and QoL during the shared decision-making process preoperatively.

Journal article

Frilling A, Clift AK, Frampton AE, Bomanji J, Kaemmerer D, Al-Nahhas A, Alsafi A, Kidd M, Modlin IM, Hoersch D, Baum RPet al., 2021, A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms, International Journal of Medical Sciences, Vol: 18, Pages: 2166-2175, ISSN: 1449-1907

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Journal article

Glasbey JC, Omar O, Nepogodiev D, Minaya-Bravo A, Bankhead-Kendall BK, Fiore M, Futaba K, Gabre-Kidan A, Gujjuri RR, Isik A, Kaafarani HMA, Kamarajah SK, Li E, Loeffler MW, McLean KA, Outani O, Ntirenganya F, Satoi S, Shaw R, Simoes JFF, Stewart GD, Tabiri S, Trout IM, Bhangu AA, Glasbey JC, Omar O, Bhangu AA, Siaw-Acheampong K, Benson RA, Bywater E, Chaudhry D, Dawson BE, Evans JP, Glasbey JC, Gujjuri RR, Heritage E, Jones CS, Kamarajah SK, Khatri C, Khaw RA, Keatley JM, Knight A, Lawday S, Li E, Mann HS, Marson EJ, McLean KA, Mckay SC, Mills EC, Nepogodiev D, Pellino G, Picciochi M, Taylor EH, Tiwari A, Simoes JFF, Trout IM, Venn ML, Wilkin RJW, Bhangu A, Glasbey JC, Smart NJ, Minaya-Bravo A, Evans JP, Gallo G, Moug S, Pata F, Pockney P, Di Saverio S, Vallance A, Vimalchandran D, Griffiths EA, Kamarajah SK, Evans RPT, Townend P, Roberts K, McKay S, Isaac J, Satoi S, Edwards J, Coonar AS, Marchbank A, Caruana EJ, Layton GR, Patel A, Brunelli A, Ford S, Desai A, Gronchi A, Fiore M, Almond M, Tirotta F, Dumitra S, Kolias A, Price SJ, Fountain DM, Jenkinson MD, Hutchinson P, Marcus HJ, Piper RJ, Lippa L, Servadei F, Esene I, Freyschlag C, Neville I, Rosseau G, Schaller K, Demetriades AK, Robertson F, Alamri A, Shaw R, Schache AG, Winter SC, Ho M, Nankivell P, Biel JR, Batstone M, Ganly I, Vidya R, Wilkins A, Singh JK, Thekinkattil D, Sundar S, Fotopoulou C, Leung E, Khan T, Chiva L, Sehouli J, Fagotti A, Cohen P, Gutelkin M, Ghebre R, Konney T, Pareja R, Bristow R, Dowdy S, Rajkumar STS, Ng J, Fujiwara K, Stewart GD, Lamb B, Narahari K, McNeill A, Colquhoun A, McGrath J, Bromage S, Barod R, Kasivisvanathan V, Klatte T, Simoes JFF, Abbott TEF, Abukhalaf S, Adamina M, Ademuyiwa AO, Agarwal A, Akkulak M, Alameer E, Alderson D, Alakaloko F, Albertsmeiers M, Alser O, Alshaar M, Alshryda S, Arnaud AP, Augestad KM, Ayasra F, Azevedo J, Bankhead-Kendall BK, Barlow E, Beard D, Benson RA, Blanco-Colino R, Brar A, Minaya-Bravo A, Breen KA, Bretherton C, Buarque IL, Burke J, Caruet al., 2021, Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 88-96, ISSN: 0007-1323

Journal article

Mantini G, Meijer LL, Glogovitis I, In't Veld SGJG, Paleckyte R, Capula M, Le Large TYS, Morelli L, Pham TV, Piersma SR, Frampton AE, Jimenez CR, Kazemier G, Koppers-Lalic D, Wurdinger T, Giovannetti Eet al., 2021, Omics analysis of educated platelets in cancer and benign disease of the pancreas, Cancers, Vol: 13, ISSN: 2072-6694

Pancreatic ductal adenocarcinoma (PDAC) is traditionally associated with thrombocytosis/hypercoagulation and novel insights on platelet-PDAC “dangerous liaisons” are warranted. Here we performed an integrative omics study investigating the biological processes of mRNAs and expressed miRNAs, as well as proteins in PDAC blood platelets, using benign disease as a reference for inflammatory noise. Gene ontology mining revealed enrichment of RNA splicing, mRNA processing and translation initiation in miRNAs and proteins but depletion in RNA transcripts. Remarkably, correlation analyses revealed a negative regulation on SPARC transcription by isomiRs involved in cancer signaling, suggesting a specific ”education” in PDAC platelets. Platelets of benign patients were enriched for non-templated additions of G nucleotides (#ntaG) miRNAs, while PDAC presented length variation on 3′ (lv3p) as the most frequent modification on miRNAs. Additionally, we provided an actionable repertoire of PDAC and benign platelet-ome to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in patients with PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can “educate” the platelet. These novel findings could be further exploited for innovative liquid biopsies platforms as well as possible therapeutic targets.

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

Limb C, Liu D, Veno M, Rees E, Krell J, Bagwan I, Giovannetti E, Pandha H, Strobel O, Rockall T, Frampton Aet al., 2020, The role of circular RNAs in pancreatic ductal adenocarcinoma and biliary-tract cancers, Cancers, Vol: 12, ISSN: 2072-6694

Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.

Journal article

Randazzo O, Papini F, Mantini G, Gregori A, Parrino B, Liu D, Cascioferro S, Carbone D, Peters G, Frampton A, Garajova I, Giovannetti Eet al., 2020, “Open Sesame?”: biomarker status of the human equilibrative nucleoside transporter-1 and molecular mechanisms influencing its expression and activity in the uptake and cytotoxicity of gemcitabine in pancreatic cancer, Cancers, Vol: 12, ISSN: 2072-6694

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. Gemcitabine has been for more than twenty years the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. We discuss this analysis and lists molecular factors influencing hENT-1. Improved knowledge on these factors should help in the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

Journal article

Liu D, Upton F, Rees E, Limb C, Jiao L, Krell J, Frampton Aet al., 2020, Size exclusion chromatography as a technique for the investigation of novel extracellular vesicles in cancer, Cancers, Vol: 12, ISSN: 2072-6694

Abstract: (1) Background: Cancer cells release extracellular vesicles that are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. SEC is an increasingly popular technique which has been rediscovered for the purposes of EV isolation and purification from diverse biofluids. (2) Methods: A review was undertaken to identify all papers which described size exclusion as their primary EV isolation method in cancer research. (3) Results: 37 papers were identified and discussed which showcases the breadth of applications that EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. (4) Conclusions: EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts and remain functionally active for further experiments.

Journal article

Glasbey JC, Bhangu A, 2020, Elective cancer surgery in COVID-19–free surgical pathways during the SARS-CoV-2 pandemic: an international, multicenter, comparative cohort study, Journal of Clinical Oncology, Vol: 39, Pages: 66-78, ISSN: 0732-183X

PURPOSEAs cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway.PATIENTS AND METHODSThis international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation).RESULTSOf 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76).CONCLUSIONWithin available resources, dedicated COVID-19–free

Journal article

Farkas N, Wong J, Bethel J, Monib S, Frampton A, Thomson Set al., 2020, A systematic review of symptomatic small bowel lipomas of the jejunum and ileum, Annals of Medicine and Surgery, Vol: 58, Pages: 52-67, ISSN: 2049-0801

IntroductionSmall bowel lipomas are rarely encountered benign adipose growths found within the small intestine wall or mesentery. Limited up-to-date evidence exists regarding such lipomas. We aim to aid clinical decision-making and improve patient outcomes through this comprehensive review.MethodologyThe terms ‘small bowel,’ ‘small intestine,’ ‘jejunum’ and ‘ileum’ were combined with ‘lipoma.’ EMBASE, Medline and PubMed database searches were performed. All papers published in English from 01/01/2000-31/12/2019 were included. Simple statistical analysis (t-test, Anova) was performed.Results142 papers yielded 147 cases (adults = 138, pediatric = 9). Male = 88, female = 59 (average age = 49.9 years). Presenting symptoms: abdominal pain = 68.7%; nausea/vomiting = 35.3%, hematochezia/GI bleeding = 33.3%; anaemia = 10.9%; abdominal distension = 12.2%; constipation = 8.9%; weight loss = 7.5%. Mean preceding symptom length = 58.1 days (symptoms >1 year excluded (n = 9)). Diagnostic imaging utilised: abdominal X-Ray = 33.3%; endoscopy = 46.3%; CT = 78.2%; ultrasound = 23.8%. 124/137 (90.5%) required definitive surgical management (laparotomy = 89, laparoscopcic = 35). 9 patients were successfully managed endoscopically. Lipoma location: ileum = 59.9%, jejunum = 32%, mesentery = 4.8%. Maximal recorded lipoma size ranged 1.2–22 cm.Mean maximum lipoma diameter and management strategy comparison: laparotomy 5.6 cm, laparoscopic = 4.4 cm, endoscopic = 3.7 cm, conservative = 4.5 cm. One-way Anova test, p value = 0.21. Average length of stay (LOS) was 7.4 days (range = 2–30). T-test p value = 0.13 when comparing management modalities and LOS. 4 complications, 0 mortality.ConclusionsImportant previously undocumented points are illustrated; a clearer symptom profile, diagnostic investigations utilised, size and site of lipomas, types and effectiveness of management modalities, associated morbidity and mortali

Journal article

COVIDSurg Collaborative, 2020, Delaying surgery for patients with a previous SARS-CoV-2 infection, British Journal of Surgery, ISSN: 0007-1323

Journal article

Meijer LL, Garajova I, Caparello C, Le Large TYS, Frampton AE, Vasile E, Funel N, Kazemier G, Giovannetti Eet al., 2020, Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma, ANNALS OF SURGERY, Vol: 271, Pages: 1137-1147, ISSN: 0003-4932

Journal article

Kostalas M, Frampton AE, Low N, Lahiri R, Ban EJ, Kumar R, Riga AT, Worthington TR, Karanjia NDet al., 2020, Left hepatic trisectionectomy for hepatobiliary malignancies: Its’ role and outcomes. A retrospective cohort study, Annals of Medicine and Surgery, Vol: 51, Pages: 11-16, ISSN: 2049-0801

Background: Left hepatic trisectionectomy (LHT) is a complex hepatic resection; its’ role and outcomes in hepatobiliary malignancies remains unclear. Materials and methods: All patients undergoing LHT at the tertiary HPB referral unit at RSCH, Guildford, UK from September 1996 to October 2015 were included. Data were collected from a prospectively maintained database. Results: Twenty-eight patients underwent LHT. The M:F ratio was 1.8:1. Median age was 60 years (range 43–76 years). Diagnoses included colorectal liver metastases (CRLM; n = 20); cholangiocarcinoma (CCA; n = 4); and other (neuroendocrine tumour metastases (NET; n = 3) and breast metastases (n = 1)). Median duration of surgery was 270 min (range 210–585 min). Median blood loss was 750 ml (300–2400 ml) with a perioperative transfusion rate of 21% (n = 6/28). The rate of all post-operative complications was 21% for all patients, and given the extensive resection performed four patients (14%) developed varying degrees of hepatic insufficiency. One patient with cholangiocarcinoma developed severe hepatic insufficiency, which was fatal within 90 days of surgery. 1 and 3-year survivals were 92% and 68% respectively. Conclusion: This study supports LHT in patients with significant tumour burden. Despite extensive resection, our favourable morbidity and mortality rates show this is a safe and beneficial procedure for patients with all hepatobiliary malignancies. Given the nature of resection the incidence of post-operative hepatic insufficiency is higher than less extensive hepatic resections.

Journal article

Frampton AE, Giovannetti E, 2020, Diagnostic pancreatic ductal adenocarcinoma using plasma extracellular vesicle RNA profiles, GUT, Vol: 69, Pages: 404-405, ISSN: 0017-5749

Journal article

Malczewska A, Frampton A, Prado MM, Ameri S, Dabrowska AF, Zagorac S, Clift A, Kos-Kudla B, Faiz O, Stebbing J, Castellano L, Frilling Aet al., 2020, Diagnosis and Assessment of Effectiveness of Surgical Resection of Small Bowel Neuroendocrine Tumours: The Roles of Circulating MicroRNAs, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 145-145, ISSN: 0028-3835

Conference paper

Van Der Steen N, Keller K, Dekker H, Porcelli L, Honeywell RJ, Van Meerloo J, Musters RJP, Kathmann I, Frampton AE, Liu DSK, Ruijtenbeek R, Rolfo C, Pauwels P, Giovannetti E, Peters GJet al., 2020, Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function, Journal of Cellular Physiology, Vol: 235, Pages: 8085-8097, ISSN: 0021-9541

In non‐small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR‐inhibitor erlotinib and the cMET‐inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live‐cell microscopy. We observed additive effects in EBC‐1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR‐inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live‐cell microscopy with a pH‐sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib–erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.

Journal article

Ottaviani S, Stebbing J, Frampton AE, Zagorac S, Krell J, de Giorgio A, Trabulo SM, Nguyen VTM, Magnani L, Feng H, Giovannetti E, Funel N, Gress TM, Jiao LR, Lombardo Y, Lemoine NR, Heeschen C, Castellano Let al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723

Journal article

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