Dr Adam Frampton

Head of Oncology; Assoc. Professor in Surgical Oncology; Consultant General & Hepato-Pancreato-Biliary (HPB) Surgeon
BSc(Hons), MSc, PhD, DipMedTox, MBBS, FRCS(Gen Surg), FRSB, FESSR


Agnieszka Lemanska, Colm Andrews, Louis Fisher, Seb Bacon, Amir Mehrkar, Peter Inglesby, Simon Davy, Praveetha Patalay, Ben Goldacre, Brian MacKenna, The OpenSAFELY Collaborative, Alex Walker, Adam Frampton (2023)Healthcare in England was affected by the COVID-19 pandemic across the pancreatic cancer pathway: a cohort study using OpenSAFELY-TPP, In: ELife12e85332 Cold Spring Harbor Laboratory Press

Background Healthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We analysed healthcare services delivered to people with pancreatic cancer from January 2015 to March 2023 to investigate the effect of the COVID-19 pandemic. Methods With the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models (GLM) and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to March 2023. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. Results The rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 26,840 people diagnosed with pancreatic cancer from January 2015 to March 2023. The mean age at diagnosis was 72 (±11 SD), 48% of people were female, 95% were of White ethnicity and 40% were diagnosed with diabetes. We found a reduction in surgical resections by 25% to 28% during the pandemic. In addition, 20%, 10% and 4% fewer people received BMI, HbA1c and liver function tests respectively before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1 to 2 per person amongst those who made contact. Reporting of jaundice decreased by 28%, but recovered within twelve months into the pandemic. Emergency department visits, hospital admissions and deaths were not affected. Conclusions The pandemic affected healthcare in England across the pancreatic cancer pathway. Positive lessons could be learnt from the services that were resilient and those that recovered quickly. The reductions in healthcare experienced by people with cancer have the potential to lead to worse outcomes. Current efforts should focus on addressing the unmet needs of people with cancer.

Agnieszka Lemanska, Colm Andrews, Louis Fisher, Seb Bacon, Adam E Frampton, Amir Mehrkar, Peter Inglesby, Simon Davy, Keith Roberts, Praveetha Patalay, Ben Goldacre, Brian MacKenna, Alex J Walker (2023)Healthcare in england was affected by the covid-19 pandemic across the pancreatic cancer pathway: A cohort study using opensafely-tpp, In: eLife1285332 eLife Sciences Publications

Healthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We analysed healthcare services delivered to people with pancreatic cancer from January 2015 to March 2023 to investigate the effect of the COVID-19 pandemic. With the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to March 2023. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. The rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 26,840 people diagnosed with pancreatic cancer from January 2015 to March 2023. The mean age at diagnosis was 72 (±11 SD), 48% of people were female, 95% were of White ethnicity, and 40% were diagnosed with diabetes. We found a reduction in surgical resections by 25-28% during the pandemic. In addition, 20%, 10%, and 4% fewer people received body mass index, glycated haemoglobin, and liver function tests, respectively, before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1-2 per person amongst those who made contact. Reporting of jaundice decreased by 28%, but recovered within 12 months into the pandemic. Emergency department visits, hospital admissions, and deaths were not affected. The pandemic affected healthcare in England across the pancreatic cancer pathway. Positive lessons could be learnt from the services that were resilient and those that recovered quickly. The reductions in healthcare experienced by people with cancer have the potential to lead to worse outcomes. Current efforts should focus on addressing the unmet needs of people with cancer. This work was jointly funded by the Wellcome Trust (222097/Z/20/Z); MRC (MR/V015757/1, MC_PC-20059, MR/W016729/1); NIHR (NIHR135559, COV-LT2-0073), and Health Data Research UK (HDRUK2021.000, 2021.0157). This work was funded by Medical Research Council (MRC) grant reference MR/W021390/1 as part of the postdoctoral fellowship awarded to AL and undertaken at the Bennett Institute, University of Oxford. The views expressed are those of the authors and not necessarily those of the NIHR, NHS England, UK Health Security Agency (UKHSA), or the Department of Health and Social Care. Funders had no role in the study design, collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

James M. Halle-Smith, Lewis A. Hall, Sarah F. Powell-Brett, Nabeel Merali, Adam Frampton, Keith J. Roberts (2023)Realising the therapeutic potential of the human microbiota in metastatic pancreatic ductal adenocarcinoma, In: Clinical Surgical Oncology2(4)100020 Elsevier B.V

Treatment options for metastatic pancreatic ductal adenocarcinoma (mPDAC) patients remain limited, meaning that death within weeks of diagnosis unfortunately remains a common occurrence. Whilst metastases from other malignancy sites, such as colorectal and breast, are amenable to resection in selected patients, consensus remains largely against resection of mPDAC. Without surgical resection, chemotherapy remains the main treatment option and despite advances in regimens, a large proportion of mPDAC patients do not respond to these treatments. Understandably, investigation into whether different genetic subtypes of PDAC can explain the changes in response to chemotherapy have been carried out but as yet has not demonstrated any marked differences between those that do and do not respond to chemotherapy treatment. This review outlines the emerging role that both the gut and tumour microbiome play in modulating the progression of PDAC, ranging from chemosensitivity to immune infiltration of the tumour This puts the gut microbiome in a promising position as a potential future therapeutic route for mPDAC patients. Possible methods to modulate the gut and tumour microbiome include antibiotics, probiotics and faecal microbiota transplantation (FMT). The next steps should therefore be to focus upon how we can effectively and safely introduce these beneficial bacteria into the gut and tumour microbiome of mPDAC patients through clinical trials.

D. McDonnell, C.D. Byrne, S. Wilding, J.R. Swann, A.E. Frampton, N. Merali, Z.Z. Hamady (2023)The Plasma Glutamine: Glucose Ratio as a Diagnostic Test for Pancreatic Ductal Adenocarcinoma, In: HPB25(Supplement 2)pp. S271-S271 Elsevier

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with decreased plasma glutamine and increased plasma glucose, but using both measurements together has not been utilised as a diagnostic test for PDAC. Glutamine is used by the tricarboxylic acid cycle during glucose metabolism, and is a substrate for gluconeogenesis during periods of starvation; which might be augmented by insulin resistance associated with PDAC. Our aim was to examine the utility of a plasma glutamine:glucose ratio as a diagnostic test for PDAC, and investigate the influence of fasting on this ratio. Method: Plasma samples were taken from 50 fasted participants, who were starved for 12 hours, and compared to 50 separate non-fasted participants. The relative abundance of glucose and glutamine from both groups was measured with 1H-NMR spectroscopy. The intensity of the signal on the vertical axis represents the quantity of each metabolite. Mann-Whitney U tests compared the differences between each metabolite, and receiver operator characteristic curves based on the ratios between the groups were generated using Stata 16. Results: Twenty-six fasted PDAC patients (aged 65.9 ± 11.2, 65.3% male) and 24 fasted controls (aged 68.3 ± 8.2, 54% male) were studied, alongside 40 non-fasted PDAC patients (aged 68.1 ± 9.9, 47.5% male) and 10 non-fasted controls (aged 60.5 ± 14.4, 60% male). The intensity of the glutamine signal was lower in those with PDAC compared to controls in the fasted group (3.64AU, vs 3.94AU, P = 0.025), whereas in the non-fasted there was no significant difference between PDAC and controls (4.39AU, vs 4.02AU, P = 0.22). The intensity of the glucose signal was increased in those with PDAC compared to controls in the fasted state (10.16AU vs 8.59AU, P < 0.001). This was also the case in the non-fasted state (10.60AU vs 7.17AU, P = 0.001). The AUROC for the ratio of glutamine:glucose for a diagnosis of PDAC compared to controls in the fasted state was 0.82 (95% CI: 0.58 – 0.93). In the non-fasted state the AUROC was 0.75 (95% CI: 0.69 – 0.94). There was no significant difference in AUROCs between fasted and non-fasted participants (P = 0.56). Conclusion: Glutamine uptake is higher in PDAC amongst fasted individuals. The data indicates that the plasma glutamine:glucose ratio has a good diagnostic performance for diagnosing PDAC, and further research is needed to study the utility of this test in PDAC.

N. Merali, J. Terroire, D. Liu, E. Giovannetti, S. Sivakumar, J. Krell, E. Velliou, J. Jimenez, A. Demirkan, N. Annels, A.E. Frampton (2023)Bile Microbiome Signatures as Biomarkers for Differentiating Pancreatic Ductal Adenocarcinoma from Benign Disease, In: HPB (Oxford, England)25pp. S270-S271 Elsevier

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is lethal. It is projected that by 2030, PDAC will become the 2nd leading cause of cancer-related death. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance, and therefore patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease to develop novel cancer biomarkers. Method: Prospective bile samples were obtained from 37 patients who underwent either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC). Variable regions (V3–V4) of the 16S rRNA genes were amplified by PCR and next generation sequencing was performed. The cohort consisted of 12 PDAC, 6 cholangiocarcinoma, 10 choledocholithiasis, 7 gallstone pancreatitis, and 2 primary sclerosing cholangitis patients. Bile samples from 8 patients were excluded from the analysis because of low read count. Results: Using the 16S rRNA method, we identified a total of 108 genera from 29 individuals (12 PDAC and 17 benign). Bile microbial diversity significantly differed between patients with PDAC vs. benign disease (p=0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering based on Canberra distances shown in Figure 1. We found 4 genera to be of significantly different abundance between PDAC vs. benign groups by association p-value and supported by false discovery rate (fdr). These were Escherichia (p=6.5x10-6, fdr=0.0002), Rothia (p=0.011, fdr=0.074), Streptococcus (p=0.012, fdr=0.074) and Prevotella (p=0.015, fdr=0.079). Conclusion: We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile, compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.

Mark Lythgoe, Paola Dama, Adam Enver Frampton, Emily Pickford, Laura Tookman, Paula Cunnea, Christina Fotopoulou, Daniel Liu, James Clark, Jingky Lozano-kuehne, Philip David Badman, Aaron Clarke, Sasha Chetal, Gayle Fyvie, Alex Stevenson, Jonathan Krell (2023)Immune modulation and the oral live biotherapeutic product, MRx0518, in treatment-naïve patients with cancer: Updated safety data, In: Journal of clinical oncology41(16_suppl)3145 American Society of Clinical Oncology

Background: Live biotherapeutic products (LBPs) are emerging novel anti-cancer therapies. MRx0518 is a gut microbiome-derived oral LBP, consisting of a single strain of Enterococcus gallinarum, which has demonstrated potent anti-tumorigenic efficacy pre-clinically. We have previously shown MRx0518 monotherapy is associated with significant genomic, immune, microbiome, and metabolomic changes, consistent with anti-cancer efficacy in treatment-naïve patients. Here, we report long-term subject follow-up, and further signals of immune modulatory changes from flow cytometry analysis. Methods: NCT03934827 is a Phase 1B single-centre study in treatment-naive patients with confirmed cancer, planned for surgical resection. 17 patients (8 breast, 4 prostate, 3 uterine, 1 bladder & 1 melanoma) received MRx0518 (1x10 10 -1x10 11 CFU) BID monotherapy for 7-28 days from inclusion until surgery. Safety data was collected from dosing until 1-year following cessation. Exploratory analysis included evaluation of pre- and post-treatment peripheral blood mononuclear cells (PBMCs) by multiparametric flow cytometry for leucocyte activation, indicative of anti-cancer efficacy. Results: A total of 29 adverse events (AEs), all CTCAE grade 1 (96%) and grade 2 (4%), were reported. Only 8 (28%) were deemed related to MRx0518. No grade 3/4 toxicities or serious AEs were recorded. At 30-days, and 1-year follow-up no further serious AEs occurred. At a median follow-up of 41 months, 13 (76%) patients remain cancer-free, with 2 (11%) reoccurrences and 2 (11%) lost to follow-up. Analysis of pre- and post-treatment PBMCs identified statistically significant increases in CD3 + CD56 + (p

Bhavik Y. Patel, Rahul Bhome, Daniel S. K. Liu, Elisa Giovannetti, Nabeel Merali, John N. Primrose, Alex H. Mirnezami, Timothy A. Rockall, Nicola Annels, Adam E. Frampton (2023)Cancer cell-derived extracellular vesicles activate hepatic stellate cells in colorectal cancer, In: Expert review of molecular diagnostics23(10)pp. 843-849 Taylor and Francis

Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths worldwide, primarily due to the development of metastatic disease. The liver is the most frequently affected site. The metastatic cascade relies on a complex interaction between the immune system, tumor, and distant organs. Communication between the tumor and the metastatic site can be mediated by tumor-derived extracellular vesicles (EVs) and their cargo. The mechanisms underlying this process are starting to be understood through research that has rapidly expanded over the past 15 years. One crucial aspect is the remodeling of the microenvironment at the site of metastasis, which is essential for the formation of a premetastatic niche and the subsequent establishment of metastatic deposits. In the evaluated study, the authors use cellular experiments and a mouse model to investigate how tumour derived extracellular vesicles and their microRNA contents interact with hepatic stellate cells (HSCs). They demonstrate how this may lead to remodelling of the microenvironment and the formation of colorectal liver metastasis using their experimental model. In this mini review, we examine the current evidence surrounding tumour derived EVs and their effect on the tumour microenvironment to highlight potential areas for future research in CRC and other malignancies.

Tarak Chouari, Nabeel Merali, Francesca La Costa, Jonas Santol, Shelley Chapman, Alex Horton, Somaiah Aroori, John Connell, Timothy A. Rockall, Damian Mole, Patrick Starlinger, Fenella Welsh, Myrddin Rees, Adam E. Frampton (2023)The Role of the Multiparametric MRI LiverMultiScan™ in the Quantitative Assessment of the Liver and Its Predicted Clinical Applications in Patients Undergoing Major Hepatic Resection for Colorectal Liver Metastasis, In: Cancers15(19)4863 MDPI

Liver biopsy remains the gold standard for the histological assessment of the liver. With clear disadvantages and the rise in the incidences of liver disease, the role of neoadjuvant chemotherapy in colorectal liver metastasis (CRLM) and an explosion of surgical management options available, non-invasive serological and imaging markers of liver histopathology have never been more pertinent in order to assess liver health and stratify patients considered for surgical intervention. Liver MRI is a leading modality in the assessment of hepatic malignancy. Recent technological advancements in multiparametric MRI software such as the LiverMultiScanTM offers an attractive non-invasive assay of anatomy and histopathology in the pre-operative setting, especially in the context of CRLM. This narrative review examines the evidence for the LiverMultiScanTM in the assessment of hepatic fibrosis, steatosis/steatohepatitis, and potential applications for chemotherapy-associated hepatic changes. We postulate its future role and the hurdles it must surpass in order to be implemented in the pre-operative management of patients undergoing hepatic resection for colorectal liver metastasis. Such a role likely extends to other hepatic malignancies planned for resection.

Max Julve, Oliver Kennedy, Adam Enver Frampton, Izhar Bagwan, Mark P Lythgoe (2023)Gene of the month: Cancer testis antigen gene 1b (NY-ESO-1), In: Journal of clinical pathology BMJ Publishing Group

Cancer testis antigen gene 1B (CTAG1B) and its associated gene product; New York oesophageal squamous carcinoma 1 (NY-ESO-1), represent a unique and promising target for cancer immunotherapy. As a member of the cancer testis antigen family (CTA), the protein’s restricted expression pattern and ability to elicit spontaneous humoural and cellular immune responses has resulted in a plethora of novel modalities and approaches attempting to harness its immunotherapeutic anti-cancer potential. Here, we discuss the structure and function of CTAG1B/NY-ESO-1 in both health and disease, immunohistochemical detection, as well as the most promising advances in the development of associated anti-cancer therapies. From cancer vaccines to engineered cellular therapy approaches, a multitude of immunotherapies targeting CTA’s are coming to the forefront of oncology. Although the efficacy of such approaches have yet to provide convincing evidence of durable response, early phase clinical trial data has resulted in some exciting findings which will have significant potential to act as a platform for future practice changing technologies.

Asif Ali, Nigel Balfour Jamieson, Ishaq N Khan, David Chang, Elisa Giovannetti, Nicola Funel, Adam E Frampton, Jennifer Morton, Owen Sansom, Thomas R Jeffry Evans, Fraser Duthie, Colin J McKay, Jas Samra, Anthony J Gill, Andrew Biankin, Karin A Oien (2022)Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients, In: American journal of cancer research12(12)pp. 5668-5683 e-Century Publishing Corporation

Despite progress in genomic characterization, no single prognostic marker that can be evaluated using an easy-to-perform and relatively inexpensive method is available for pancreatic ductal adenocarcinoma (PDAC). MicroRNAs, which are stable, tumor- and tissue-specific molecules, are potentially ideal biomarkers, and we established an inter-laboratory validated method to investigate miR-21 as a prognostic biomarker in PDAC. The study samples of PDAC patients were recruited from a test cohort of Glasgow (n = 189) and three validation cohorts of Pisa (n = 69), Sydney (n = 249), and International Cancer Genome Consortium (ICGC) (n = 249). Tissue microarrays were used for miR-21 staining by chromogenic in situ hybridization (CISH). The patients were subdivided into no/low and high miR-21 staining groups using a specific histoscore. Furthermore, miR-21 staining was evaluated against clinicopathological variables and follow-up data by Fisher/log-rank test and Cox proportional models. The prognostic variables found to be significant in univariate analysis ( P value < 0.10) were included in multivariate analysis in a backward-stepwise fashion. MiR-21 expression was cytoplasmic, with more consistent staining in the malignant ductal epithelium than in the stroma. The expression of miR-21 was significantly associated with tumor size and lymph node metastasis, whereas no association was observed with other clinicopathological variables. High miR-21 staining (histoscore ≥ 45 [median score]) was an independent predictor of survival in the Glasgow test cohort (HR 2.37, 95% CI: 1.42-3.96, P < 0.0001) and three validation cohorts (Pisa, HR 2.03, 95% CI: 1.21-3.39, P = 0.007; Sydney, HR 2.58, 95% CI (1.21-3.39), P < 0.0001; and ICGC, HR 3.34, 95% CI: 2.07-5.84, P = 0.002) when adjusted for clinical variables in a multivariate model. In comparison to the patients with low miR-21, the patients with high miR-21 expression had significant increase in OS as they benefit from gemcitabine-based adjuvant chemotherapy (Glasgow 16.5 months [with chemotherapy] vs 10.5 months [without chemotherapy]); Sydney 25.0 vs 10.6; ICGC 25.2 vs 11.9. These results indicated that miR-21 is a predictor of survival, prompting prospective trials. Evaluation of miR-21 offers new opportunities for the stratification of patients with PDAC and might facilitate the implementation of clinical management and therapeutic interventions for this devastating disease.

James M. Halle-Smith, Lewis A. Hall, Sarah F. Powell-Brett, Nabeel Merali, Adam E. Frampton, Andrew D. Beggs, Paul Moss, Keith J. Roberts (2023)Pancreatic Exocrine Insufficiency and the Gut Microbiome in Pancreatic Cancer: A Target for Future Diagnostic Tests and Therapies?, In: Cancers15(21)

Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature review is to summarise the current evidence linking PEI with microbiome dysbiosis, assess how microbiome composition may be impacted by PERT treatment, and look towards possible future diagnostic and therapeutic targets in this area. Early evidence in the literature reveals that there are complex mechanisms by which pancreatic secretions modulate the gut microbiome, so when these are disturbed, as in PEI, gut microbiome dysbiosis occurs. PERT has been shown to return the gut microbiome towards normal, so called rebiosis, in animal studies. Gut microbiome dysbiosis has multiple downstream effects in pancreatic cancer such as modulation of the immune response and the response to chemotherapeutic agents. It therefore represents a possible future target for future therapies. In conclusion, it is likely that the gut microbiome of pancreatic cancer patients with PEI exhibits dysbiosis and that this may potentially be reversible with PERT. However, further human studies are required to determine if this is indeed the case.

Angeliki Kosti, Aditya Borakati, Aarti Varma, Aayush Gupta, Abdalla Mustafa, Abdul Hakeem, Abdul Quddus, Abdullah Bin Sahl, Abhijeet Beniwal, Abidemi Adesuyi, Ada Maria Krzak, Adam Brooks, Adam Frampton, Adam Gadhvi, Adam Talbot, Ahmed Elnogoomi, Ahmed Mahgoub, Ahmed Naqvi, Ahmed Pervez, Ahmed Salman Bodla, Ahmed Taha, Ahmed Tawfik, Aishwarya Prabhu, Aiysha Puri, Ajay Belgaumkar, Ajay Gupta, Alan McCrorie, Alasdair Findlay, Albert Healey, Alexandra De Prendergast, Alexia Farrugia, Alexios Dosis, Alfie Adiamah, Ali Sallam, Alicia Wong, Alison Bradley, Allie Martin, Alma Collins, Altaf Awan, Amanda Bond, Amanda Koh, Amar Kourdouli, Ameet G Patel, Amenah Dhannoon, Amjad Khalil, Amlan Banerjee, Amnah Khan, Amr Elserafy, Amro Alamassi, Amy Owen, Anastasia Benjafield, Andrea Zuccarrelli, Andreas Luhmann, Andrew Jones, Andrew Kennedy-Dalby, Andrew M Smith, Anil Kaul, Anil Kumar, Annabelle White, Annalie Baker, Annamaria Minicozzi, Antonio Bardoli, Antonio Leyte Golpe, Antonio Manzelli, Aran Sivakumar, Arin Saha, Arjun Shajpal, Artemisia Lango, Arthur Cotton, Ashitha Nair, Ashley Brown, Ashok Menon, Ashutosh Tandon, Asma Afza, Asma Hassan, Awad Shamali, Ayesha Khalid, Azel Regan, Balasubramanian Piramanayagam, Bankole Oyewole, Basil Ibrahim, Ben Murphy, Bethan Clayton, Bethan Jenkins, Bhaskar Kumar, Blazej Rybinski, Bo Yuan Khor, Brian R Davidson, Bryony Lees, Callum Blacklock, Callum Johnstone, Camila Hidalgo Salinas, Carine Boven, Caroline Wolstenholme, Carven Chin, Catherine Gilmore, Catherine Sharp, Cerys Walker, Chad Harris, Chaitra Khanna, Chanoka Ferguson, Charis Kyriakides, Charlotte Bee, Chelise Currow, Chetan Parmar, Chris Collins, Christopher Halloran, Chris J Smart, Christodoulos Neophytou, Christopher Delaney, Chukwuemeka Anele, Claire Heugh, Clarisa Thian Puay Choh, Cleo Kenington, Craig Wyatt, Cynthia-Michelle Borg, Damian Mole, Danaradja Arumugam, Dariusz Gunia, Darren Porter, David Berry, David Griffith, David Hou, David Longbotham, David Mitton, David Strachan, Davide Di Mauro, Dawit Worku, Deborah Heaphy, Declan Dunne, Denise Yeung, Devika Arambepola, Dhya Al Leswas, Dimitri J Pournaras, Dimitrios Damaskos, Dina Saleh, Dixon Osilli, Douglas Pearman, Douglas Whitelaw, Ehsan Ul Haq, Eleanor Mack, Eleanor Spurring, Elias Jamieson, Elisa Lenzi, Elizabeth Gemmill, Emanuele Gammeri, Emil Bota, Emily Britton, Emily Farrow, Emily Lloyd, Emily Moran, Emmanuel Itobi, Eoin Craig, Ermal Tanaka, Ezzat Chohda, Fahad Ullah Muhammad, Fahed Youssef, Farah Roslan, Farhat Amir, Farid Froghi, Filippo Di Franco, Francesco Abbadessa, Francesco DiMaggio, Ganga Gurung, Gemma Faulkner, George Choa, George Kerans, George N Davis, Georgios Galanopoulos, Georgios Karagiannidis, Gerard McCabe, Ghazaleh Mohammadi-Zaniani, Ghulam Nawaz, Gijs Van Boxel, Giles Bond-Smith, Gillian M Tierney, Girivasan Muthukumarasamy, Grace Grey, Grace Wong, Guy Finch, Hamad Khan, Hannah Bourne, Hannah Javanmard-Emamghissi, Hannah Murray, Hannah Rottenburg, Hannah Wright, Hany Khalil, Harry V M Spiers, Hazem Bashiti, Hiba Shanti, Husam Ebied, Hwei Jene Ng, Hytham K S Hamid, Hyun Kim, Iain Wilson, Ilayaraja Rajendran, Ioannis Gerogiannis, Ishaan Patel, Islam El-Abbassy, Isobel Burridge, Jade Caldwll, Jamaall Jackman, James Clark, James Duncan, James Milburn, James O’Kelly, James Olivier, James Rink, James Royle, Jason Rai, Javed Latif, Jawad Ahmad, Jed Maliyil, Jenna Carr, Jennifer Coles, Jennifer McGarry, Jeyakumar Apollos, Jie Lim, Joanna Gray, Joel Thomas, John Bennett, John Findlay, John Spearman, John Young, Jonathan N Lund, Joseph Meilak, Joshua Alfred, Joshua Welsh, Juen Hao Chan, Julia Martin, Kamlesh Patel, Kar Yeung Kenneth Ko, Karl Isand, Kasra Razi, Kasturi Sarathy, Katarzyna Powezka, Kate Foster, Katerina Peleki, Katharine Bevan, Katherine Fox, Katie Edwards, Katy Larsen, Kayleigh Spellar, Ke En Oh, Keh Kong, Keiran Brown, Keith J Roberts, Keith Seymour, Kevin Beatson, Kevin Etherson, Kevin Willis, Kulbir Mann, Kulsoom Nizami, Kunal Rajput, Lauren Lavery, Lauren Sawdon, Lawrence Nip, Layal Al-Hamed, Leah Fagan, Leo Watton, Alexander Les Saint-Grant, Liam Convie, Louis-Pierre Girard, Lucy Huppler, Luke Marsh, Luke Seretny, Lydia Newton, Mahfooz Buksh, Mahmoud Sallam, Malayil Mathew, Manju Nadh Prasanth, Manu Nayar, Manuk Wijeyaratne, Marianne Hollyman, Marina Ransome, Mariuca Popa, Mark Galea, Mark Taylor, Martha Gismondi, Martin Michel, Martin Wadley, Marwa Al-Azzawi, Mary Claxton, Matta Kuzman, Matthew Bonomaully, Matthew Newman, Mayank Bhandari, Michael Courtney, Michael Jones, Michael Rarity, Michael Wilson, Mohamed Ebraheem, Mohamed Elnaghi, Mohamed Saleem Noor Mohamed, Mohammed Al-Hijaji, Mohammed Al-Rashedy, Mohammed Kaif Qayum, Mohammed Zourob, Mohannad Gaber, Milind Rao, Muhammad Ariful Islam, Muhammad Umair Rashid, Muneeb Zafar, Mushal Naqvi, Mustafa Nabeel Ahmad, Muwaffaq Telfah, Nabeel Merali, Nabih Hanbali, Nadia Gulnaz, Nagappan Kumar, Najam Husain, Natarajan Angamuthu, Navanith Murali, Naveed Kirmani, Nazrin Assaf, Neel Doshi, Nehal Sureshkumar Shah, Nersheranjeet Basra, Neville Menezes, Nick Dai, Nicolaas Schuijtvlot, Nisheeth Kansal, Nnaemeka Chidumije, Nuha Yassin, Olaitan Babalola, Olamide Oyende, Olatoyosi Williams, Olga Pawlik, Olivia O'Connor, Omar Abdel Jalil, Ondrej Ryska, Osborne Vaz, Panchali Sarmah, Panduka Jayawardena, Panna Patel, Patrick Hart, Paul Cromwell, Paul Manby, Paul Marriott, Paul Needham, Paula Ghaneh, Pawan Kumar Dhruva Rao, Peter Eves, Peter O Coe, Peter May-Miller, Peter Szatmary, Philip Ireland, Pooja Seta, Prabhu Ravi, Pradeep Janardhanan, Pradeep Patil, Pritesh Mistry, Priya Heer, Puja Patel, Quentin Nunes, Quratul Ain, Rachael Clifford, Rachel Brindle, Rachel Xue Ning Lee, Rachel Qian Hui Lim, Rafid Rahman, Rahul Mohan Kumar, Raimundas Lunevicius, Rajarshi Mukherjee, Rajiv Lahiri, Rami Behmida, Ramprasad Rajebhosale, Raphael Levy, Raunaq Chhabra, Raymond Oliphant, Rebecca Freeman, Rebecca M Jones, Rema Elkalbash, Rhiannon Brignall, Richard Bell, Richard Byrom, Richard W Laing, Rikhilroy Patel, Robert Buhain, Robert Clark, Robert Sutton, Roberto Presa, Roger Lawther, Roshni Patel, Roxanna Zakeri, Ruchir Mashar, Rui Wei, Ryan Baron, Sadia Tasleem, Safwan Shafeeque Kadambot, Saima Azam, Saj Wajed, Sakhawat Ali, Samantha Body, Samerah Saeed, Samik Bandyopadhyay, Samy Mohamed, Sanjay Pandanaboyana, Sapna Hassasing, Sarah Dyer, Sarah Small, Sarangan Seeralakandapalan, Sathyaseelan Arumugam, Saurav Chakravartty, Seok Ling Ong, Setthasorn Zhi Yang Ooi, Shahani Nazir, Shahbaz Zafar, Shahram Shirazi, Shameena Bharucha, Shaukat Majid, Shehzad Ahmed, Shenbaga Kumar Rajamanickam, Sherif Albalkiny, Sherwin Ng, Shihab Chowdhury, Shuker Yahia, Siddhartha Handa, Simon Fallis, Simon Fisher, Simon Jones, Simon Phillips, Smrthi Mitra, Somaiah Aroori, Sonam Thanki, Sophie Rozwadowski, Sophie Tucker, Soraya Conroy, Sowrav Barman, Srushti Bhat, Stephen McCallion, Stephen R Knight, Stergios Tezas, Stijn van Laarhoven, Stuart Cowie, Sudhi Rao, Sujeewa Sellahewa, Sumbal Bhatti, Sumesh Kaistha, Susan J Moug, Susannah Argyropoulos, Suvi Virupaksha, Tabitha Difford, Tamanna Shikh-Bahaei, Tamer Saafan, Tammy Lo, Tania Magro, Tanzeela Gala, Tarek Katbeh, Tejinderjit Athwal, Terence Lo, Tessa Fraser, Theophilus Anyomih, Thomas J G Chase, Thomas Walker, Thomas Ward, Tom K Gallagher, Tom Richardson, Tom Wiggins, Uzair Ali, Varun Patnam, Venkatesh Kanakala, Victoria Beynon, Victoria E Hudson, Victoria Morrison-Jones, Vijay Korwar, Virginia Massella, Vishal Parekh, Vivian Ng, Wei Hann Toh, Wei Toh, William Hawkins, William Cambridge, William Harrison, Yan Yu Tan, Yasser Abdul Aal, Yogeshkumar Malam, Zaher Toumi, Ziad Al Khaddar, Zoe Bleything (2023)PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK, In: BJS open7(3)zrad008

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions.

Tianyi Yin, Lizhou Xu, Bruno Gil, Nabeel Merali, Maria S. Sokolikova, David C. A. Gaboriau, Daniel S. K. Liu, Ahmad Nizamuddin Muhammad Mustafa, Sarah Alodan, Michael Chen, Oihana Txoperena, María Arrastua, Juan Manuel Gomez, Nerea Ontoso, Marta Elicegui, Elias Torres, Danyang Li, Cecilia Mattevi, Adam E. Frampton, Long R. Jiao, Sami Ramadan, Norbert Klein (2023)Graphene Sensor Arrays for Rapid and Accurate Detection of Pancreatic Cancer Exosomes in Patients’ Blood Plasma Samples, In: ACS nano17(15)pp. 14619-14631 American Chemical Society

Biosensors based on graphene field effect transistors (GFETs) have the potential to enable the development of point-of-care diagnostic tools for early stage disease detection. However, issues with reproducibility and manufacturing yields of graphene sensors, but also with Debye screening and unwanted detection of nonspecific species, have prevented the wider clinical use of graphene technology. Here, we demonstrate that our wafer-scalable GFETs array platform enables meaningful clinical results. As a case study of high clinical relevance, we demonstrate an accurate and robust portable GFET array biosensor platform for the detection of pancreatic ductal adenocarcinoma (PDAC) in patients’ plasma through specific exosomes (GPC-1 expression) within 45 min. In order to facilitate reproducible detection in blood plasma, we optimized the analytical performance of GFET biosensors via the application of an internal control channel and the development of an optimized test protocol. Based on samples from 18 PDAC patients and 8 healthy controls, the GFET biosensor arrays could accurately discriminate between the two groups while being able to detect early cancer stages including stages 1 and 2. Furthermore, we confirmed the higher expression of GPC-1 and found that the concentration in PDAC plasma was on average more than 1 order of magnitude higher than in healthy samples. We found that these characteristics of GPC-1 cancerous exosomes are responsible for an increase in the number of target exosomes on the surface of graphene, leading to an improved signal response of the GFET biosensors. This GFET biosensor platform holds great promise for the development of an accurate tool for the rapid diagnosis of pancreatic cancer.

Mary E. Phillips, Kathryn H. Hart, Adam E. Frampton, M. Denise Robertson (2023)Do Patients Benefit from Micronutrient Supplementation following Pancreatico-Duodenectomy?, In: Nutrients15(12)2804 Mdpi

Pancreatico-duodenectomy (PD) includes resection of the duodenum and use of the proximal jejunum in a blind loop, thus reducing the absorptive capacity for vitamins and minerals. Several studies have analysed the frequency of micronutrient deficiencies, but there is a paucity of data on those taking routine supplements. A retrospective review of medical notes was undertaken on 548 patients under long-term follow-up following PD in a tertiary hepato-pancreatico-biliary centre. Data were available on 205 patients from 1-14 years following PD, and deficiencies were identified as follows: vitamin A (3%), vitamin D (46%), vitamin E (2%), iron (42%), iron-deficiency anaemia (21%), selenium (3%), magnesium (6%), copper (1%), and zinc (44%). Elevated parathyroid hormone was present in 11% of cases. There was no significant difference over time (p > 0.05). Routine supplementation with a vitamin and mineral supplement did appear to reduce the incidence of biochemical deficiency in vitamin A, vitamin E, and selenium compared to published data. However, iron, vitamin D, and zinc deficiencies were prevalent despite supplementation and require surveillance.

Daniel S K Liu, Qi Zhi Clayton Yang, Mohammad Asim, Jonathan Krell, Adam E Frampton (2022)The Clinical Significance of Transfer RNAs Present in Extracellular Vesicles, In: International journal of molecular sciences23(7)3692

Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organisms. 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 present 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 1 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 most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging between 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.

Charles Rayner, Sophie Allen, Tadd Seymour, Shaun Preston, Adam Frampton, David Bartlett, Nicola Annels, Nima Abbassi-Ghadi (2023)434. INCREASING TUMOUR INFILTRATING LYMPHOCYTES THROUGH EXERCISE ALONE—A PILOT RCT IN ESOPHAGEAL ADENOCARCINOMA, In: Diseases of the esophagus36(Supplement_2)

Abstract Background The immune system is highly responsive and positively adapts to exercise. A single bout of exercise results in the mobilisation of highly functional effector CD8+ T cells and NK-cells into the circulation. Murine cancer models have shown that exercise reduces tumour burden by increasing the frequency of tumour-infiltrating lymphocytes (TILs). There are no studies assessing the impact of an exercise programme on the levels of TILs in patients’ solid tumours in any cancer. Methods We recently completed a 16-week randomised prehabilitation exercise program (NCT02950324) in esophageal cancer patients before esophagogastric cancer resection. Exercise training was a low-to-moderate intensity twice supervised, thrice home-based weekly program. Tumour specimens obtained at the time of resection were formalin fixed paraffin embedded (FFPE) for multispectral immunohistochemical analysis. Tumour tissues were stained with primary antibodies for CD68, CD57, CD8, CD4, FoxP3, Granzyme B, PDL1 and pancytokeratin. Cell populations and spatial relationships were analysed using the Phenoimager HT (Akoya Biosciences) and QuPath. Results Although our exercise program was ~33% of the physical activity guidelines for cancer patients, physical fitness and well-being were maintained rather than significantly reduced in the intervention group compared to the control group. Multispectral analysis observed that 3.2% ± 1.1% of cells in the tumours were CD8+ T cells compared to 1.4% ± 0.5% in the control group (p < 0.001). Furthermore, we observed positive associations between increased frequencies of CD8 + TILs (Fig 1C: r = 0.562, p = 0.016), Granzyme B+/CD8 + TILs (r = 0.637, p = 0.003) and larger increases in exercise induced aerobic capacity. This data suggests that the more exercise can increase aerobic fitness, the greater the likelihood of increasing functional TILs. Conclusion New approaches to improve outcomes following surgery for esophageal adenocarcinoma are required. One such approach is immunotherapy. However, immunotherapy is relatively ineffective in esophageal adenocarcinoma due to the lack of CD8+ T cells and NK cells in the tumours. Increasing TILs through exercise programmes that are designed to focus on maintaining or improving aerobic capacity may improve patients’ response to immunotherapy and positively impact prognosis and survival.

Adam E Frampton, Shivan Sivakumar (2022)A New Combination Immunotherapy in Advanced Melanoma, In: The New England journal of medicine386(1)pp. 91-92 Massachusetts Medical Society

With combination immunotherapy, the 5-year survival of patients with advanced melanoma is now approximately 50%. Outcomes can still be further improved, and evaluating new immune checkpoint targets is an attractive possibility. Patients with advanced melanoma have a reduced immune response to tumors, owing to an elevated expression of inhibitory receptors on tumor antigen–specific T cells, combined with exhaustion of the immune system by persistent antigenic stimulation. An immune checkpoint is a regulator of the immune system that is important for maintaining self-tolerance (the ability of the immune system to recognize self antigens as harmless while appropriately mounting a response to . . .

Mark P. Lythgoe, Benjamin H. Mullish, Adam E. Frampton, Jonathan Krell (2022)Polymorphic microbes: a new emerging hallmark of cancer, In: Trends in microbiology (Regular ed.)30(12)1131pp. 1131-1134 Elsevier

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 may be key effectors in determining the efficacy of anticancer therapy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.

Harry V. M. Spiers, Francesco Lancellotti, Nicola de Liguori Carino, Sanjay Pandanaboyana, Adam E. Frampton, Santhalingam Jegatheeswaran, Vinotha Nadarajah, Ajith K. Siriwardena (2023)Irreversible Electroporation for Liver Metastases from Colorectal Cancer: A Systematic Review, In: Cancers15(9)2428 Mdpi

Background: Irreversible electroporation (IRE) is a non-thermal form of ablation based on the delivery of pulsed electrical fields. It has been used to treat liver lesions, particularly those in proximity to major hepatic vasculature. The role of this technique in the portfolio of treatments for colorectal hepatic metastases has not been clearly defined. This study undertakes a systematic review of IRE for treatment of colorectal hepatic metastases. Methods: The study protocol was registered with the PROSPERO register of systematic reviews (CRD42022332866) and reports in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The Ovid MEDLINE (R), EMBASE, Web of Science and Cochrane databases were queried in April 2022. The search terms 'irreversible electroporation', 'colon cancer', 'rectum cancer' and 'liver metastases' were used in combinations. Studies were included if they provided information on the use of IRE for patients with colorectal hepatic metastases and reported procedure and disease-specific outcomes. The searches returned 647 unique articles and the exclusions left a total of eight articles. These were assessed for bias using the methodological index for nonrandomized studies (MINORS criteria) and reported using the synthesis without meta-analysis guideline (SWiM). Results: One hundred eighty patients underwent treatment for liver metastases from colorectal cancer. The median transverse diameter of tumours treated by IRE was

Nabeel Merali, Tarak Chouari, Julien Marc Terroire, Maria-Danae Jessel, Daniel S K Liu, James-Halle Smith, Tyler Wooldridge, Tony Singh Dhillon, Jose I Jimenez, Jonathan Krell, Keith J. Roberts, Timothy A Rockall, Eirini Velliou, Shivan Sivakumar, Elisa Giovannetti, Ayse Demirkan, Nicola E. Annels, Adam E. Frampton (2023)Bile Microbiome Signatures Associated with Pancreatic Ductal Adenocarcinoma Compared to Benign Disease: A UK Pilot Study, In: International journal of molecular sciences24(23)16888 MDPI

Pancreatic ductal adenocarcinoma (PDAC) has a very poor survival. The intra-tumoural microbiome can influence pancreatic tumourigenesis and chemoresistance and, therefore, patient survival. The role played by bile microbiota in PDAC is unknown. We aimed to define bile microbiome signatures that can effectively distinguish malignant from benign tumours in patients presenting with obstructive jaundice caused by benign and malignant pancreaticobiliary disease. Prospective bile samples were obtained from 31 patients who underwent either Endoscopic Retrograde Cholangiopancreatography (ERCP) or Percutaneous Transhepatic Cholangiogram (PTC). Variable regions (V3–V4) of the 16S rRNA genes of microorganisms present in the samples were amplified by Polymerase Chain Reaction (PCR) and sequenced. The cohort consisted of 12 PDAC, 10 choledocholithiasis, seven gallstone pancreatitis and two primary sclerosing cholangitis patients. Using the 16S rRNA method, we identified a total of 135 genera from 29 individuals (12 PDAC and 17 benign). The bile microbial beta diversity significantly differed between patients with PDAC vs. benign disease (Permanova p = 0.0173). The separation of PDAC from benign samples is clearly seen through unsupervised clustering of Aitchison distance. We found three genera to be of significantly lower abundance among PDAC samples vs. benign, adjusting for false discovery rate (FDR). These were Escherichia (FDR = 0.002) and two unclassified genera, one from Proteobacteria (FDR = 0.002) and one from Enterobacteriaceae (FDR = 0.011). In the same samples, the genus Streptococcus (FDR = 0.033) was found to be of increased abundance in the PDAC group. We show that patients with obstructive jaundice caused by PDAC have an altered microbiome composition in the bile compared to those with benign disease. These bile-based microbes could be developed into potential diagnostic and prognostic biomarkers for PDAC and warrant further investigation.

Ashwin Jainarayanan, Nithishwer Mouroug-Anand, Edward H. Arbe-Barnes, Adam J. Bush, Rachael Bashford-Rogers, Adam Frampton, Lara Heij, Mark Middleton, Michael L. Dustin, Enas Abu-Shah, Shivan Sivakumar (2023)Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells, In: iScience26(4)106324pp. 106324-106324 Elsevier

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T cells in the PDAC microenvironment to develop alternative therapeutic strate-gies. In this study, we performed RNA velocity-based pseudotime analysis on a scRNA-seq dataset from surgically resected human PDAC specimens to gain insight into temporal gene expression patterns that best characterize the cell fates. The tumor microenvironment was seen to encompass a range of terminal states for the T cell trajectories with suppressive and non-tumor-responsive T cells dominating them. However, the results also reveal the existence of a functional branch of the T cell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving T cell patterns which can be useful in identifying new therapeutic avenues.

Nele Van Der Steen, Kaylee Keller, Henk Dekker, Letizia Porcelli, Richard J Honeywell, Johan Van Meerloo, René J P Musters, Ietje Kathmann, Adam E Frampton, Daniel S K Liu, Rob Ruijtenbeek, Christian Rolfo, Patrick Pauwels, Elisa Giovannetti, Godefridus J Peters (2020)Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function, In: Journal of cellular physiology235(11)pp. 8085-8097

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.

Christopher Limb, Daniel S. K. Liu, Morten T. Veno, Eleanor Rees, Jonathan Krell, Izhar N. Bagwan, Elisa Giovannetti, Hardev Pandha, Oliver Strobel, Timothy A. Rockall, Adam E. Frampton (2020)The role of circular rnas in pancreatic ductal adenocarcinoma and biliary-tract cancers, In: Cancers12(11)3250pp. 1-29 Mdpi

Simple Summary Pancreatic and biliary tract cancers often present with non-specific symptoms, resulting in diagnosis at a late stage. This may be too late for curative surgery. Earlier detection and characterisation may guide treatment options and increase survival. Natural "circles" of RNA (circRNAs) are shown to regulate cancer-related genes, and act as cancer "biomarkers". Recent research has shown that circRNAs are both abundant and stable, both of which are desirable characteristics for clinically useful biomarkers. In this systematic review, we describe the roles of circRNAs in pancreatic and biliary tract cancers, summarise the current published research and explore their utility as a biomarker. A total of 32 articles were included: 22 considering Pancreatic Cancer, 7 for Bile Duct Cancer and 3 for Gallbladder Cancer. CircRNA proved an exciting prospect as a biomarker for these cancers and future work should continue to develop and expand this field of research. 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.

Ornella Randazzo, Filippo Papini, Giulia Mantini, Alessandro Gregori, Barbara Parrino, Daniel S. K. Liu, Stella Cascioferro, Daniela Carbone, Godefridus J. Peters, Adam E. Frampton, Ingrid Garajova, Elisa Giovannetti (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, In: Cancers12(11)3206pp. 1-20 Mdpi

Simple Summary Despite the enormous advance in biomarker discovery, many potential biomarkers of drug activity are unable to satisfy the clinical need due to inadequate sensitivity and specificity. The nucleoside transporter hENT-1 has been studied as a potential biomarker to predict the effect of the widely used anticancer drug gemcitabine in pancreatic cancer. However, several studies showed controversial results regarding the predictive value of hENT-1, prompting new analyses with larger cohorts of patients and standardized methodologies. Improved insights on molecular mechanisms underlying hENT-1 expression and activity should also help in the identification of subsets of patients who are more likely to benefit from specific treatments and improve their clinical outcome. The establishment of such biomarker is especially valuable in pancreatic cancer, which is frequently characterized by complex disease biology and high mortality. Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an 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 status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.

Siobhan C McKay, Samir Pathak, Richard J W Wilkin, Sivesh K Kamarajah, Stephen J Wigmore, Jonathan Rees, Declan F J Dunne, Giuseppe Garcea, Jawad Ahmad, Nicola de Liguori Carino, Asma Sultana, Mike Silva, Pavlos Lykoudis, David Nasralla, James Milburn, Nehal Shah, Hemant M Kocher, Ricky Bhogal, Ryan D Baron, Alex Navarro, James Halle-Smith, Bilal Al-Sarireh, Gourab Sen, Nigel B Jamieson, Christopher Briggs, David Stell, Somaiah Aroori, Matthew Bowles, Aditya Kanwar, Simon Harper, Krishna Menon, Andreas Prachalias, Parthi Srinivasan, Adam E Frampton, Claire Jones, Ali Arshad, Iain Tait, Duncan Spalding, Alastair L Young, Damien Durkin, Manijeh Ghods-Ghorbani, Robert P Sutcliffe, Keith J Roberts (2021)Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience, In: HPB (Oxford, England)23(11)pp. 1656-1665

The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic. A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved. Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic. The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised.

Stavros P. Papadakos, Nikolaos Machairas, Ioanna E. Stergiou, Konstantinos Arvanitakis, Georgios Germanidis, Adam Enver Frampton, Stamatios Theocharis (2023)Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation, In: Cells (Basel, Switzerland)12(16)2036 Mdpi

Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.

Giulia Mantini, Laura L. Meijer, Ilias Glogovitis, Sjors G. J. G. In't Veld, Rosita Paleckyte, Mjriam Capula, Tessa Y. S. Le Large, Luca Morelli, Thang V. Pham, Sander R. Piersma, Adam E. Frampton, Connie R. Jimenez, Geert Kazemier, Danijela Koppers-Lalic, Thomas Wurdinger, Elisa Giovannetti (2020)Omics analysis of educated platelets in cancer and benign disease of the pancreas, In: Cancers13(1)66pp. 1-20 Mdpi

Simple Summary: Tumor cells are known to produce and secrete pro-coagulants that recruit blood particles such as platelets, inducing hypercoagulability. However, platelets can also influence tumor carcinogenesis and metastasis, creating a reciprocal, vicious loop with the tumors. Confrontation of platelets with tumor cells via transfer of tumor-associated biomolecules or influencing platelets biology ("education") is an emerging concept, that has been recently proposed to create innovative platforms for biomarkers within blood-based "liquid biopsies". In this study, we explore the intrinsic regulation and the potential "education" of platelets using -omics profiling in pancreatic cancer patients. Our results showed: (i) a high activity on RNA splicing that can lead to subsequent platelets education; (ii) enrichment of specific modified forms (isomiRs) of canonical miRNAs; and (iii) inhibition of SPARC transcription by specific class of isomiRs. Moreover, we created an interactive tool to visualize expected correlations, to facilitate further investigations on additional potential biomarkers and therapeutic tools. 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.

Rocio I R Macias, Vincenzo Cardinale, Timothy J Kendall, Matias A Avila, Maria Guido, Cedric Coulouarn, Chiara Braconi, Adam E Frampton, John Bridgewater, Diletta Overi, Stephen P Pereira, Marco Rengo, Jakob N Kather, Angela Lamarca, Federica Pedica, Alejandro Forner, Juan W Valle, Eugenio Gaudio, Domenico Alvaro, Jesus M Banales, Guido Carpino (2022)Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions, In: Gut71(8)pp. 1669-1683 BMJ Publishing Group Ltd and British Society of Gastroenterology

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers.

Stavros P Papadakos, Daniele Ferraro, Gabriele Carbone, Adam Enver Frampton, Giovanni Vennarecci, Stylianos Kykalos, Dimitrios Schizas, Stamatios Theocharis, Nikolaos Machairas (2023)The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?, In: Cancers15(12)3161

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

Daniel S. K. Liu, Flora M. Upton, Eleanor Rees, Christopher Limb, Long R. Jiao, Jonathan Krell, Adam E. Frampton (2020)Size-exclusion chromatography as a technique for the investigation of novel extracellular vesicles in cancer, In: Cancers12(11)3156pp. 1-19 Mdpi

Simple Summary Extracellular vesicles (EVs) are small particles that are released by cancer cells, and they may hold vital information for researchers looking for early markers for diagnosis. Size-exclusion chromatography (SEC) is a classical technique that has become increasingly popular and can be used for rapid isolation and investigation of both their cargo and functionality. This systematic review highlights its main technical aspects, the type of materials involved and by covering the findings of the identified papers hopes to demonstrate the utility of this method in cancer research to date. Cancer cells release extracellular vesicles, which are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. Size-exclusion chromatography (SEC) is an increasingly popular technique, which has been rediscovered for the purposes of extracellular vesicle (EV) isolation and purification from diverse biofluids. A systematic review was undertaken to identify all papers that described size exclusion as their primary EV isolation method in cancer research. In all, 37 papers were identified and discussed, which showcases the breadth of applications in which EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. 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.

Sarah Blacker, Rajiv P. Lahiri, Mary Phillips, Graham Pinn, Tim D. Pencavel, Rajesh Kumar, Angela T. Riga, Tim R. Worthington, Nariman D. Karanjia, Adam E. Frampton (2021)Which patients benefit from preoperative biliary drainage in resectable pancreatic cancer?, In: Expert review of gastroenterology & hepatology15(8)pp. 855-863 Taylor & Francis

Recent studies have indicated that preoperative biliary drainage (PBD) should not be routinely performed in all patients suffering from obstructive jaundice before pancreatic surgery. The severity of jaundice that mandates PBD has yet to be defined. The evaluated paper examines the impact of PBD on intra-operative, and post-operative outcomes in patients initially presenting with severe obstructive jaundice (bilirubin ≥250 μmol/L). In this key paper evaluation, the impact of PBD versus a direct surgery (DS) approach is discussed. The arguments for and against each approach are considered with regards to drainage associated morbidity and mortality, resection rates, survival and the impact of chemotherapy and malnutrition. Concentrating on resectable head of pancreas tumors, this mini-review aims to scrutinize the authors' recommendations, alongside those of prominent papers in the field.

Nabeel Merali, Hajra Ashraf, Tarak Chouari, Badriya Al Araimi, Rajiv Lahiri, Timothy A. Rockall, Adam E. Frampton (2021)Systematic Review Comparing the Effectiveness of Robotic verse Laparoscopic Liver Surgery in Colorectal Liver Metastasis (CRLM), In: Surgeries2(4)357pp. 357-370

Introduction: Colorectal cancer (CRC) is the third most common cancer in the world. The liver is the most common site of metastasis with 15 to 25% of patients presenting with synchronous colorectal liver metastasis (CRLM). This study is aimed at evaluating the long- and short-term outcomes of laparoscopic and robotic CRLM surgery, and directly comparing their respective effectiveness. Methodology: A literature search was performed and all studies that reported on operative characteristics, oncological outcomes for CRLM, morbidity or mortality and cost-effectiveness on robotic or laparoscopic surgery were included. The study design was in keeping with the PRISMA guidelines. Results: From the initial 606 manuscripts identified, 19 studies were included in the final qualitative analysis. A total of 1340 patients with 1194 LLR (Laparoscopic Liver Resection) and 146 RLR (Robotic Liver Resection) cases were analysed. Within the LLR group, the average tumour size excised was 32.1 mm compared to the RLR group of 33.8 mm. The average operative time in the LLR was 193 min, CI of 95% (147.4 min to 238.6 min) compared to RLR 257 min, CI of 95% (201.5 min to 313.8 min) with a p-value < 0.0001. Estimated blood loss was lower in the RLR group (210 mL) compared with the LLR group (246 mL). Conclusion: Despite the higher operative cost, RLRs do not result in statistically better treatment outcomes, with the exception of lower estimated blood loss and excision of larger CRLMs. Operative time and total complication rate are significantly more favourable with LLRs. Our study has shown that robotic liver surgery is safe and feasible in well-selected patients.

Bhavik Y. Patel, Laura White, Paschalis Gavriilidis, Thomas Satyadas, Adam E. Frampton, Madhava Pai (2021)A systematic review into patient reported outcomes following pancreaticoduodenectomy for malignancy, In: European journal of surgical oncology47(5)970pp. 970-978 Elsevier Ltd

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. Pancreaticoduodenectomy is the operation used to resect cancers of the periampullary region, head of the pancreas and duodenum. This surgery can be associated with post-operative complications, which combined with the psychological burden of cancer, may impact on a patient’s quality of life (QoL). Patient reported outcomes can be used to understand recovery from their perspective. The aim of this study is to evaluate the measurement of patient reported outcomes after pancreaticoduodenectomy within the available literature. Following a literature search of 7 databases 27 publications were included in the final review. In conclusion, there are different instruments available to measure patient reported outcomes. The quality of the included studies’ methodology improved over time, as has the number of studies measuring patient reported outcomes. Future trials should aim to be more consistent so that data may be collated in the future to improve understanding of post-operative recovery and QoL.

Adam Enver Frampton, Elisa Giovannetti (2020)Diagnosing pancreatic ductal adenocarcinoma using plasma extracellular vesicle RNA profiles, In: Gut69(3)pp. 404-405 Bmj Publishing Group
Nabeel Merali, Tarak Chouari, Kayani Kayani, Charles J. Rayner, Jose I. Jimenez, Jonathan Krell, Elisa Giovannetti, Izhar Bagwan, Kate Relph, Timothy A. Rockall, Tony Dhillon, Hardev Pandha, Nicola E. Annels, Adam E. Frampton (2022)A Comprehensive Review of the Current and Future Role of the Microbiome in Pancreatic Ductal Adenocarcinoma, In: Cancers14(4) Mdpi

Simple Summary This review summarizes the current literature related to the microbiome and pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to explore the current role of the microbiome in the disease process, screening/diagnostics and to postulate the future role with regards to therapeutic strategies including chemotherapy, immunotherapy and surgery. We further explore the future of microbiome modulation (faecal microbiome transplants, bacterial consortiums, anti-microbials and probiotics), their applications and how we can improve the future of microbiome modulation in a bid to improve PDAC outcomes. 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.

Tarak Chouari, Francesca Soraya La Costa, Nabeel Merali, Maria-Danae Jessel, Shivan Sivakumar, Nicola Annels, Adam E. Frampton (2023)Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma, In: Cancers15(17)4265 MDPI

Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, responsible for the majority of cases and ranking seventh as a leading cause of cancer-related deaths. It is difficult to treat because is it often detected at advanced stages, there are no effective screening tests available, and patients can develop resistance to standard treatments like chemotherapy and radiation. Recent interest has involved immunotherapy, which stimulate the immune system to recognise and attack cancer cells. Therefore, our paper aims to summarise the findings of studies investigating immunotherapies in PDAC and we discuss the limitations of such therapies and avenues of future research. In a bid to address the outcomes associated with the disease.Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines.

Declan Mcdonnell, Adrian W. E. Cheang, Sam Wilding, Sarah H. Wild, Adam E. Frampton, Christopher D. Byrne, Zaed Z. Hamady (2023)Elevated Glycated Haemoglobin (HbA1c) Is Associated with an Increased Risk of Pancreatic Ductal Adenocarcinoma: A UK Biobank Cohort Study, In: Cancers15(16)4078 Mdpi

Background: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. Methods: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42-47 mmol/mol, or >= 48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. Results: PDAC occurred in 1157 participants during 11.6 (10.9-12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42-47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31-3.37, p = 0.002); and was 8.55 (4.58-15.99, p < 0.001) for HbA1c >= 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. Conclusions: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.

Louisa Bolm, Natalie Petruch, Shivan Sivakumar, Nicola E Annels, Adam Enver Frampton (2022)Gene of the month: T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), In: Journal of clinical pathology75(4)217pp. 217-221 BMJ Publishing Group Ltd and Association of Clinical Pathologists

Immune modulators play a crucial role in carcinogenesis and cancer progression by impairing cancer cell-targeted immune responses. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) regulates T-cell function and cancer cell recognition and was therefore identified as a promising target for cancer immunotherapy. TIGIT is expressed in T cells and natural killer (NK) cells and has three ligands: CD155, CD112 and CD113. CD155 binds TIGIT with the highest affinity and promotes direct and indirect downregulation of T-cell response. TIGIT signalling further inhibits NK function and secretion of proinflammatory cytokines. An association between TIGIT expression and poor survival was identified in multiple cancer entities. Blocking TIGIT with monoclonal antibodies, and a combination of TIGIT and programmed cell death protein 1 blockade in particular, prevented tumour progression, distant metastasis and tumour recurrence in in vivo models. Inhibition of TIGIT is currently evaluated in first clinical trials.

Sofia Miron-Barroso, Joana S. Correia, Adam E. Frampton, Mark P. Lythgoe, James Clark, Laura Tookman, Silvia Ottaviani, Leandro Castellano, Alexandra E. Porter, Theoni K. Georgiou, Jonathan Krell (2022)Polymeric Carriers for Delivery of RNA Cancer Therapeutics, In: Non-coding RNA8(4)58 Mdpi

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.

Florian Primavesi, Manuel Maglione, Federica Cipriani, Timm Denecke, Christian E. Oberkofler, Patrick Starlinger, Bobby V. M. Dasari, Jan Heil, Olivia Sgarbura, Kjetil Soreide, Rafael Diaz-Nieto, Constantino Fondevila, Adam E. Frampton, Dominik Geisel, Benjamin Henninger, Amelia J. Hessheimer, Mickael Lesurtel, Damian Mole, Robert Ollinger, Pim Olthof, Thomas Reiberger, Andreas A. Schnitzbauer, Christoph Schwarz, Ernesto Sparrelid, Martin Stockmann, Stephanie Truant, Luca Aldrighetti, Eva Braunwarth, Mathieu D'Hondt, Michelle L. DeOliveira, Joris Erdmann, David Fuks, Thomas Gruenberger, Klaus Kaczirek, Hassan Malik, Dietmar Oefner, Nuh N. Rahbari, Georg Goebel, Ajith K. Siriwardena, Stefan Staettner (2023)E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy, In: British journal of surgery110(10)pp. 1331-1347 Oxford Univ Press

Posthepatectomy liver failure is a significant contributor to morbidity and mortality after liver resections, and a standardized assessment of preoperative liver function is crucial. These inaugural European consensus guidelines provide guidance for clinicians involved in the perioperative care of patients undergoing liver surgery. Based on 271 publications, 21 statements were produced through a structured modified Delphi process implementing systematic evidence assessment and expert opinion. Lay Summary Liver surgery is an effective treatment for liver tumours. Liver failure is a major problem in patients with a poor liver quality or having large operations. The treatment options for liver failure are limited, with high death rates. To estimate patient risk, assessing liver function before surgery is important. Many methods exist for this purpose, including functional, blood, and imaging tests. This guideline summarizes the available literature and expert opinions, and aids clinicians in planning safe liver surgery. Background Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. Methods A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. Results Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx(& REG;) according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. Conclusion These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.

Marcos Kostalas, Adam E. Frampton, Nadeen Low, Rajiv Lahiri, Ee Jun Ban, Rajesh Kumar, Angela T. Riga, Tim R. Worthington, Nariman D. Karanjia (2020)Left hepatic trisectionectomy for hepatobiliary malignancies: Its’ role and outcomes. A retrospective cohort study, In: Annals of medicine and surgery5111pp. 11-16 Elsevier Ltd

Left hepatic trisectionectomy (LHT) is a complex hepatic resection; its’ role and outcomes in hepatobiliary malignancies remains unclear. 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. 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. 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. •LHT is an extended resection reported to have higher incidences of morbidity and mortality compared with less extensive hepatic resections.•This procedure is useful for the surgical management of patients with hepatic lesions that were previously considered unresectable.•We report favourable outcomes following LHT at our institution compared with less extensive hepatic resections.•An initial post-operative lactate of >1.5 mmol/L was associated with an increased risk of developing post-operative complications (p = 0.035).

Thomas B. Russell, Peter L. Labib, Fabio Ausania, Elizabeth Pando, Keith J. Roberts, Ambareen Kausar, Vasileios K. Mavroeidis, Gabriele Marangoni, Sarah C. Thomasset, Adam E. Frampton, Pavlos Lykoudis, Manuel Maglione, Nassir Alhaboob, Hassaan Bari, Andrew M. Smith, Duncan Spalding, Parthi Srinivasan, Brian R. Davidson, Ricky H. Bhogal, Daniel Croagh, Ismael Dominguez, Rohan Thakkar, Dhanny Gomez, Michael A. Silva, Pierfrancesco Lapolla, Andrea Mingoli, Alberto Porcu, Nehal S. Shah, Zaed Z.R. Hamady, Bilal Al-Sarrieh, Alejandro Serrablo, Peter L. Labib, Thomas B. Russell, Adam Streeter, Jemimah Denson, Mark Puckett, Shang-Ming Zhou, Matthew Browning, Somaiah Aroori, Fabio Ausania, Elizabeth Pando, Keith Roberts, Ambareen Kausar, Vasileios K. Mavroeidis, Gabriele Marangoni, Sarah Thomasset, Adam Frampton, Pavlos Lykoudis, Manuel Maglione, Nassir Alhaboob, Hassaan Bari, Andrew Smith, Duncan Spalding, Parthi Srinivasan, Brian Davidson, Ricky Bhogal, Daniel Croagh, Ismael Dominguez, Rohan Thakkar, Dhanny Gomez, Michael Silva, Pierfrancesco Lapolla, Andrea Mingoli, Alberto Porcu, Nehal Sureshkumar Shah, Zaed Hamady, Bilal Al-Sarrieh, Alejandro Serrablo, Carolina Gonzalez-Abos, Nair Fernandes, Elsa Garcia Moller, Cristina Dopazo Taboada, Rupaly Pande, Jameel Alfarah, Samik Bandyopadhyay, Ahmed Abdelrahim, Ayesha Khan, Caitlin Jordan, Jonathan R.E. Rees, Harry Blege, William Cambridge, Olga White, Sarah Blacker, Jessie Blackburn, Casie Sweeney, Daniel Field, Mohammed Gouda, Ruben Bellotti, Hytham K.S. Hamid, Hassan Ahmed, Catherine Moriarty, Louise White, Mark Priestley, Kerry Bode, Judith Sharp, Rosie Wragg, Beverley Jackson, Samuel Craven, Matyas Fehervari, Madhava Pai, Laith Alghazawi, Anjola Onifade, Julliette Ribaud, Ashitha Nair, Michael Mariathasan, Niamh Grayson, Stephanos Pericleous, Krishna Patel, Conrad Shaw, Nolitha Morare, Mohamad Khish Zaban, Joseph Doyle, Vasileios K. Mavroeidis, Alan Guerrero, Andre Moguel, Carlos Chan, Michael Jones, Edward Buckley, Nasreen Akter, Kyle Treherne, Gregory Gordon, Daniel Hughes, Tomas Urbonas, Gioia Brachini, Roberto Caronna, Piero Chirletti, Teresa Perra, Nurul Nadhirah Abd Kahar, Thomas Hall, Nabeegh Nadeem, Shoura Karar, Ali Arshad, Adam Yarwood, Mohammed Hammoda, Maria Artigas, Sandra Paterna-López, Somaiah Aroori (2023)Serious complications of pancreatoduodenectomy correlate with lower rates of adjuvant chemotherapy: Results from the recurrence after Whipple's (RAW) study, In: European journal of surgical oncology49(9)106919pp. 106919-106919 Elsevier Ltd

Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS. Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests. Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p 

Richard Wilkin, Adam Frampton (2021)Pancreatic enzyme replacement therapy in patients with pancreatic cancer: A national prospective study, In: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]21(6)1127pp. 1127-1134 Elsevier

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. (c) 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.

Thomas B. Russell, Peter L. Labib, Jemimah Denson, Fabio Ausania, Elizabeth Pando, Keith J. Roberts, Ambareen Kausar, Vasileios K. Mavroeidis, Gabriele Marangoni, Sarah C. Thomasset, Adam E. Frampton, Pavlos Lykoudis, Manuel Maglione, Nassir Alhaboob, Hassaan Bari, Andrew M. Smith, Duncan Spalding, Parthi Srinivasan, Brian R. Davidson, Ricky H. Bhogal, Daniel Croagh, Ismael Dominguez, Rohan Thakkar, Dhanny Gomez, Michael A. Silva, Pierfrancesco Lapolla, Andrea Mingoli, Alberto Porcu, Nehal S. Shah, Zaed Z. R. Hamady, Bilal Al-Sarrieh, Alejandro Serrablo, Somaiah Aroori (2023)Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study, In: HPB (Oxford, England)25(7)pp. 788-797 Elsevier

Background: Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival. Methods: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retro-spective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012-May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not.Results: 394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and >1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, >1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence.Conclusions: This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.

Ajith K. Siriwardena, Alejandro Serrablo, Asmund A. Fretland, Stephen J. Wigmore, Jose M. Ramia-Angel, Hassan Z. Malik, Stefan Staettner, Kjetil Soreide, Oded Zmora, Martijn Meijerink, Nikolaos Kartalis, Mickael Lesurtel, Cornelis Verhoef, Anita Balakrishnan, Thomas Gruenberger, Eduard Jonas, John Devar, Saurabh Jamdar, Robert Jones, Mohammad A. Hilal, Bodil Anderson, Karim Boudjema, Saifee Mullamitha, Laurents Stassen, Bobby V. M. Dasari, Adam E. Frampton, Luca Aldrighetti, Gianluca Pellino, Pamela Buchwald, Bengi Gurses, Nir Wasserberg, Birgit Gruenberger, Harry V. M. Spiers, William Jarnagin, Jean-Nicholas Vauthey, Norihiro Kokudo, Sabine Tejpar, Andres Valdivieso, Rene Adam (2023)The multi-societal European consensus on the terminology, diagnosis and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE, In: HPB (Oxford, England)25(9)pp. 985-999 Elsevier

Background: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases with a focus on terminology, diagnosis and management.Methods: This project was a multi-organisational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis and management. Statements were refined during an online Delphi process and those with 70% agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising twelve key statements.Results: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term "early metachronous metastases" applies to those absent at presentation but detectedwithin 12 months of diagnosis of the primary tumour with "late metachronous metastases" applied to those detected after 12 months. Disappearing metastases applies to lesions which are no longer detectable on MR scan after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways including systemic chemotherapy, synchronous surgery and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed.Conclusions: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Mary E Phillips, Jessica Zekavica, Rajesh Kumar, Rajiv Lahiri, Justin Kirk-Bayley, Amish Patel, Adam E Frampton (2023)Bedside naso-jejunal placement is more difficult, but successful in patients with COVID-19 in critical care: A retrospective service evaluation of a dietitian-led service, In: Journal of the Intensive Care Society24(4)pp. 435-437

The COVID-19 pandemic presented clinical and logistical challenges in the delivery of adequate nutrition in the critical care setting. The use of neuromuscular-blocking drugs, presence of maxilla-facial oedema, strict infection control procedures, and patients placed in a prone position complicated feeding tube placement. We audited the outcomes of dietitian-led naso-jejunal tube (NJT) insertions using the IRIS ® (Kangaroo, USA) device, before and during the COVID-19 pandemic. NJT placement was successful in 78% of all cases ( n = 50), and 87% of COVID-19 cases. Anaesthetic support was only required in COVID-19 patients (53%). NJT placement using IRIS was more difficult but achievable in patients with COVID-19.

Antonio D’urso, Emanuele Felli, Didier Mutter, Patrick Pessaux, Barbara Seeliger, Adam Frampton (2021)Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic, In: British journal of surgery108(12)pp. 1448-1464 Wiley

BACKGROUND: This study aimed to determine the impact of pulmonary complications on death after surgery both before and during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: This was a patient-level, comparative analysis of two, international prospective cohort studies: one before the pandemic (January-October 2019) and the second during the SARS-CoV-2 pandemic (local emergence of COVID-19 up to 19 April 2020). Both included patients undergoing elective resection of an intra-abdominal cancer with curative intent across five surgical oncology disciplines. Patient selection and rates of 30-day postoperative pulmonary complications were compared. The primary outcome was 30-day postoperative mortality. Mediation analysis using a natural-effects model was used to estimate the proportion of deaths during the pandemic attributable to SARS-CoV-2 infection. RESULTS: This study included 7402 patients from 50 countries; 3031 (40.9 per cent) underwent surgery before and 4371 (59.1 per cent) during the pandemic. Overall, 4.3 per cent (187 of 4371) developed postoperative SARS-CoV-2 in the pandemic cohort. The pulmonary complication rate was similar (7.1 per cent (216 of 3031) versus 6.3 per cent (274 of 4371); P = 0.158) but the mortality rate was significantly higher (0.7 per cent (20 of 3031) versus 2.0 per cent (87 of 4371); P 

James C Glasbey, Dmitri Nepogodiev, Joana F F Simoes, Omar Omar, Elizabeth Li, Mary L Venn, Pgdme, Mohammad K Abou Chaar, Vita Capizzi, Daoud Chaudhry, Anant Desai, Jonathan G Edwards, Jonathan P Evans, Marco Fiore, Jose Flavio Videria, Samuel J Ford, Ian Ganly, Ewen A Griffiths, Rohan R Gujjuri, Angelos G Kolias, Haytham M A Kaafarani, Ana Minaya-Bravo, Siobhan C McKay, Helen M Mohan, Keith J Roberts, Carlos San Miguel-Méndez, Peter Pockney, Richard Shaw, Neil J Smart, Grant D Stewart, Sudha Sundar Mrcog, Raghavan Vidya, Aneel A Bhangu, Adam Frampton (2021)Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International, Multicenter, Comparative Cohort Study, In: Journal of clinical oncology39(1)66pp. 66-78

As 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. This 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). Of 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% 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% 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76). Within available resources, dedicated COVID-19-free surgical pathways should be established to provide safe elective cancer surgery during current and before future SARS-CoV-2 outbreaks.

Nicholas Farkas, Joshua Wong, Jordan Bethel, Sherif Monib, Adam Frampton, Simon Thomson (2020)A systematic review of symptomatic small bowel lipomas of the jejunum and ileum, In: Annals of medicine and surgery58pp. 52-67 Elsevier Ltd

Small 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. The 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. 142 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. Important 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 mortality. Open surgery remains the primary management. No statistically significant difference in LOS and lipoma size is demonstrated between management strategies. Endoscopic and laparoscopic techniques may reduce utilising invasive surgery in the future as skillset and availability improve. •Up to date overview of symptomatic lipomas of the jejunum and ileum which no other paper has previously covered.•Highlights associated symptom profile, investigations, site and size of symptomatic lipomas, morbidity and mortality.•Evaluates the effectiveness of management strategies.•Offers a practical summary that may help guide other clinicians faced with similar presentations in the future.

Andrea Frilling, Ashley K. Clift, Adam E. Frampton, Jamshed Bomanji, Daniel Kaemmerer, Adil Al-Nahhas, Ali Alsafi, Mark Kidd, Irvin M. Modlin, Dieter Hoersch, Richard P. Baum (2021)A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms, In: International journal of medical sciences18(10)2166pp. 2166-2175 Ivyspring International Publisher

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 68 Ga somatostatin analogue PET/CT, eligible for surgery, and 177 Lu 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 177 Lu 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 177 Lu 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.

Antonio d'Urso, Emanuele Felli, Patrick Pessaux, Barbara Seeliger, Adam Frampton (2020)Delaying surgery for patients with a previous SARS-CoV-2 infection, In: British journal of surgery107(12)e601pp. e601-e602 Wiley
Ajith K Siriwardena, Alejandro Serrablo, Åsmund Avdem Fretland, Stephen J Wigmore, Jose Manuel Ramia-Angel, Hassan Z Malik, Stefan Stättner, Kjetil Søreide, Oded Zmora, Martijn Meijerink, Nikolaos Kartalis, Mickaёl Lesurtel, Kees Verhoef, Anita Balakrishnan, Thomas Gruenberger, Eduard Jonas, John Devar, Saurabh Jamdar, Robert Jones, Mohammad Abu Hilal, Bodil Andersson, Karim Boudjema, Saifee Mullamitha, Laurents Stassen, Bobby V M Dasari, Adam E Frampton, Luca Aldrighetti, Gianluca Pellino, Pamela Buchwald, Bengi Gürses, Nir Wasserberg, Birgit Gruenberger, Harry V M Spiers, William Jarnagin, Jean-Nicholas Vauthey, Norihiro Kokudo, Sabine Tejpar, Andres Valdivieso, René Adam (2023)Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE, In: British journal of surgery110(9)124pp. 1161-1170

Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.

Lenka N. C. Boyd, Mahsoem Ali, Annalisa Comandatore, Ingrid Garajova, Laura Kam, Jisce R. Puik, Stephanie M. Fraga Rodrigues, Laura L. Meijer, Tessa Y. S. Le Large, Marc G. Besselink, Luca Morelli, Adam Frampton, Hanneke W. M. van Laarhoven, Elisa Giovannetti, Geert Kazemier (2023)Prediction Model for Early-Stage Pancreatic Cancer Using Routinely Measured Blood Biomarkers, In: JAMA network open6(8)2331197pp. e2331197-e2331197 American Medical Association

This multicenter diagnostic study assessed a prediction model that uses readily available blood biomarkers to possibly distinguish early-stage pancreatic cancer from benign periampullary diseases.

Laura L Meijer, Ingrid Garajová, Chiara Caparello, Tessa Y S Le Large, Adam E Frampton, Enrico Vasile, Niccola Funel, Geert Kazemier, Elisa Giovannetti (2020)Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma, In: Annals of surgery271(6)pp. 1137-1147

The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.

Anna Malczewska, Adam E. Frampton, Mireia Mato Prado, Shima Ameri, Aleksandra F. Dabrowska, Sladjana Zagorac, Ashley K. Clift, Beata Kos-Kudla, Omar Faiz, Justin Stebbing, Leandro Castellano, Andrea Frilling (2021)Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection, In: Annals of surgery274(1)pp. E1-E9 Lippincott Williams & Wilkins

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 -500a5p) 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 miR362-5p have potential to be used to detect RSD/RCD.

Antonio d'Urso, Emanuele Felli, Didier Mutter, Patrick Pessaux, Barbara Seeliger, Adam Frampton (2021)Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic, In: British journal of surgery108(1)pp. 88-96 Wiley

BACKGROUND: Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association between preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. METHODS: This international cohort study included adult patients undergoing elective surgery for cancer in areas affected by SARS-CoV-2 up to 19 April 2020. Patients suspected of SARS-CoV-2 infection before operation were excluded. The primary outcome measure was postoperative pulmonary complications at 30 days after surgery. Preoperative testing strategies were adjusted for confounding using mixed-effects models. RESULTS: Of 8784 patients (432 hospitals, 53 countries), 2303 patients (26.2 per cent) underwent preoperative testing: 1458 (16.6 per cent) had a swab test, 521 (5.9 per cent) CT only, and 324 (3.7 per cent) swab and CT. Pulmonary complications occurred in 3.9 per cent, whereas SARS-CoV-2 infection was confirmed in 2.6 per cent. After risk adjustment, having at least one negative preoperative nasopharyngeal swab test (adjusted odds ratio 0.68, 95 per cent confidence interval 0.68 to 0.98; P = 0.040) was associated with a lower rate of pulmonary complications. Swab testing was beneficial before major surgery and in areas with a high 14-day SARS-CoV-2 case notification rate, but not before minor surgery or in low-risk areas. To prevent one pulmonary complication, the number needed to swab test before major or minor surgery was 18 and 48 respectively in high-risk areas, and 73 and 387 in low-risk areas. CONCLUSION: Preoperative nasopharyngeal swab testing was beneficial before major surgery and in high SARS-CoV-2 risk areas. There was no proven benefit of swab testing before minor surgery in low-risk areas.