Publications
161 results found
Phillips ME, Zekavica J, Kumar R, et al., 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, Journal of the Intensive Care Society, ISSN: 1751-1437
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.
Lythgoe MP, Mullish BH, Frampton A, et al., 2022, Polymorphic microbes: a new emerging hallmark of cancer, Trends in Microbiology, Vol: 30, Pages: 1131-1134, ISSN: 0966-842X
Recognition of the microbiome (and ‘polymorphic microbes’ within them) as a new emerging hallmark of cancer reflects a wide body of rapidly evolving research. Microbes may be directly carcinogenic, impact host immune responses to promote malignancy, and key effectors in determining anti-cancer therapy efficacy. Manipulation of the microbiome is showing promise as an opportunity to influence cancer outcomes.
Lythgoe M, Mullish B, Frampton A, et al., 2022, 627 Oral administration of MRx0518 in treatment-naïve cancer patients is associated with compositional taxonomic and metabolomic changes indicative of anti-tumorigenic efficacy, SITC 37th Annual Meeting (SITC 2022) Abstracts, Publisher: BMJ Publishing Group Ltd
Mirón-Barroso S, Correia JS, Frampton AE, et al., 2022, Polymeric carriers for delivery of RNA cancer therapeutics, Non-Coding RNA, Vol: 8, Pages: 58-58, ISSN: 2311-553X
As research uncovers the underpinnings of cancer biology, new targeted therapies have been developed. Many of these therapies are small molecules, such as kinase inhibitors, that target specific proteins; however, only 1% of the genome encodes for proteins and only a subset of these proteins has ‘druggable’ active binding sites. In recent decades, RNA therapeutics have gained popularity due to their ability to affect targets that small molecules cannot. Additionally, they can be manufactured more rapidly and cost-effectively than small molecules or recombinant proteins. RNA therapeutics can be synthesised chemically and altered quickly, which can enable a more personalised approach to cancer treatment. Even though a wide range of RNA therapeutics are being developed for various indications in the oncology setting, none has reached the clinic to date. One of the main reasons for this is attributed to the lack of safe and effective delivery systems for this type of therapeutic. This review focuses on current strategies to overcome these challenges and enable the clinical utility of these novel therapeutic agents in the cancer clinic.
Macias RIR, Cardinale V, Kendall TJ, et al., 2022, Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions., Gut, Vol: 71, Pages: 1669-1683
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.
Liu D, Yang QZC, Asim M, et al., 2022, The clinical significance of transfer RNAs present in extracellular vesicles, International Journal of Molecular Sciences, Vol: 23, ISSN: 1422-0067
Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organ-isms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs pre-sent within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1st January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included the most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging be-tween 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.
Merali N, Chouari T, Kayani K, et al., 2022, A comprehensive review of the current and future role of the microbiome in pancreatic ductal adenocarcinoma, Cancers, Vol: 14, Pages: 1-34, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.
Bolm L, Petruch N, Sivakumar S, et al., 2022, Gene of the month: T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), JOURNAL OF CLINICAL PATHOLOGY, Vol: 75, Pages: 217-221, ISSN: 0021-9746
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- Citations: 3
Frampton AE, Sivakumar S, 2022, A New Combination Immunotherapy in Advanced Melanoma, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 386, Pages: 91-92, ISSN: 0028-4793
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- Citations: 5
Ali A, Jamieson NB, Khan IN, et al., 2022, Prognostic implications of microRNA-21 overexpression in pancreatic ductal adenocarcinoma: an international multicenter study of 686 patients., Am J Cancer Res, Vol: 12, Pages: 5668-5683, ISSN: 2156-6976
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 gem
McLean KA, Kamarajah SK, Chaudhry D, et al., 2021, Death following pulmonary complications of surgery before and during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 1448-1464, ISSN: 0007-1323
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- Citations: 7
Liu DSK, Frampton AE, 2021, Plasma extracellular vesicles contain unannotated small RNA clusters suitable as biomarkers for detecting early hepatocellular carcinoma, GUT, Vol: 71, Pages: 1935-1936, ISSN: 0017-5749
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- Citations: 1
McKay SC, Pathak S, Wilkin RJW, et al., 2021, Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience, HPB, Vol: 23, Pages: 1656-1665, ISSN: 1365-182X
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- Citations: 4
Glasbey J, Ademuyiwa A, Adisa A, et al., 2021, Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study, The Lancet Oncology, Vol: 22, Pages: 1507-1517, ISSN: 1470-2045
BackgroundSurgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction.MethodsThis international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index <20), moderate lockdowns (20–60), and full lockdowns (>60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926.FindingsOf eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notif
Lythgoe MP, Liu DSK, Annels NE, et al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3), JOURNAL OF CLINICAL PATHOLOGY, Vol: 74, Pages: 543-547, ISSN: 0021-9746
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- Citations: 17
Lythgoe M, Adriani M, Stebbing J, et al., 2021, 543P Neoadjuvant MRx0518 treatment is associated with significant gene and metagene signature changes in solid tumours, Annals of Oncology, Vol: 32, Pages: S607-S607, ISSN: 0923-7534
BackgroundMRx0518 is an oral live biotherapeutic with potent immunostimulatory activity and anti-tumorigenic efficacy in murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer. Previous reports have demonstrated a favourable safety profile in neoadjuvant and metastatic clinical settings, with emerging evidence of immune modulation. We performed a comprehensive analysis of the gene and metagene signature in cancer patients treated with MRx0518 monotherapy.MethodsTreatment-naïve patients with a histologically confirmed diagnosis of cancer scheduled for surgical resection were recruited from April 2019 to February 2020. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011CFU) twice daily from inclusion until the day preceding surgery. Safety and tolerability (CTCAE v4.03) were the primary endpoints of this study. Comprehensive biomarker analysis was also performed in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples using the NanoString IO 360 panel to explore gene and metagene signatures.Results31 samples were collected across tumour groups including breast (n=13) prostate (n=8), uterine (n=6), melanoma (n=2) and bladder (n=2). Differential expression analysis showed significant (p<0.05) increases in genes and metagenes associated with anti-tumour activity, including antigen presentation (AXL & CXCL12), innate immune processes (CHUK, RELA, PPARG & HRAS), interferon response (IFNGR1 & IFNGR2), Th1 cells and CD8+ cells following MRx0518 therapy, echoing preclinical findings. Novel changes, not previously detected in murine models, involving endothelial, mast cells, inflammatory myeloid and inflammatory chemokines were also observed, suggesting MRx0518 may have additional in vivo anti-tumorigenic effects. These changes were more pronounced in the breast cancer cohort.ConclusionsThis analysis, mirrors previous immunostimulatory activity and anti-tumorigenic efficacy observations seen in pre-clini
RICOCHET Study Group on behalf of the West Midlands Research Collaborative, 2021, Pancreatic enzyme replacement therapy in patients with pancreatic cancer: A national prospective study., Pancreatology, Vol: 21, Pages: 1127-1134, ISSN: 1424-3903
OBJECTIVE: UK national guidelines recommend pancreatic enzyme replacement therapy (PERT) in pancreatic cancer. Over 80% of pancreatic cancers are unresectable and managed in non-surgical units. The aim was to assess variation in PERT prescribing, determine factors associated with its use and identify potential actions to improve prescription rates. DESIGN: RICOCHET was a national prospective audit of malignant pancreatic, peri-ampullary lesions or malignant biliary obstruction between April and August 2018. This analysis focuses on pancreatic cancer patients and is reported to STROBE guidelines. Multivariable regression analysis was undertaken to assess factors associated with PERT prescribing. RESULTS: Rates of PERT prescribing varied among the 1350 patients included. 74.4% of patients with potentially resectable disease were prescribed PERT compared to 45.3% with unresectable disease. PERT prescription varied across surgical hospitals but high prescribing rates did not disseminate out to the respective referring network. PERT prescription appeared to be related to the treatment aim for the patient and the amount of clinician contact a patient has. PERT prescription in potentially resectable patients was positively associated with dietitian referral (p = 0.001) and management at hepaticopancreaticobiliary (p = 0.049) or pancreatic unit (p = 0.009). Prescription in unresectable patients also had a negative association with Charlson comorbidity score 5-7 (p = 0.045) or >7 (p = 0.010) and a positive association with clinical nurse specialist review (p = 0.028). CONCLUSION: Despite national guidance, wide variation and under-treatment with PERT exists. Given that most patients with pancreatic cancer have unresectable disease and are treated in non-surgical hospitals, where prescribing is lowest, strategies to disseminate best practice and overcome barriers to prescribing are urgently required.
Malczewska A, Frampton AE, Mato Prado M, et al., 2021, Circulating microRNAs in small-bowel neuroendocrine tumors: a potential tool for diagnosis and assessment of effectiveness of surgical resection, Annals of Surgery, Vol: 274, Pages: e1-e9, ISSN: 0003-4932
OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.
Blacker S, Lahiri RP, Phillips M, et al., 2021, Which patients benefit from preoperative biliary drainage in resectable pancreatic cancer?, EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY, Vol: 15, Pages: 855-863, ISSN: 1747-4124
Patel BY, White L, Gavriilidis P, et al., 2021, A systematic review into patient reported outcomes following pancreaticoduodenectomy for malignancy., Eur J Surg Oncol, Vol: 47, Pages: 970-978
BACKGROUND: Pancreaticoduodenectomy is associated with high rates of morbidity. This combined with the psychological burden of cancer, may impact on a patient's quality of life (QoL), which can be measured by using patient-reported outcomes (PRO). OBJECTIVE: To perform a systematic review to evaluate the measurement of PRO after pancreaticoduodenectomy for cancer. METHODS: 7 different databases were searched using 2 groups of search terms, one relating to pancreaticoduodenectomy, and one to PRO. Three authors screened the search results independently in a systematic manner based on predefined inclusion and exclusion criteria. RESULTS: 27 studies, with 2173 eligible patients were included in the final analysis. Most of the included studies used validated instruments. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was most popular and used in 12 studies. The methodology of all included studies was also scrutinised. 12 studies were deemed to have high quality methodology according to pre-defined criteria. CONCLUSION: The instruments and methods used to measure PRO are variable. The quality of PRO within the available literature has improved over time, as has the number of studies measuring PRO. PRO should be measured with uniformity in future trials so that patients can be provided with more comprehensive information regarding post-operative recovery and QoL during the shared decision-making process preoperatively.
Frilling A, Clift AK, Frampton AE, et al., 2021, A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms, International Journal of Medical Sciences, Vol: 18, Pages: 2166-2175, ISSN: 1449-1907
Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.
Glasbey JC, Omar O, Nepogodiev D, et al., 2021, Preoperative nasopharyngeal swab testing and postoperative pulmonary complications in patients undergoing elective surgery during the SARS-CoV-2 pandemic, BRITISH JOURNAL OF SURGERY, Vol: 108, Pages: 88-96, ISSN: 0007-1323
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- Citations: 38
Mantini G, Meijer LL, Glogovitis I, et al., 2021, Omics analysis of educated platelets in cancer and benign disease of the pancreas, Cancers, Vol: 13, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is traditionally associated with thrombocytosis/hypercoagulation and novel insights on platelet-PDAC “dangerous liaisons” are warranted. Here we performed an integrative omics study investigating the biological processes of mRNAs and expressed miRNAs, as well as proteins in PDAC blood platelets, using benign disease as a reference for inflammatory noise. Gene ontology mining revealed enrichment of RNA splicing, mRNA processing and translation initiation in miRNAs and proteins but depletion in RNA transcripts. Remarkably, correlation analyses revealed a negative regulation on SPARC transcription by isomiRs involved in cancer signaling, suggesting a specific ”education” in PDAC platelets. Platelets of benign patients were enriched for non-templated additions of G nucleotides (#ntaG) miRNAs, while PDAC presented length variation on 3′ (lv3p) as the most frequent modification on miRNAs. Additionally, we provided an actionable repertoire of PDAC and benign platelet-ome to be exploited for future studies. In conclusion, our data show that platelets change their biological repertoire in patients with PDAC, through dysregulation of miRNAs and splicing factors, supporting the presence of de novo protein machinery that can “educate” the platelet. These novel findings could be further exploited for innovative liquid biopsies platforms as well as possible therapeutic targets.
Lythgoe M, Stebbing J, Pickford E, et al., 2020, 805 Safety and emerging evidence of immune modulation of the live biotherapeutic MRx0518 in the neoadjuvant setting for patients awaiting surgical removal of solid tumours, Journal for ImmunoTherapy of Cancer, Vol: 8, Pages: A481-A482, ISSN: 2051-1426
Background The gut microbiome has emerged as a promising innovative therapeutic target for immune-stimulation treatment of solid tumours. MRx0518 is a novel, gut microbiome-derived oral live biotherapeutic. It has potent anti-tumorigenic efficacy in the preclinical setting including murine models of lung (LLC1), kidney (Renca) and breast (EMT6) cancer.1 In these models, a significant reduction in tumour growth has been demonstrated, including induction of immunostimulatory responses with tumour infiltration of NK cells, CD8+ and CD4+ T-cells. MRx0518 is under investigation in various oncological settings, including in combination with immune checkpoint inhibitors (NCT03637803) and radiotherapy (NCT04193904).Methods Treatment naïve patients were recruited from April 2019 to February 2020. Patients were eligible if they received a histologically confirmed diagnosis of cancer (solid tumours) scheduled for surgical resection. Patients received 1 capsule of MRx0518 (1x1010 to 1x1011 CFU) twice daily from inclusion until the day preceding surgery (maximum 28 days therapy). The primary study outcome is to evaluate safety and tolerability of MRx0518 monotherapy in treatment naïve patients. Additional exploratory outcomes including identifying surrogate biomarkers of efficacy, microbiome analysis, effect on metabonomic markers and identification of histological and genomic alterations in paired pre-treatment (diagnostic biopsy) and post-treatment (surgical specimen) samples.Results In part A, 17 patients received treatment, across tumour groups including breast (n=8), prostate (n=4), uterine (n=3), melanoma (n=1) and bladder (n=1). MRx0518 was well tolerated by all, with no grade 3/4 CTCAE toxicity reported, no severe adverse effects or treatment discontinuations. All patients proceeded to surgery, however the COVID-19 pandemic delayed surgery in 3 cases.Analysis of the first 5* patient paired samples utilising the NanoString Pan Cancer IO 360TM Gene Expression pan
Limb C, Liu D, Veno M, et al., 2020, The role of circular RNAs in pancreatic ductal adenocarcinoma and biliary-tract cancers, Cancers, Vol: 12, ISSN: 2072-6694
Pancreatic Ductal Adenocarcinoma (PDAC) and biliary-tract cancers (BTC) often present at a late stage, and consequently patients have poor survival-outcomes. Circular RNAs (circRNAs) are non-coding RNA molecules whose role in tumourigenesis has recently been realised. They are stable, conserved and abundant, with tissue-specific expression profiles. Therefore, significant interest has arisen in their use as potential biomarkers for PDAC and BTC. High-throughput methods and more advanced bioinformatic techniques have enabled better profiling and progressed our understanding of how circRNAs may function in the competing endogenous RNA (ceRNA) network to influence the transcriptome in these cancers. Therefore, the aim of this systematic review was to describe the roles of circRNAs in PDAC and BTC, their potential as biomarkers, and their function in the wider ceRNA network in regulating microRNAs and the transcriptome. Medline, Embase, Scopus and PubMed were systematically reviewed to identify all the studies addressing circRNAs in PDAC and BTC. A total of 32 articles were included: 22 considering PDAC, 7 for Cholangiocarcinoma (CCA) and 3 for Gallbladder Cancer (GBC). There were no studies investigating Ampullary Cancer. Dysregulated circRNA expression was associated with features of malignancy in vitro, in vivo, and ex vivo. Overall, there have been very few PDAC and BTC tissues profiled for circRNA signatures. Therefore, whilst the current studies have demonstrated some of their functions in these cancers, further work is required to elucidate their potential role as cancer biomarkers in tissue, biofluids and biopsies.
Randazzo O, Papini F, Mantini G, et al., 2020, “Open Sesame?”: biomarker status of the human equilibrative nucleoside transporter-1 and molecular mechanisms influencing its expression and activity in the uptake and cytotoxicity of gemcitabine in pancreatic cancer, Cancers, Vol: 12, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. Gemcitabine has been for more than twenty years the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. We discuss this analysis and lists molecular factors influencing hENT-1. Improved knowledge on these factors should help in the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.
Liu D, Upton F, Rees E, et al., 2020, Size exclusion chromatography as a technique for the investigation of novel extracellular vesicles in cancer, Cancers, Vol: 12, ISSN: 2072-6694
Abstract: (1) Background: Cancer cells release extracellular vesicles that are a rich target for biomarker discovery and provide a promising mechanism for liquid biopsy. SEC is an increasingly popular technique which has been rediscovered for the purposes of EV isolation and purification from diverse biofluids. (2) Methods: A review was undertaken to identify all papers which described size exclusion as their primary EV isolation method in cancer research. (3) Results: 37 papers were identified and discussed which showcases the breadth of applications that EVs can be utilised, from proteomics, to RNA, and through to functionality. A range of different methods are highlighted, with Sepharose-based techniques predominating. (4) Conclusions: EVs isolated using SEC are able to identify cancer cells, highlight active pathways in tumourigenesis, clinically distinguish cohorts and remain functionally active for further experiments.
Glasbey JC, Bhangu A, 2020, Elective cancer surgery in COVID-19–free surgical pathways during the SARS-CoV-2 pandemic: an international, multicenter, comparative cohort study, Journal of Clinical Oncology, Vol: 39, Pages: 66-78, ISSN: 0732-183X
PURPOSEAs cancer surgery restarts after the first COVID-19 wave, health care providers urgently require data to determine where elective surgery is best performed. This study aimed to determine whether COVID-19–free surgical pathways were associated with lower postoperative pulmonary complication rates compared with hospitals with no defined pathway.PATIENTS AND METHODSThis international, multicenter cohort study included patients who underwent elective surgery for 10 solid cancer types without preoperative suspicion of SARS-CoV-2. Participating hospitals included patients from local emergence of SARS-CoV-2 until April 19, 2020. At the time of surgery, hospitals were defined as having a COVID-19–free surgical pathway (complete segregation of the operating theater, critical care, and inpatient ward areas) or no defined pathway (incomplete or no segregation, areas shared with patients with COVID-19). The primary outcome was 30-day postoperative pulmonary complications (pneumonia, acute respiratory distress syndrome, unexpected ventilation).RESULTSOf 9,171 patients from 447 hospitals in 55 countries, 2,481 were operated on in COVID-19–free surgical pathways. Patients who underwent surgery within COVID-19–free surgical pathways were younger with fewer comorbidities than those in hospitals with no defined pathway but with similar proportions of major surgery. After adjustment, pulmonary complication rates were lower with COVID-19–free surgical pathways (2.2% v 4.9%; adjusted odds ratio [aOR], 0.62; 95% CI, 0.44 to 0.86). This was consistent in sensitivity analyses for low-risk patients (American Society of Anesthesiologists grade 1/2), propensity score–matched models, and patients with negative SARS-CoV-2 preoperative tests. The postoperative SARS-CoV-2 infection rate was also lower in COVID-19–free surgical pathways (2.1% v 3.6%; aOR, 0.53; 95% CI, 0.36 to 0.76).CONCLUSIONWithin available resources, dedicated COVID-19–free
Farkas N, Wong J, Bethel J, et al., 2020, A systematic review of symptomatic small bowel lipomas of the jejunum and ileum, Annals of Medicine and Surgery, Vol: 58, Pages: 52-67, ISSN: 2049-0801
IntroductionSmall bowel lipomas are rarely encountered benign adipose growths found within the small intestine wall or mesentery. Limited up-to-date evidence exists regarding such lipomas. We aim to aid clinical decision-making and improve patient outcomes through this comprehensive review.MethodologyThe terms ‘small bowel,’ ‘small intestine,’ ‘jejunum’ and ‘ileum’ were combined with ‘lipoma.’ EMBASE, Medline and PubMed database searches were performed. All papers published in English from 01/01/2000-31/12/2019 were included. Simple statistical analysis (t-test, Anova) was performed.Results142 papers yielded 147 cases (adults = 138, pediatric = 9). Male = 88, female = 59 (average age = 49.9 years). Presenting symptoms: abdominal pain = 68.7%; nausea/vomiting = 35.3%, hematochezia/GI bleeding = 33.3%; anaemia = 10.9%; abdominal distension = 12.2%; constipation = 8.9%; weight loss = 7.5%. Mean preceding symptom length = 58.1 days (symptoms >1 year excluded (n = 9)). Diagnostic imaging utilised: abdominal X-Ray = 33.3%; endoscopy = 46.3%; CT = 78.2%; ultrasound = 23.8%. 124/137 (90.5%) required definitive surgical management (laparotomy = 89, laparoscopcic = 35). 9 patients were successfully managed endoscopically. Lipoma location: ileum = 59.9%, jejunum = 32%, mesentery = 4.8%. Maximal recorded lipoma size ranged 1.2–22 cm.Mean maximum lipoma diameter and management strategy comparison: laparotomy 5.6 cm, laparoscopic = 4.4 cm, endoscopic = 3.7 cm, conservative = 4.5 cm. One-way Anova test, p value = 0.21. Average length of stay (LOS) was 7.4 days (range = 2–30). T-test p value = 0.13 when comparing management modalities and LOS. 4 complications, 0 mortality.ConclusionsImportant previously undocumented points are illustrated; a clearer symptom profile, diagnostic investigations utilised, size and site of lipomas, types and effectiveness of management modalities, associated morbidity and mortali
COVIDSurg Collaborative, 2020, Delaying surgery for patients with a previous SARS-CoV-2 infection, British Journal of Surgery, ISSN: 0007-1323
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