144 results found
Lythgoe MP, Liu DSK, Annels NE, et al., 2021, Gene of the month: lymphocyte-activation gene 3 (LAG-3)., J Clin Pathol, Vol: 74, Pages: 543-547
Lymphocyte-activation gene 3 (LAG-3) is a coreceptor found on activated T-lymphocytes activated B-lymphocytes and natural killer (NK) cells. It is closely related to CD4 where it shares multiple common and divergent features. It contains specific binding sites with high affinity to major histocompatibility complex (MHC) Class II and functions as an inhibitor of T-cell signalling. Tumour-infiltrating lymphocytes with high LAG-3 expression have been found in many solid tumours including ovarian cancer, melanoma, colorectal cancer and haematological malignancies including Hodgkin and diffuse large B-cell lymphoma. LAG-3 antagonism has been demonstrated to restore the anti-tumourigenic function of T-cells in vivo, however, mechanistic knowledge remains relatively poorly defined. As other immune checkpoint inhibitors have transformed the management of difficult to treat cancers, such as melanoma, it is hoped that LAG-3 might have the same potential. This review will explore LAG-3 modulation as an anticancer therapy, highlighting recent clinical developments.
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.
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
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
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
Meijer LL, Garajova I, Caparello C, et al., 2020, Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma, ANNALS OF SURGERY, Vol: 271, Pages: 1137-1147, ISSN: 0003-4932
Kostalas M, Frampton AE, Low N, et al., 2020, Left hepatic trisectionectomy for hepatobiliary malignancies: Its’ role and outcomes. A retrospective cohort study, Annals of Medicine and Surgery, Vol: 51, Pages: 11-16, ISSN: 2049-0801
Background: Left hepatic trisectionectomy (LHT) is a complex hepatic resection; its’ role and outcomes in hepatobiliary malignancies remains unclear. Materials and methods: All patients undergoing LHT at the tertiary HPB referral unit at RSCH, Guildford, UK from September 1996 to October 2015 were included. Data were collected from a prospectively maintained database. Results: Twenty-eight patients underwent LHT. The M:F ratio was 1.8:1. Median age was 60 years (range 43–76 years). Diagnoses included colorectal liver metastases (CRLM; n = 20); cholangiocarcinoma (CCA; n = 4); and other (neuroendocrine tumour metastases (NET; n = 3) and breast metastases (n = 1)). Median duration of surgery was 270 min (range 210–585 min). Median blood loss was 750 ml (300–2400 ml) with a perioperative transfusion rate of 21% (n = 6/28). The rate of all post-operative complications was 21% for all patients, and given the extensive resection performed four patients (14%) developed varying degrees of hepatic insufficiency. One patient with cholangiocarcinoma developed severe hepatic insufficiency, which was fatal within 90 days of surgery. 1 and 3-year survivals were 92% and 68% respectively. Conclusion: This study supports LHT in patients with significant tumour burden. Despite extensive resection, our favourable morbidity and mortality rates show this is a safe and beneficial procedure for patients with all hepatobiliary malignancies. Given the nature of resection the incidence of post-operative hepatic insufficiency is higher than less extensive hepatic resections.
Frampton AE, Giovannetti E, 2020, Diagnostic pancreatic ductal adenocarcinoma using plasma extracellular vesicle RNA profiles, GUT, Vol: 69, Pages: 404-405, ISSN: 0017-5749
Malczewska A, Frampton A, Prado MM, et al., 2020, Diagnosis and Assessment of Effectiveness of Surgical Resection of Small Bowel Neuroendocrine Tumours: The Roles of Circulating MicroRNAs, 17th Annual European-Neuroendocrine-Tumor-Society (ENETS) Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 145-145, ISSN: 0028-3835
Van Der Steen N, Keller K, Dekker H, et al., 2020, Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function, Journal of Cellular Physiology, Vol: 235, Pages: 8085-8097, ISSN: 0021-9541
In non‐small cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFR‐inhibitor erlotinib and the cMET‐inhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and live‐cell microscopy. We observed additive effects in EBC‐1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFR‐inhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, live‐cell microscopy with a pH‐sensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib–erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.
Ottaviani S, Stebbing J, Frampton AE, et al., 2019, Author Correction: TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 10, ISSN: 2041-1723
Liu DSK, Prado MM, Giovannetti E, et al., 2019, Can circulating tumor and exosomal nucleic acids act as biomarkers for pancreatic ductal adenocarcinoma?, Expert Review of Molecular Diagnostics: new diagnostic technologies are set to revolutionise healthcare, Vol: 19, Pages: 553-558, ISSN: 1473-7159
El Hassouni B, Li Petri G, Liu DSK, et al., 2019, Pharmacogenetics of treatments for pancreatic cancer, Expert Opinion on Drug Metabolism and Toxicology, Vol: 15, Pages: 437-447, ISSN: 1742-5255
Introduction: Despite clinical efforts, pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The scarcity of effective therapies can be reflected by the lack of reliable biomarkers to adapt anticancer drugs prescription to tumors’ and patients’ features.Areas covered: Pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best matches individual and tumor genetic profile, but it has not yet led to gains in outcome. This review describes PDAC pharmacogenetics findings, critically reappraising studies on polymorphisms and -omics profiles correlated to response to gemcitabine, FOLFIRINOX, and nab-paclitaxel combinations, as well as limitations of targeted therapies. Further, we question whether personalized approaches will benefit patients to any significant degree, supporting the need of new strategies within well-designed trials and validated genomic tests for treatment decision-making.Expert opinion: A major challenge in PDAC is the identification of subgroups of patients who will benefit from treatments. Minimally-invasive tests to analyze biomarkers of drug sensitivity/toxicity should be developed alongside anticancer treatments. However, progress might fall below expectations because of tumor heterogeneity and clonal evolution. Whole-genome sequencing and liquid biopsies, as well as prospective validation in selected cohorts, should overcome the limitations of traditional pharmacogenetic approaches.
Jiao LR, Fajardo Puerta AB, Gall TMH, et al., 2019, Rapid induction of liver regeneration for major hepatectomy (REBIRTH): A randomized controlled trial of portal vein embolisation versus ALPPS assisted with radiofrequency., Cancers, Vol: 11, ISSN: 2072-6694
To avoid liver insufficiency following major hepatic resection, portal vein embolisation (PVE) is used to induce liver hypertrophy pre-operatively. Associating liver partition with portal vein ligation for staged hepatectomy assisted with radiofrequency (RALPPS) was introduced as an alternative method. A randomized controlled trial comparing PVE with RALPPS for the pre-operative manipulation of liver volume in patients with a future liver remnant volume (FLRV) ≤25% (or ≤35% if receiving preoperative chemotherapy) was conducted. The primary endpoint was increase in size of the FLRV. The secondary endpoints were length of time taken for the volume gain, morbidity, operation length and post-operative liver function. Between July 2015 and October 2017, 57 patients were randomised to RALPPS (n = 29) and PVE (n = 28). The mean percentage of increase in the FLRV was 80.7 ± 13.7% after a median 20 days following RALPPS compared to 18.4 ± 9.8% after 35 days (p < 0.001) following PVE. Twenty-four patients after RALPPS and 21 after PVE underwent stage-2 operation. Final resection was achieved in 92.3% and 66.6% patients in RALPPS and PVE, respectively (p = 0.007). There was no difference in morbidity, and one 30-day mortality after RALPPS (p = 0.991) was reported. RALPPS is more effective than PVE in increasing FLRV and the number of patients for surgical resection.
Gall TMH, Gerrard G, Frampton AE, et al., 2019, Can we predict long-term survival in resectable pancreatic ductal adenocarcinoma?, Oncotarget, Vol: 10, Pages: 696-706, ISSN: 1949-2553
Objective: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumour associated with poor 5-year survival. We aimed to determine factors which differentiate short and long-term survivors and identify a prognostic biomarker. Methods: Over a ten-year period, patients with resected PDAC who developed disease recurrence within 12 months (Group I) and those who had no disease recurrence for 24 months (Group II) were identified. Clinicopathological data was analysed. Ion Torrent high-throughput sequencing on DNA extracted from FFPE tumour samples was used to identify mutations. Additionally, peripheral blood samples were analysed for variants in cell-free DNA, circulating tumour cells (CTCs), and microRNAs. Results: Multivariable analysis of clinicopathological factors showed that a positive medial resection margin was significantly associated with short disease-free survival (p = 0.007). Group I patients (n = 21) had a higher frequency of the KRAS mutant mean variant allele (16.93% ± 11.04) compared to those in Group II (n = 13; 7.55% ± 5.76, p = 0.0078). Group I patients also trended towards having a KRAS c.35G>A p.Gly12Asp mutation in addition to variants in other genes, such as TP53, CDKN2A, and SMAD4. Mutational status of cell-free DNA, and number of CTCs, was not found to be useful in this study. A circulating miRNA (hsa-miR-548ah-5p) was found to be significantly differentially expressed. Conclusions: Medial resection margin status and the frequency of KRAS mutation in the tumour tissue are independent prognostic indicators for resectable PDAC. Circulating miRNA hsa-miR-548ah-5p has the potential to be used as a prognostic biomarker.
Gall TM, Belete S, Khanderia E, et al., 2019, Circulating tumour cells and cell-free DNA in pancreatic ductal adenocarcinoma, American Journal of Pathology, Vol: 189, Pages: 71-81, ISSN: 0002-9440
Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and potentially allow for personalised treatment, would be of great benefit. This review analyses the literature regarding two potential biomarkers: circulating tumour cells (CTCs) and cell-free DNA (cfDNA) with regards to pancreatic ductal adenocarcinoma (PDAC). The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of CTCs and analyzing their molecular characteristics, and how this may affect survival in both advanced and early disease and allow for treatment monitoring. The origin of cfDNA is discussed and the literature over the past 15 years is summarized. This includes analyzing cfDNA for genetic mutations and methylation abnormalities which has the potential to be used for PDAC detection and prognosis. However, the research certainly remains in the experimental stage warranting future large trials in these areas.
Ottaviani S, Stebbing J, Frampton AE, et al., 2018, TGF-beta induces miR-100 and miR-125b but blocks let-7a through LIN28B controlling PDAC progression, Nature Communications, Vol: 9, ISSN: 2041-1723
TGF-β/Activin induces epithelial-to-mesenchymal transition and stemness in pancreatic ductal adenocarcinoma (PDAC). However, the microRNAs (miRNAs) regulated during this response have remained yet undetermined. Here, we show that TGF-β transcriptionally induces MIR100HG lncRNA, containing miR-100, miR-125b and let-7a in its intron, via SMAD2/3. Interestingly, we find that although the pro-tumourigenic miR-100 and miR-125b accordingly increase, the amount of anti-tumourigenic let-7a is unchanged, as TGF-β also induces LIN28B inhibiting its maturation. Notably, we demonstrate that inactivation of miR-125b or miR-100 affects the TGF-β-mediated response indicating that these miRNAs are important TGF-β effectors. We integrate AGO2-RIP-seq with RNA-seq to identify the global regulation exerted by these miRNAs in PDAC cells. Transcripts targeted by miR-125b and miR-100 significantly overlap and mainly inhibit p53 and cell–cell junctions’ pathways. Together, we uncover that TGF-β induces an lncRNA, whose encoded miRNAs, miR-100, let-7a and miR-125b play opposing roles in controlling PDAC tumourigenesis.
Frampton AE, Mato Prado M, Lopez Jimenez ME, et al., 2018, Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden, Oncotarget, Vol: 9, Pages: 19006-19013, ISSN: 1949-2553
Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stroma fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. This study investigated the usefulness of crExos GPC1 as a biomarker for PDAC.Methods: Plasma was obtained from patients with benign pancreatic disease (n = 16) and PDAC (n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos (n = 11), compared to the source tumors (n = 11; 97 ± 54 vs. 20.9 ± 12.3 pg/mL; P < 0.001). In addition, PDACs with high GPC1 expression tended to have crExos with high GPC1 levels. Despite these findings, we were unable to distinguish PDAC from benign pancreatic disease using crExos GPC1 levels. Interestingly, we found that in matched pre and post-operative plasma samples there was a significant drop in crExos GPC1 levels after surgical resection for PDAC (n = 11 vs. 11; 97 ± 54 vs. 77.8 ± 32.4 pg/mL; P = 0.0428). Furthermore, we found that patients with high crExos GPC1 levels have significantly larger PDACs (>4 cm; P = 0.012). Conclusions: High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients.
Farkas N, Kaur V, Shanmuganandan A, et al., 2018, A systematic review of gallstone sigmoid ileus management, Annals of Medicine and Surgery, Vol: 27, Pages: 32-39, ISSN: 2049-0801
Introduction: Gallstone sigmoid ileus is a rare although serious complication of cholelithiasis resulting in large bowel obstruction. The condition accounts for 4% of all gallstone ileus patients. There are no recognized management guidelines currently. Management strategies range from minimally invasive endoscopy and lithotripsy to substantial surgery. We aim to identify trends when managing patients with gallstone sigmoid ileus to help improve outcomes. Methods: Literature searches of EMBASE, Medline and by hand were conducted. All English language papers published from 2000 to 2017(Oct) were included. The terms 'gallstone' 'sigmoid' 'colon' 'ileus' 'coleus' and 'large bowel obstruction' were used. Results: 38 papers included, male:female ratio was 8:30. Average age was 81.11 (SD ± 7.59). Average length of preceding symptoms was 5.31days (+/-SD3.16). 20/38 (59%) had diverticulosis. 89% of patients had significant comorbidities documented. 34/38 patients underwent computerized tomography. 31 stones were located within sigmoid colon, 4 at rectosigmoid junction and 2 within descending colon. Average impacted gallstone size was 4.14 cm (2.3–7 cm range). 23/38 (61%) patients' initial management was conservative or with endoscopy ± lithotripsy. Conservative management successfully treated 26% of patients. 28/38 (74%) patients ultimately underwent surgical intervention. 5/38 patients died post-operatively. Patients treated non-operatively had shorter hospital stays (4:12.3days) although not significant (p-value = 0.0056). Conclusions: There is no management consensus from the literature. Current evidence highlights endoscopy and lithotripsy as practical firstline strategies. However, surgical intervention should not be delayed if non-operative measures fail or in emergency. Given the complexity of such patients, less invasive timesaving surgery appears practical, avoiding bowel resection and associated complications.
Castellano L, Ottaviani S, Frampton AE, 2017, ATGF-beta-lin28b-miRNA Circuit Regulates EMT and Stemness in Pancreatic Cancer, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1393-1393, ISSN: 0885-3177
Frampton AE, Miller HC, Malczewska A, et al., 2017, MicroRNAs Associated with Small Bowel Neuroendocrine Tumours and Their Metastases, 14th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: Karger Publishers, Pages: 22-22, ISSN: 0028-3835
Puik JR, Meijer LL, Le Large TYS, et al., 2017, miRNA profiling for diagnosis, prognosis and stratification of cancer treatment in cholangiocarcinoma, PHARMACOGENOMICS, Vol: 18, Pages: 1341-1357, ISSN: 1462-2416
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