Publications
199 results found
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
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
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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
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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.
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
Ammendola M, Gadaleta CD, Frampton AE, et al., 2017, The density of mast cells c-Kit+ and tryptase+ correlates with each other and with angiogenesis in pancreatic cancer patients., Oncotarget, Vol: 8, Pages: 70463-70471
Literature data suggest that inflammatory cells such as mast cells (MCs) are involved in angiogenesis. MCs can stimulate angiogenesis by releasing of well identified pro-angiogenic cytokines stored in their cytoplasm. In particular, MCs can release tryptase, a potent in vivo and in vitro pro-angiogenic factor. Nevertheless, few data are available concerning the role of MCs positive to tryptase in primary pancreatic cancer angiogenesis. This study analyzed the correlation between mast cells positive to c-Kit receptor (c-Kit+ MCs), the density of MCs expressing tryptase (MCD-T) and microvascular density (MVD) in primary tumor tissue from patients affected by pancreatic ductal adenocarcinoma (PDAC). A series of 35 PDAC patients with stage T2-3N0-1M0 (by AJCC for Pancreas Cancer Staging 7th Edition) were selected and then undergone to surgery. Tumor tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of number of c-Kit+ MCs, MCD-T and MVD. The above parameters were related each other and with the most important main clinico-pathological features. A significant correlation between c-Kit+ MCs, MCD-T and MVD groups each other was found by Pearson t-test analysis (r ranged from 0.75 to 0.87; p-value ranged from 0.01 to 0.04). No other significant correlation was found. Our in vivo preliminary data, suggest that tumor microenvironmental MCs evaluated in terms of c-Kit+ MCs and MCD-T may play a role in PDAC angiogenesis and they could be further evaluated as a novel tumor biomarker and as a target of anti-angiogenic therapy.
Frampton AE, Funel N, Giovannetti E, et al., 2017, y Dicing and slicing pancreatic cancer, 20th Annual Scientific Meeting of the Association-of-Upper-Gastrointestinal-Surgeons-of-Great-Britain-and-Ireland (AUGIS), Publisher: WILEY, Pages: 13-13, ISSN: 0007-1323
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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Frampton AE, Ottaviani S, Stebbing J, et al., 2017, TGF-Beta Induces miR-100 and miR-125b Promoting EMT and Stemness in Pancreatic Cancer, International Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: 6-6, ISSN: 0007-1323
Frampton AE, Ottaviani S, Stebbing J, et al., 2017, TGF-Beta Induces miR-100 and miR-125b Promoting EMT and Stemness in Pancreatic Cancer, International Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: 21-21, ISSN: 0007-1323
Giovannetti E, van der Borden CL, Frampton AE, et al., 2017, Never let it go: Stopping key mechanisms underlying metastasis to fight pancreatic cancer., Semin Cancer Biol, Vol: 44, Pages: 43-59
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive neoplasm, predicted to become the second leading cause of cancer-related deaths before 2030. This dismal trend is mainly due to lack of effective treatments against its metastatic behavior. Therefore, a better understanding of the key mechanisms underlying metastasis should provide new opportunities for therapeutic purposes. Genomic analyses revealed that aberrations that fuel PDAC tumorigenesis and progression, such as SMAD4 loss, are also implicated in metastasis. Recently, microRNAs have been shown to play a regulatory role in the metastatic behavior of many tumors, including PDAC. In particular, miR-10 and miR-21 have appeared as master regulators of the metastatic program, while members of the miR-200 family are involved in the epithelial-to-mesenchymal switch, favoring cell migration and invasiveness. Several studies have also found a close relationship between cancer stem cells (CSCs) and biological features of metastasis, and the CSC markers ALDH1, ABCG2 and c-Met are expressed at high levels in metastatic PDAC cells. Emerging evidence reveals that exosomes are involved in the modulation of the tumor microenvironment and can initiate PDAC pre-metastatic niche formation in the liver and lungs. In this review, we provide an overview of the role of all these pivotal factors in the metastatic behavior of PDAC, and discuss their potential exploitation in the clinic to improve current therapeutics and identify new drug targets.
Meijer LL, Frampton AE, Garajova I, et al., 2017, Circulating microRNAs as dynamic biomarkers of response to treatment with FOLFIRINOX combination therapy in advanced pancreatic ductal adenocarcinoma, LANCET, Vol: 389, Pages: 68-68, ISSN: 0140-6736
Castellano L, Dabrowska A, Pellegrino L, et al., 2017, Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR, Nucleic Acids Research, Vol: 45, Pages: 4401-4412, ISSN: 1362-4962
MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.
Prado MM, Frampton AE, Giovannetti E, et al., 2016, Investigating miRNA-mRNA regulatory networks using crosslinking immunoprecipitation methods for biomarker and target discovery in cancer, EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, Vol: 16, Pages: 1155-1162, ISSN: 1473-7159
Miller HC, Frampton AE, Malczewska A, et al., 2016, MicroRNAs associated with small bowel neuroendocrine tumours and their metastases, Endocrine-Related Cancer, Vol: 23, Pages: 711-726, ISSN: 1479-6821
Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n=90), including primary SBNETs (n=28), adjacent normal small bowel (NSB; n=14), matched lymph node (LN) metastases (n=24), normal LNs (n=7), normal liver (n=2) and liver metastases (n=15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA–mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.
Giglio MC, Giakoustidis A, Draz A, et al., 2016, Oncological outcomes of major liver resection following portal vein embolization: a systematic review and a meta-analysis, Annals of Surgical Oncology, Vol: 23, Pages: 3709-3717, ISSN: 1534-4681
Background Preoperative portal vein occlusion with either percutaneous portal vein embolization (PVE) or portal vein ligation (PVL) is routinely used to induce liver hypertrophy prior to major liver resection in patients with hepatic malignancy. While this increases the future liver remnant (FLR) and hence the number of patients suitable for resection, recent evidence suggests that induction of liver hypertrophy pre-operatively may promote tumour growth and increase recurrence rates. Aim of the current study is to evaluate the impact of PVE on hepatic recurrence rate and survival in patients with colorectal liver metastases (CRLM).Methods Medline, Embase and Web of Science databases were searched to identify studies assessing the oncological outcomes of patients undergoing major liver resection for CRLM following PVE. Studies comparing patients undergoing one stage liver resection with or without pre-operative PVE were included. The primary outcome was hepatic recurrence (HR). Secondary outcomes were 3- and 5-year overall survival (OS). Results Of the 2131 studies identified, six nonrandomized studies (n=668) met the eligibility criteria comparing outcomes of patients undergoing major liver resection with or without PVE (n=182 vs. n=486 respectively). The median follow-up time ranged from 23.5 to 46 months. There was no significant difference in HR (OR, 0.78; 95% CI, 0.42 to 1.44, p=0.41), 3-year OS (OR, 0.80; 95% CI, 0.56 to 1.14, p=0.22) or 5-year OS (OR, 1.12; 95% CI, 0.40 to 3.11, p=0.82). Conclusion PVE in patients with CRLM has no adverse effect on hepatic recurrence or overall survival following major liver resection.
Stebbing J, Frampton AE, Miller HC, et al., 2016, MicroRNAs associated with small bowel neuroendocrine tumors and their metastases., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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