179 results found
Halle-Smith JM, Hall LA, Powell-Brett SF, et al., 2023, Realising the therapeutic potential of the human microbiota in metastatic pancreatic ductal adenocarcinoma, Clinical Surgical Oncology, Vol: 2, Pages: 100020-100020, ISSN: 2773-160X
Primavesi F, Maglione M, Cipriani F, et al., 2023, E-AHPBA-ESSO-ESSR Innsbruck consensus guidelines for preoperative liver function assessment before hepatectomy., Br J Surg, Vol: 110, Pages: 1331-1347
BACKGROUND: Posthepatectomy liver failure (PHLF) contributes significantly to morbidity and mortality after liver surgery. Standardized assessment of preoperative liver function is crucial to identify patients at risk. These European consensus guidelines provide guidance for preoperative patient assessment. METHODS: A modified Delphi approach was used to achieve consensus. The expert panel consisted of hepatobiliary surgeons, radiologists, nuclear medicine specialists, and hepatologists. The guideline process was supervised by a methodologist and reviewed by a patient representative. A systematic literature search was performed in PubMed/MEDLINE, the Cochrane library, and the WHO International Clinical Trials Registry. Evidence assessment and statement development followed Scottish Intercollegiate Guidelines Network methodology. RESULTS: Based on 271 publications covering 4 key areas, 21 statements (at least 85 per cent agreement) were produced (median level of evidence 2- to 2+). Only a few systematic reviews (2++) and one RCT (1+) were identified. Preoperative liver function assessment should be considered before complex resections, and in patients with suspected or known underlying liver disease, or chemotherapy-associated or drug-induced liver injury. Clinical assessment and blood-based scores reflecting liver function or portal hypertension (for example albumin/bilirubin, platelet count) aid in identifying risk of PHLF. Volumetry of the future liver remnant represents the foundation for assessment, and can be combined with indocyanine green clearance or LiMAx® according to local expertise and availability. Functional MRI and liver scintigraphy are alternatives, combining FLR volume and function in one examination. CONCLUSION: These guidelines reflect established methods to assess preoperative liver function and PHLF risk, and have uncovered evidence gaps of interest for future research.
Russell TB, Labib PL, Ausania F, et al., 2023, Serious complications of pancreatoduodenectomy correlate with lower rates of adjuvant chemotherapy: Results from the recurrence after Whipple's (RAW) study., Eur J Surg Oncol, Vol: 49
INTRODUCTION: Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS. MATERIALS AND METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests. RESULTS: Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p < 0.0001). Those who commenced AC were younger (mean difference: 2.7 years, p = 0.0002), more often (preoperative) American Society of Anesthesiologists (ASA) grade I-II (74% vs 63%, p = 0.004) and had less often experienced a serious postoperative complication (10% vs 18%, p = 0.002). Patients who developed a serious postoperative complication were less often ASA grade I-II (52% vs 73%, p = 0.0004) and less often commenced AC (58% vs 74%, p = 0.002). CONCLUSION: In our multicentre study of PD outcomes, PDAC patients who received AC had improved OS, and those who experienced a serious postoperative complication commenced AC less frequently. Selected high-risk patients may benefit from targeted preoperative optimisation and/or neoadjuvant chemotherapy.
Chouari T, La Costa FS, Merali N, et al., 2023, Advances in Immunotherapeutics in Pancreatic Ductal Adenocarcinoma., Cancers (Basel), Vol: 15, ISSN: 2072-6694
Pancreatic ductal adenocarcinoma (PDAC) accounts for up to 95% of all pancreatic cancer cases and is the seventh-leading cause of cancer death. Poor prognosis is a result of late presentation, a lack of screening tests and the fact some patients develop resistance to chemotherapy and radiotherapy. Novel therapies like immunotherapeutics have been of recent interest in pancreatic cancer. However, this field remains in its infancy with much to unravel. Immunotherapy and other targeted therapies have yet to yield significant progress in treating PDAC, primarily due to our limited understanding of the disease immune mechanisms and its intricate interactions with the tumour microenvironment (TME). In this review we provide an overview of current novel immunotherapies which have been studied in the field of pancreatic cancer. We discuss their mechanisms, evidence available in pancreatic cancer as well as the limitations of such therapies. We showcase the potential role of combining novel therapies in PDAC, postulate their potential clinical implications and the hurdles associated with their use in PDAC. Therapies discussed with include programmed death checkpoint inhibitors, Cytotoxic T-lymphocyte-associated protein 4, Chimeric Antigen Receptor-T cell therapy, oncolytic viral therapy and vaccine therapies including KRAS vaccines, Telomerase vaccines, Gastrin Vaccines, Survivin-targeting vaccines, Heat-shock protein (HSP) peptide complex-based vaccines, MUC-1 targeting vaccines, Listeria based vaccines and Dendritic cell-based vaccines.
Patel BY, Bhome R, Liu DSK, et al., 2023, Cancer cell-derived extracellular vesicles activate hepatic stellate cells in colorectal cancer., Expert Rev Mol Diagn, Pages: 1-7
Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths worldwide, primarily due to the development of metastatic disease. The liver is the most frequently affected site. The metastatic cascade relies on a complex interaction between the immune system, tumor, and distant organs. Communication between the tumor and the metastatic site can be mediated by tumor-derived extracellular vesicles (EVs) and their cargo. The mechanisms underlying this process are starting to be understood through research that has rapidly expanded over the past 15 years. One crucial aspect is the remodeling of the microenvironment at the site of metastasis, which is essential for the formation of a premetastatic niche and the subsequent establishment of metastatic deposits. In the evaluated study, the authors use cellular experiments and a mouse model to investigate how tumour derived extracellular vesicles and their microRNA contents interact with hepatic stellate cells (HSCs). They demonstrate how this may lead to remodelling of the microenvironment and the formation of colorectal liver metastasis using their experimental model. In this mini review, we examine the current evidence surrounding tumour derived EVs and their effect on the tumour microenvironment to highlight potential areas for future research in CRC and other malignancies.
McDonnell D, Cheang AWE, Wilding S, et al., 2023, Elevated Glycated Haemoglobin (HbA1c) Is Associated with an Increased Risk of Pancreatic Ductal Adenocarcinoma: A UK Biobank Cohort Study., Cancers (Basel), Vol: 15, ISSN: 2072-6694
BACKGROUND: The role of dysglycaemia as a risk marker for Pancreatic Ductal Adenocarcinoma (PDAC) is uncertain. We investigated the relationship between glycated haemoglobin (HbA1c) and incident PDAC using a retrospective cohort study within the UK Biobank. METHODS: A study involving 499,804 participants from the UK Biobank study was undertaken. Participants were stratified by diabetes mellitus (DM) status, and then by HbA1c values < 42 mmol/mol, 42-47 mmol/mol, or ≥48 mmol/mol. Cox proportional hazard models were used to describe the association between HbA1c category (with time-varying interactions) and incident PDAC. RESULTS: PDAC occurred in 1157 participants during 11.6 (10.9-12.3) years follow up [(median (interquartile range)]. In subjects without known DM at baseline, 12 months after recruitment, the adjusted hazard ratios (aHR, 95% CI) for incident PDAC for HbA1c 42-47 mmol/mol compared to HbA1c < 42 mmol/mol (reference group) was 2.10 (1.31-3.37, p = 0.002); and was 8.55 (4.58-15.99, p < 0.001) for HbA1c ≥ 48 mmol/mol. The association between baseline HbA1c and incident PDAC attenuated with increasing duration of time of follow-up to PDAC diagnosis. CONCLUSIONS: Dysglycaemia detected by elevated HbA1c is associated with an increased risk of PDAC. The strength of the association between elevated HbA1c and incident PDAC is inversely proportional to the time from detecting dysglycaemia but remains significant for at least 60 months following HbA1c testing.
Siriwardena AK, Serrablo A, Fretland ÅA, et al., 2023, Multisocietal European consensus on the terminology, diagnosis, and management of patients with synchronous colorectal cancer and liver metastases: an E-AHPBA consensus in partnership with ESSO, ESCP, ESGAR, and CIRSE., Br J Surg, Vol: 110, Pages: 1161-1170
BACKGROUND: Contemporary management of patients with synchronous colorectal cancer and liver metastases is complex. The aim of this project was to provide a practical framework for care of patients with synchronous colorectal cancer and liver metastases, with a focus on terminology, diagnosis, and management. METHODS: This project was a multiorganizational, multidisciplinary consensus. The consensus group produced statements which focused on terminology, diagnosis, and management. Statements were refined during an online Delphi process, and those with 70 per cent agreement or above were reviewed at a final meeting. Iterations of the report were shared by electronic mail to arrive at a final agreed document comprising 12 key statements. RESULTS: Synchronous liver metastases are those detected at the time of presentation of the primary tumour. The term 'early metachronous metastases' applies to those absent at presentation but detected within 12 months of diagnosis of the primary tumour, the term 'late metachronous metastases' applies to those detected after 12 months. 'Disappearing metastases' applies to lesions that are no longer detectable on MRI after systemic chemotherapy. Guidance was provided on the recommended composition of tumour boards, and clinical assessment in emergency and elective settings. The consensus focused on treatment pathways, including systemic chemotherapy, synchronous surgery, and the staged approach with either colorectal or liver-directed surgery as first step. Management of pulmonary metastases and the role of minimally invasive surgery was discussed. CONCLUSION: The recommendations of this contemporary consensus provide information of practical value to clinicians managing patients with synchronous colorectal cancer and liver metastases.
Lemanska A, Andrews C, Fisher L, et al., 2023, Healthcare in England was affected by the COVID-19 pandemic across the pancreatic cancer pathway: A cohort study using OpenSAFELY-TPP., Elife, Vol: 12
BACKGROUND: Healthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We analysed healthcare services delivered to people with pancreatic cancer from January 2015 to March 2023 to investigate the effect of the COVID-19 pandemic. METHODS: With the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to March 2023. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. RESULTS: The rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 26,840 people diagnosed with pancreatic cancer from January 2015 to March 2023. The mean age at diagnosis was 72 (±11 SD), 48% of people were female, 95% were of White ethnicity, and 40% were diagnosed with diabetes. We found a reduction in surgical resections by 25-28% during the pandemic. In addition, 20%, 10%, and 4% fewer people received body mass index, glycated haemoglobin, and liver function tests, respectively, before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1-2 per person amongst those who made contact. Reporting of jaundice decreased by 28%, but recovered within 12 months into the pandemic. Emergency department visits, hospital a
Papadakos SP, Machairas N, Stergiou IE, et al., 2023, Unveiling the Yin-Yang Balance of M1 and M2 Macrophages in Hepatocellular Carcinoma: Role of Exosomes in Tumor Microenvironment and Immune Modulation., Cells, Vol: 12
Hepatocellular carcinoma (HCC) is a primary liver cancer with a high mortality rate and limited treatment options. Recent research has brought attention to the significant importance of intercellular communication in the progression of HCC, wherein exosomes have been identified as critical agents facilitating cell-to-cell signaling. In this article, we investigate the impact of macrophages as both sources and targets of exosomes in HCC, shedding light on the intricate interplay between exosome-mediated communication and macrophage involvement in HCC pathogenesis. It investigates how exosomes derived from HCC cells and other cell types within the tumor microenvironment (TME) can influence macrophage behavior, polarization, and recruitment. Furthermore, the section explores the reciprocal interactions between macrophage-derived exosomes and HCC cells, stromal cells, and other immune cells, elucidating their role in tumor growth, angiogenesis, metastasis, and immune evasion. The findings presented here contribute to a better understanding of the role of macrophage-derived exosomes in HCC progression and offer new avenues for targeted interventions and improved patient outcomes.
Yin T, Xu L, Gil B, et al., 2023, Graphene Sensor Arrays for Rapid and Accurate Detection of Pancreatic Cancer Exosomes in Patients' Blood Plasma Samples., ACS Nano, Vol: 17, Pages: 14619-14631
Biosensors based on graphene field effect transistors (GFETs) have the potential to enable the development of point-of-care diagnostic tools for early stage disease detection. However, issues with reproducibility and manufacturing yields of graphene sensors, but also with Debye screening and unwanted detection of nonspecific species, have prevented the wider clinical use of graphene technology. Here, we demonstrate that our wafer-scalable GFETs array platform enables meaningful clinical results. As a case study of high clinical relevance, we demonstrate an accurate and robust portable GFET array biosensor platform for the detection of pancreatic ductal adenocarcinoma (PDAC) in patients' plasma through specific exosomes (GPC-1 expression) within 45 min. In order to facilitate reproducible detection in blood plasma, we optimized the analytical performance of GFET biosensors via the application of an internal control channel and the development of an optimized test protocol. Based on samples from 18 PDAC patients and 8 healthy controls, the GFET biosensor arrays could accurately discriminate between the two groups while being able to detect early cancer stages including stages 1 and 2. Furthermore, we confirmed the higher expression of GPC-1 and found that the concentration in PDAC plasma was on average more than 1 order of magnitude higher than in healthy samples. We found that these characteristics of GPC-1 cancerous exosomes are responsible for an increase in the number of target exosomes on the surface of graphene, leading to an improved signal response of the GFET biosensors. This GFET biosensor platform holds great promise for the development of an accurate tool for the rapid diagnosis of pancreatic cancer.
Boyd LNC, Ali M, Comandatore A, et al., 2023, Prediction Model for Early-Stage Pancreatic Cancer Using Routinely Measured Blood Biomarkers., JAMA Netw Open, Vol: 6
IMPORTANCE: Accurate risk prediction models using routinely measured biomarkers-eg, carbohydrate antigen 19-9 (CA19-9) and bilirubin serum levels-for pancreatic cancer could facilitate early detection of pancreatic cancer and prevent potentially unnecessary diagnostic tests for patients at low risk. An externally validated model using CA19-9 and bilirubin serum levels in a larger cohort of patients with pancreatic cancer or benign periampullary diseases is needed. OBJECTIVE: To assess the discrimination, calibration, and clinical utility of a prediction model using readily available blood biomarkers (carbohydrate antigen 19-9 [CA19-9] and bilirubin) to distinguish early-stage pancreatic cancer from benign periampullary diseases. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study used data from 4 academic hospitals in Italy, the Netherlands, and the UK on adult patients with pancreatic cancer or benign periampullary disease treated from 2014 to 2022. Analyses were conducted from September 2022 to February 2023. EXPOSURES: Serum levels of CA19-9 and bilirubin from samples collected at diagnosis and before start of any medical intervention. MAIN OUTCOMES AND MEASURES: Discrimination (measured by the area under the curve [AUC]), calibration, and clinical utility of the prediction model and the biomarkers, separately. RESULTS: The study sample comprised 249 patients in the development cohort (mean [SD] age at diagnosis, 67  years; 112 [45%] female individuals), and 296 patients in the validation cohort (mean [SD] age at diagnosis, 68  years; 157 [53%] female individuals). At external validation, the prediction model showed an AUC of 0.89 (95% CI, 0.84-0.93) for early-stage pancreatic cancer vs benign periampullary diseases, and outperformed CA19-9 (difference in AUC [ΔAUC], 0.10; 95% CI, 0.06-0.14; P < .001) and bilirubin (∆AUC, 0.07; 95% CI, 0.02-0.12; P = .004). In the subset of patients without elevated tumor marker l
Russell TB, Labib PL, Denson J, et al., 2023, Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study., HPB (Oxford), Vol: 25, Pages: 788-797
BACKGROUND: Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival. METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012-May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not. RESULTS: 394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, ≥1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence. CONCLUSIONS: This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.
Phillips ME, Hart KH, Frampton AE, et al., 2023, Do Patients Benefit from Micronutrient Supplementation following Pancreatico-Duodenectomy?, Nutrients, Vol: 15
Pancreatico-duodenectomy (PD) includes resection of the duodenum and use of the proximal jejunum in a blind loop, thus reducing the absorptive capacity for vitamins and minerals. Several studies have analysed the frequency of micronutrient deficiencies, but there is a paucity of data on those taking routine supplements. A retrospective review of medical notes was undertaken on 548 patients under long-term follow-up following PD in a tertiary hepato-pancreatico-biliary centre. Data were available on 205 patients from 1-14 years following PD, and deficiencies were identified as follows: vitamin A (3%), vitamin D (46%), vitamin E (2%), iron (42%), iron-deficiency anaemia (21%), selenium (3%), magnesium (6%), copper (1%), and zinc (44%). Elevated parathyroid hormone was present in 11% of cases. There was no significant difference over time (p > 0.05). Routine supplementation with a vitamin and mineral supplement did appear to reduce the incidence of biochemical deficiency in vitamin A, vitamin E, and selenium compared to published data. However, iron, vitamin D, and zinc deficiencies were prevalent despite supplementation and require surveillance.
Papadakos SP, Ferraro D, Carbone G, et al., 2023, The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?, Cancers (Basel), Vol: 15, ISSN: 2072-6694
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.
Kosti A, Borakati A, Varma A, et al., 2023, PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK, BJS Open, Vol: 7
Background: Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods: All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results: A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion: Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions.
Spiers HVM, Lancellotti F, de Liguori Carino N, et al., 2023, Irreversible Electroporation for Liver Metastases from Colorectal Cancer: A Systematic Review., Cancers (Basel), Vol: 15, ISSN: 2072-6694
BACKGROUND: Irreversible electroporation (IRE) is a non-thermal form of ablation based on the delivery of pulsed electrical fields. It has been used to treat liver lesions, particularly those in proximity to major hepatic vasculature. The role of this technique in the portfolio of treatments for colorectal hepatic metastases has not been clearly defined. This study undertakes a systematic review of IRE for treatment of colorectal hepatic metastases. METHODS: The study protocol was registered with the PROSPERO register of systematic reviews (CRD42022332866) and reports in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The Ovid MEDLINE®, EMBASE, Web of Science and Cochrane databases were queried in April 2022. The search terms 'irreversible electroporation', 'colon cancer', 'rectum cancer' and 'liver metastases' were used in combinations. Studies were included if they provided information on the use of IRE for patients with colorectal hepatic metastases and reported procedure and disease-specific outcomes. The searches returned 647 unique articles and the exclusions left a total of eight articles. These were assessed for bias using the methodological index for nonrandomized studies (MINORS criteria) and reported using the synthesis without meta-analysis guideline (SWiM). RESULTS: One hundred eighty patients underwent treatment for liver metastases from colorectal cancer. The median transverse diameter of tumours treated by IRE was <3 cm. Ninety-four (52%) tumours were adjacent to major hepatic inflow/outflow structures or the vena cava. IRE was undertaken under general anaesthesia with cardiac cycle synchronisation and with the use of either CT or ultrasound for lesion localisation. Probe spacing was less than 3.2 cm for all ablations. There were two (1.1%) procedure-related deaths in 180 patients. There was one (0.5%) post-operative haemorrhage requiring laparotomy, one (0.5%) bile leak, five (2.8%) post-proced
Jainarayanan A, Mouroug-Anand N, Arbe-Barnes EH, et al., 2023, Pseudotime dynamics of T cells in pancreatic ductal adenocarcinoma inform distinct functional states within the regulatory and cytotoxic T cells, iScience, Vol: 26
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest types of cancer and has a 5-year survival of less than 8% owing to its complex biology. As PDAC is refractory to immunotherapy, we need to understand the functional dynamics of T cells in the PDAC microenvironment to develop alternative therapeutic strategies. In this study, we performed RNA velocity-based pseudotime analysis on a scRNA-seq dataset from surgically resected human PDAC specimens to gain insight into temporal gene expression patterns that best characterize the cell fates. The tumor microenvironment was seen to encompass a range of terminal states for the T cell trajectories with suppressive and non-tumor-responsive T cells dominating them. However, the results also reveal the existence of a functional branch of the T cell population that was not transitioning to exhausted and senescent states. These findings reveal various microenvironmental signals driving T cell patterns which can be useful in identifying new therapeutic avenues.
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
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
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
Merali N, Ashraf H, Chouari T, et al., 2021, Systematic Review Comparing the Effectiveness of Robotic verse Laparoscopic Liver Surgery in Colorectal Liver Metastasis (CRLM), Surgeries (Switzerland), Vol: 2, Pages: 357-370
Introduction: Colorectal cancer (CRC) is the third most common cancer in the world. The liver is the most common site of metastasis with 15 to 25% of patients presenting with synchronous colorectal liver metastasis (CRLM). This study is aimed at evaluating the long- and short-term outcomes of laparoscopic and robotic CRLM surgery, and directly comparing their respective effectiveness. Methodology: A literature search was performed and all studies that reported on operative characteristics, oncological outcomes for CRLM, morbidity or mortality and cost-effectiveness on robotic or laparoscopic surgery were included. The study design was in keeping with the PRISMA guidelines. Results: From the initial 606 manuscripts identified, 19 studies were included in the final qualitative analysis. A total of 1340 patients with 1194 LLR (Laparoscopic Liver Resection) and 146 RLR (Robotic Liver Resection) cases were analysed. Within the LLR group, the average tumour size excised was 32.1 mm compared to the RLR group of 33.8 mm. The average operative time in the LLR was 193 min, CI of 95% (147.4 min to 238.6 min) compared to RLR 257 min, CI of 95% (201.5 min to 313.8 min) with a p-value < 0.0001. Estimated blood loss was lower in the RLR group (210 mL) compared with the LLR group (246 mL). Conclusion: Despite the higher operative cost, RLRs do not result in statistically better treatment outcomes, with the exception of lower estimated blood loss and excision of larger CRLMs. Operative time and total complication rate are significantly more favourable with LLRs. Our study has shown that robotic liver surgery is safe and feasible in well-selected patients.
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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