Imperial College London

MrDuncanSpalding

Faculty of MedicineDepartment of Surgery & Cancer

Clinical Senior Lecturer in Hepato-Biliary Surgery
 
 
 
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Contact

 

+44 (0)20 3313 3941d.spalding

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

100 results found

Gavriilidis P, Sutcliffe RP, Roberts KJ, Pai M, Spalding D, Habib N, Jiao LR, Sodergren MHet al., 2020, No difference in mortality among ALPPS, two-staged hepatectomy, and portal vein embolization/ligation: A systematic review by updated traditional and network meta-analyses, HEPATOBILIARY & PANCREATIC DISEASES INTERNATIONAL, Vol: 19, Pages: 411-419, ISSN: 1499-3872

Journal article

Sarker D, Plummer R, Meyer T, Sodergren MH, Basu B, Chee CE, Huang K-W, Palmer DH, Ma YT, Evans TRJ, Spalding DRC, Pai M, Sharma R, Pinato DJ, Spicer J, Hunter S, Kwatra V, Nicholls JP, Collin D, Nutbrown R, Glenny H, Fairbairn S, Reebye V, Voutila J, Dorman S, Andrikakou P, Lloyd P, Felstead S, Vasara J, Habib R, Wood C, Saetrom P, Huber HE, Blakey DC, Rossi JJ, Habib Net al., 2020, MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial, Clinical Cancer Research, Vol: 26, Pages: 3936-3946, ISSN: 1078-0432

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Journal article

Noor MS, Dennis J, Al-Hinai K, Arhi C, Spalding Det al., 2020, Quality Improvement Project: Improving the External Referrals Service of the Hepato-Pancreato-Biliary (HPB) Surgery in a Tertiary Centre, International Surgical Conference of the Association-of-Surgeons-in-Training, Publisher: WILEY, Pages: 187-187, ISSN: 0007-1323

Conference paper

Sarker D, Sodergren M, Plummer ER, Basu B, Meyer T, Huang K-W, Evans TRJ, Spalding D, Ma YT, Palmer DH, Chee CE, Pinato DJ, Reebye V, McVeigh D, Raulf N, Vasara J, Andrikakou P, Habib R, Blakey D, Habib NAet al., 2020, Phase Ib dose escalation and cohort expansion study of the novel myeloid differentiating agent MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC)., Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

da Costa AC, Sodergren M, Jayant K, Santa Cruz F, Spalding D, Pai M, Habib Net al., 2020, Radiofrequency combined with immunomodulation for hepatocellular carcinoma: State of the art and innovations, WORLD JOURNAL OF GASTROENTEROLOGY, Vol: 26, Pages: 2040-2048, ISSN: 1007-9327

Journal article

Sarker D, Sodergren M, Plummer ER, Basu B, Meyer T, Huang K-W, Evans TRJ, Spalding D, Ma YT, Palmer DH, Chee CE, Pinato DJ, Reebye V, McVeigh D, Raulf N, Vasara J, Andrikakou P, Habib R, Blakey D, Habib NAet al., 2020, First-in-human phase I trial of small activating RNA (saRNA) oligonucleotide MTL-CEBPA in combination with sorafenib in patients with advanced hepatocellular carcinoma (HCC), Gastrointestinal Cancers Symposium of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Sarker D, Plummer R, Basu B, Meyer T, Ma Y-T, Evans J, Palmer DH, Huang K-W, Chee E, Spalding D, Sodergren M, Habib Net al., 2019, First-in-human, first-in-class phase I study of MTL-CEBPA, a RNA oligonucleotide targeting the myeloid cell master regulator C/EBP-alpha, in patients with advanced hepatocellular cancer (HCC), 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 168-+, ISSN: 0923-7534

Conference paper

Poovathoor AJ, Belete S, Afoke J, Spalding D, Punjabi Pet al., 2019, Cardiopulmonary exercise testing and major hepatobiliary surgery: An effective way to judge fitness for surgery?, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY, Pages: 68-69, ISSN: 0007-1323

Conference paper

Dindyal S, Wing V, Adebayo D, Pai M, Spalding Det al., 2019, Elective and emergency splenectomise at a tertiary referral teaching hospital - an audit of current practice, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY, Pages: 94-94, ISSN: 0007-1323

Conference paper

Dindyal S, Siddique H, Pai M, Spalding Det al., 2019, Can a virtual clinic reduce waiting times and improve patient satisfaction in a tertiary referral teaching hospital, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY, Pages: 77-77, ISSN: 0007-1323

Conference paper

Patel BY, White L, Howard AM, Tait P, Thomas R, Habib N, Pai M, Spalding D, Gall T, Jiao Let al., 2019, A Retrospective Analysis of Portal Vein Embolisation In A Tertiary Hepato Pancreato Biliary Centre, International Surgical Conference of the Association-of-Surgeons-in-Training (ASIT), Publisher: WILEY, Pages: 74-74, ISSN: 0007-1323

Conference paper

Dindyal S, Ross T, Adebayor D, Pai M, Spalding Det al., 2019, To what extent can a closed loop audit initiative successfully influence clinical care and improve safety of handover in a tertiary referral teaching hospital, International Surgical Congress of the Association-of-Surgeons-of-Great-Britain-and-Ireland (ASGBI), Publisher: WILEY, Pages: 94-94, ISSN: 0007-1323

Conference paper

Wadsworth CA, Dixon PH, Taylor-Robinso SD, Kim JU, Zabron AA, Wong JH, Chapman MH, McKay SC, Spalding DR, Wasan HS, Pereira SP, Thomas HC, Whittaker JC, Williamson C, Khan SAet al., 2019, Polymorphisms in natural killer cell receptor protein 2D (NKG2D) as a risk factor for Cholangiocarcinoma, Journal of Clinical and Experimental Hepatology, Vol: 9, Pages: 171-175, ISSN: 0973-6883

Background and aims: Understanding of the significant genetic risk factors for Cholangiocarcinoma (CC) remains limited. Polymorphisms in the natural killer cell receptor G2D (NKG2D) gene have been shown to increase risk of CC transformation in patients with Primary Sclerosing Cholangitis (PSC). We present a validation study of NKG2D polymorphisms in CC patients without PSC. Methods: Seven common Single Nucleotide Polymorphisms (SNPs) of the NKG2D gene were genotyped in 164 non-PSC related CC subjects and 257 controls with HaploView. The two SNPs that were positively identified in the previous Scandinavian study, rs11053781 and rs2617167, were included. Results: The seven genotyped SNPs were not associated with risk of CC. Furthermore, haplotype analysis revealed that there was no evidence to suggest that any haplotype differs in frequency between cases and controls (P > 0.1). Conclusion: The common genetic variation in NKG2D does not correlate significantly with sporadic CC risk. This is in contrast to the previous positive findings in the Scandinavian study with PSC-patients. The failure to reproduce the association may reflect an important difference between the pathogenesis of sporadic CC and that of PSC-related CC. Given that genetic susceptibility is likely to be multifaceted and complex, further validation studies that include both sporadic and PSC-related CC are required.

Journal article

Gall TMH, Gerrard G, Frampton AE, Castellano L, Ahmad R, Habib N, Spalding D, Pai M, Foroni L, Jiao LRet 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.

Journal article

Jayant K, Sodergren MH, Reccia I, Kusano T, Zacharoulis D, Spalding D, Pai M, Jiao LR, Huang KWet al., 2018, A systematic review and meta-analysis comparing liver resection with the rf-based device habib (TM)-4x with the clamp-crush technique, Cancers, Vol: 10, Pages: 1-17, ISSN: 2072-6694

Liver cancer is the sixth most common cancer and third most common cause of cancer-related mortality. Presently, indications for liver resections for liver cancers are widening, but the response is varied owing to the multitude of factors including excess intraoperative bleeding, increased blood transfusion requirement, post-hepatectomy liver failure and morbidity. The advent of the radiofrequency energy-based bipolar device Habib™-4X has made bloodless hepatic resection possible. The radiofrequency-generated coagulative necrosis on normal liver parenchyma provides a firm underpinning for the bloodless liver resection. This meta-analysis was undertaken to analyse the available data on the clinical effectiveness or outcomes of liver resection with Habib™-4X in comparison to the clamp-crush technique. The RF-assisted device Habib™-4X is considered a safe and feasible modality for liver resection compared to the clamp-crush technique owing to the multitude of benefits and mounting clinical evidence supporting its role as a superior liver resection device. The most intriguing advantage of the RF-device is its ability to induce systemic and local immunomodulatory changes that further expand the boundaries of survival outcomes following liver resection.

Journal article

Markar SR, Brodie B, Chin S-T, Romano A, Spalding D, Hanna GBet al., 2018, Profile of exhaled-breath volatile organic compounds to diagnose pancreatic cancer, British Journal of Surgery, Vol: 105, Pages: 1493-1500, ISSN: 1365-2168

BACKGROUND: Pancreatic cancer has a very poor prognosis as most patients are diagnosed at an advanced stage when curative treatments are not possible. Breath volatile organic compounds (VOCs) have shown potential as novel biomarkers to detect cancer. The aim of the study was to quantify differences in exhaled breath VOCs of patients with pancreatic cancers compared with cohorts without cancer. METHODS: Patients were recruited to an initial development cohort and a second validation cohort. The cancer group included patients with localized and metastatic cancers, whereas the control group included patients with benign pancreatic disease or normal pancreas. The reference test for comparison was radiological imaging using abdominal CT, ultrasound imaging or endoscopic ultrasonography, confirmed by histopathological examination as appropriate. Breath was collected from the development cohort with steel bags, and from the validation cohort using the ReCIVA™ system. Analysis was performed using gas chromatography-mass spectrometry. RESULTS: A total of 68 patients were recruited to the development cohort (25 with cancer, 43 no cancer) and 64 to the validation cohort (32 with cancer, 32 no cancer). Of 66 VOCs identified, 12 were significantly different between groups in the development cohort on univariable analysis. Receiver operating characteristic (ROC) curve analysis using significant volatile compounds and the validation cohort produced an area under the curve of 0·736 (sensitivity 81 per cent, specificity 58 per cent) for differentiating cancer from no cancer, and 0·744 (sensitivity 70 per cent, specificity 74 per cent) for differentiating adenocarcinoma from no cancer. CONCLUSION: Breath VOCs may distinguish patients with pancreatic cancer from those without cancer.

Journal article

Reccia I, Kumar J, Kusano T, Giakoustidis A, Zanellato A, Retsas P, Habib N, Jiao L, Spalding D, Pai Met al., 2018, Radiofrequency-assisted liver resection: Technique and results, Surgical Oncology, Vol: 27, Pages: 415-420, ISSN: 0960-7404

BackgroundRadiofrequency (RF)-assisted liver resection allows non-anatomical liver resection with reduced blood loss and offers the opportunity for a combination of resection and ablation. However, there are still concerns with regard to postoperative complications related to this technique. In the present study, we discuss the technical aspects of RF-assisted liver resections and analyse the rate of perioperative complications, focusing on post-hepatectomy liver failure (PLF), bile leak and abscess, and mortality.MethodsBetween 2001 and 2015, 857 consecutive open and laparoscopic elective RF-assisted liver resections for benign and malignant liver tumours were reviewed retrospectively to assess perioperative outcomes.ResultsMedian intraoperative blood loss was 130 mL, with 9.8% of patients requiring blood transfusion. Intra-abdominal collections requiring percutaneous drainage developed in 8.7% of all patients, while bile leak at resection margin developed in 2.8% of the cases. Major liver resection was performed in 34% of patients and the incidence of PLF was 1.5% with one directly related mortality (0.1%).ConclusionRF-assisted liver resection has evolved into a feasible and safe technique of liver resection with an acceptable incidence of perioperative morbidity and a low incidence of PLF and related mortality.

Journal article

Reccia I, Sodergren MH, Jayant K, Kurz E, Carneiro A, Spalding D, Pai M, Jiao L, Habib Net al., 2018, The journey of radiofrequency-assisted liver resection, Surgical Oncology, Vol: 27, Pages: A16-A18, ISSN: 0960-7404

Journal article

Sarker D, Plummer ER, Basu B, Meyer T, Huang K-W, Evans TRJ, Spalding D, Ma YT, Palmer DH, Chee CE, Habib NAet al., 2018, Preliminary results of a first-in-human, first-in-class phase I study of MTL-CEBPA, a small activating RNA (saRNA) targeting the transcription factor C/EBP-alpha in patients with advanced liver cancer., Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X

Conference paper

Kumar J, Reccia I, Sodergren MH, Kusano T, Zanellato A, Pai M, Spalding D, Zacharoulis D, Habib Net al., 2018, Radiofrequency assisted pancreaticoduodenectomy for palliative surgical resection of locally advanced pancreatic adenocarcinoma, Oncotarget, Vol: 9, Pages: 15732-15739, ISSN: 1949-2553

Background: Despite careful patient selection and preoperative investigations curative resection rate (R0) in pancreaticoduodenectomy ranges from 15% to 87%. Here we describe a new palliative approach for pancreaticoduodenectomy using a radiofrequency energy device to ablate tumor in situ in patients undergoing R1/R2 resections for locally advanced pancreatic ductal adenocarcinoma where vascular reconstruction was not feasible. Results: There was neither postoperative mortality nor significant morbidity. Each time the ablation lasted less than 15 minutes. Following radiofrequency ablation it was observed that the tumor remnant attached to the vessel had shrunk significantly. In four patients this allowed easier separation and dissection of the ablated tumor from the adherent vessel leading to R1 resection. In the other two patients, the ablated tumor did not separate from vessel due to true tumor invasion and patients had an R2 resection. The ablated remnant part of the tumor was left in situ. Conclusion: Whenever pancreaticoduodenectomy with R0 resection cannot be achieved, this new palliative procedure could be considered in order to facilitate resection and enable maximum destruction in remnant tumors. Method: Six patients with suspected tumor infiltration and where vascular reconstruction was not warranted underwent radiofrequency-assisted pancreaticoduodenectomy for locally advanced pancreatic ductal adenocarcinoma. Radiofrequency was applied across the tumor vertically 5-10 mm from the edge of the mesenteric and portal veins. Following ablation, the duodenum and the head of pancreas were removed after knife excision along the ablated line. The remaining ablated tissue was left in situ attached to the vessel.

Journal article

Loh WJ, Tharakan G, Todd J, Chahal H, Dhillo W, Martin N, Toumpanakis C, Caplin M, Spalding D, Meeran K, Tan T, Khoo Bet al., 2018, Sensitivity and Specificity of Insulin, C-Peptide and Nadir Glucose during 72 hr Supervised Fast in Diagnosis of Insulinoma, 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: KARGER, Pages: 297-297, ISSN: 0028-3835

Conference paper

Khoo B, Boshier PR, Freethy A, Tharakan G, Saeed S, Hill N, Williams EL, Moorthy K, Tolley N, Jiao LR, Spalding D, Palazzo F, Meeran K, Tan Tet al., 2017, Redefining the stress cortisol response to surgery., Clinical Endocrinology, Vol: 87, Pages: 451-458, ISSN: 1365-2265

BACKGROUND: Cortisol levels rise with the physiological stress of surgery. Previous studies have used older, less-specific assays, have not differentiated by severity or only studied procedures of a defined type. The aim of this study was to examine this phenomenon in surgeries of varying severity using a widely used cortisol immunoassay. METHODS: Euadrenal patients undergoing elective surgery were enrolled prospectively. Serum samples were taken at 8 am on surgical day, induction and 1 hour, 2 hour, 4 hour and 8 hour after. Subsequent samples were taken daily at 8 am until postoperative day 5 or hospital discharge. Total cortisol was measured using an Abbott Architect immunoassay, and cortisol-binding globulin (CBG) using a radioimmunoassay. Surgical severity was classified by POSSUM operative severity score. RESULTS: Ninety-three patients underwent surgery: Major/Major+ (n = 37), Moderate (n = 33) and Minor (n = 23). Peak cortisol positively correlated to severity: Major/Major+ median 680 [range 375-1452], Moderate 581 [270-1009] and Minor 574 [272-1066] nmol/L (Kruskal-Wallis test, P = .0031). CBG fell by 23%; the magnitude of the drop positively correlated to severity. CONCLUSIONS: The range in baseline and peak cortisol response to surgery is wide, and peak cortisol levels are lower than previously appreciated. Improvements in surgery, anaesthetic techniques and cortisol assays might explain our observed lower peak cortisols. The criteria for the dynamic testing of cortisol response may need to be reduced to take account of these factors. Our data also support a lower-dose, stratified approach to dosing of steroid replacement in hypoadrenal patients, to minimize the deleterious effects of over-replacement.

Journal article

Reccia I, Kumar J, Tomokazu K, Zanellato A, Draz A, Spalding D, Habib N, Pai Met al., 2017, A systemic review on radiofrequency assisted laparoscopic liver resection: Challenges and window to excel, Surgical Oncology, Vol: 26, Pages: 296-304, ISSN: 1879-3320

Laparoscopic liver resection has progressively gained acceptance as a safe and effective procedure in the treatment of benign and malignant liver neoplasms. However, blood loss remains the major challenge in liver surgery. Several techniques and devices have been introduced in liver surgery in order to minimize intraoperative haemorrhage during parenchymal transection. Radiofrequency (RF)-assisted liver resection has been shown to be an effective method to minimize bleeding in open and laparoscopic liver resection. A number of RF devices for parenchymal transection have been designed to assist laparoscopic liver resections. Here we have reviewed the results of various RF devices in laparoscopic liver resection. A total 15 article were considered relevant for the evaluation of technical aspects and outcomes of RF-assisted liver resections in laparoscopic procedures. In these studies, 176 patients had laparoscopic liver resection using RF-assisted parenchymal coagulation. Two monopolar and three bipolar devices were employed. Blood loss was limited in most of the studies. The need of blood transfusions was limited to two cases in all the series. Conversion was necessary due to bleeding in 3 cases. Operative and transection times varied between studies. However, RF-assisted resection with bipolar devices appeared to have taken less time in comparison to other RF devices. RF-related complications were minimum, and only one case of in-hospital death due to hepatic failure was reported. Although RF has been used in a small minority of laparoscopic liver resections, laparoscopic RF-assisted liver resection for benign and malignant disease is a safe and feasible procedure associated with reduction in blood loss, low morbidity, and lower hospital mortality rates.

Journal article

Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, Ringelhan M, Connor TO, Stadler M, Meister M, Weber J, Oellinger R, Simonavicius N, Reisinger F, Hartmann D, Meyer R, Reich M, Seehawer M, Leone V, Hoechst B, Wohlleber D, Joers S, Prinz M, Spalding D, Protzer U, Luedde T, Terracciano L, Matter M, Longerich T, Knolle P, Ried T, Keitel V, Geisler F, Unger K, Cinnamon E, Pikarsky E, Hueser N, Davis RJ, Tschaharganeh DF, Rad R, Weber A, Zender L, Haller D, Heikenwalder Met al., 2017, Kupffer cell-derived Tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS, Cancer Cell, Vol: 31, Pages: 771-+, ISSN: 1535-6108

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.

Journal article

Reccia I, Kumar J, Akladios C, Virdis F, Pai M, Habib N, Spalding Det al., 2017, Non-alcoholic fatty liver disease: a sign of systemic disease, Metabolism: clinical and experimental, Vol: 72, Pages: 94-108, ISSN: 0026-0495

Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and leading cause of cirrhosis in the United States and developed countries. NAFLD is closely associated with obesity, insulin resistance and metabolic syndrome, significantly contributing to the exacerbation of the latter. Although NAFLD represents the hepatic component of metabolic syndrome, it can also be found in patients prior to their presentation with other manifestations of the syndrome. The pathogenesis of NAFLD is complex and closely intertwined with insulin resistance and obesity. Several mechanisms are undoubtedly involved in its pathogenesis and progression. In this review, we bring together the current understanding of the pathogenesis that makes NAFLD a systemic disease.

Journal article

Brodie BA, Marker SR, Romano A, Sharma R, Spalding DR, Hanna GBet al., 2017, Non-invasive exhaled breath volatile organic compound analysis for the diagnosis of pancreatic cancer, Annual Meeting of the Society-of-Academic-and-Research-Surgery (SARS), Publisher: WILEY, Pages: 37-37, ISSN: 0007-1323

Conference paper

Yoon S, Huang K-W, Reebye V, Spalding D, Przytycka TM, Wang Y, Swiderski P, Li L, Armstrong B, Reccia I, Zacharoulis D, Dimas K, Kusano T, Shively J, Habib N, Rossi JJet al., 2016, Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 6, Pages: 80-88, ISSN: 2162-2531

Aptamer-drug conjugates (ApDCs) have the potential to improve the therapeutic index of traditional chemotherapeutic agents due to their ability to deliver cytotoxic drugs specifically to cancer cells while sparing normal cells. This study reports on the conjugation of cytotoxic drugs to an aptamer previously described by our group, the pancreatic cancer RNA aptamer P19. To this end, P19 was incorporated with gemcitabine and 5-fluorouracil (5-FU), or conjugated to monomethyl auristatin E (MMAE) and derivative of maytansine 1 (DM1). The ApDCs P19-dFdCMP and P19-5FdUMP were shown to induce the phosphorylation of histone H2AX on Ser139 (γ-H2AX) and significantly inhibited cell proliferation by 51%–53% in PANC-1 and by 54%–34% in the gemcitabine-resistant pancreatic cancer cell line AsPC-1 (p ≤ 0.0001). P19-MMAE and P19-DM1 caused mitotic G2/M phase arrest and inhibited cell proliferation by up to 56% in a dose-dependent manner when compared to the control group (p ≤ 0.001). In addition, the cytotoxicity of P19-MMAE and P19-DM1 in normal cells and the control human breast cancer cell line MCF7 was minimal. These results suggest that this approach may be useful in decreasing cytotoxic side effects in non-tumoral tissue.

Journal article

Yoon S, Huang KW, Reebye V, Mintz P, Tien YW, Lai HS, Sætrom P, Reccia I, Swiderski P, Armstrong B, Jozwiak A, Spalding D, Jiao L, Habib N, Rossi JJet al., 2016, Targeted delivery of C/EBPα -saRNA by pancreatic ductal adenocarcinoma-specific RNA aptamers inhibits tumor growth in vivo, Molecular Therapy, Vol: 24, Pages: 1106-1116, ISSN: 1525-0024

The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.

Journal article

Giglio MC, Spalding DRC, Giakoustidis A, Le Bian AZ, Jiao LR, Habib NA, Pai Met al., 2016, Meta-analysis of drain amylase content on postoperative day 1 as a predictor of pancreatic fistula following pancreatic resection, British Journal of Surgery, Vol: 103, Pages: 328-336, ISSN: 1365-2168

BackgroundDrain amylase content in the days immediately after major pancreatic resection has been investigated previously as a predictor of postoperative pancreatic fistula (POPF). Its accuracy, however, has not been determined conclusively. The purpose of this study was to evaluate the accuracy of drain amylase content on the first day after major pancreatic resection in predicting the occurrence of POPF.MethodsA literature search of the MEDLINE, Embase and Scopus® databases to 13 May 2015 was performed to identify studies evaluating the accuracy of drain amylase values on day 1 after surgery in predicting the occurrence of POPF. The area under the hierarchical summary receiver operating characteristic (ROC) curve (AUChSROC) was calculated as an index of accuracy, and pooled estimates of accuracy indices (sensitivity and specificity) were calculated at different cut-off levels. Subgroup and meta-regression analyses were performed to test the robustness of the results.ResultsThirteen studies involving 4416 patients were included. The AUChSROC was 0·89 (95 per cent c.i. 0·86 to 0·92) for clinically significant POPF and 0·88 (0·85 to 0·90) for POPF of any grade. Pooled estimates of sensitivity and specificity were calculated for the different cut-offs: 90–100 units/l (0·96 and 0·54 respectively), 350 units/l (0·91 and 0·84) and 5000 units/l (0·59 and 0·91). Accuracy was independent of the type of operation, type of anastomosis performed and octreotide administration.ConclusionEvaluation of drain amylase content on the first day after surgery is highly accurate in predicting POPF following major pancreatic resection. It may allow early drain removal and institution of an enhanced recovery pathway.

Journal article

Cheng Z, Lv Y, Pang S, Bai R, Wang M, Lin S, Xu T, Spalding D, Habib N, Xu Ret al., 2015, Kallistatin, a new and reliable biomarker for the diagnosis of liver cirrhosis., Acta Pharmaceutica Sinica B, Vol: 5, Pages: 194-200, ISSN: 2211-3843

Kallistatin, which protects organs and cells against inflammation, fibrosis and oxidative stress, is mainly synthesized and secreted in liver. However, its relationship to human liver disease remains unclear. The purpose of this study was to explore the relationship between serum kallistatin and clinical evidence of both cirrhosis and hepatocellular carcinoma (HCC), and to determine if serum kallistatin levels could be used as a diagnostic indicator of hepatic health status, especially human liver cirrhosis (LC). Our cohort consisted of 115 patients with clinically proven liver fibrosis (LF), LC, or HCC by liver biopsies, and 31 healthy controls (CON). Serum kallistatin levels were quantified by ELISA. Results of the present study demonstrated that irrespective of the underlying etiology, serum kallistatin levels were significantly lower in the LF/LC group when compared with the CON group. A decrease in serum kallistatin levels appeared to reflect the extent of cirrhosis, with the lowest levels associated with higher grades of cirrhosis. Patients with LC had a noticeable correlation between serum kallistatin levels and other serum biochemical indicators. The area under the curve (AUC) for LC, viral liver cirrhosis (VLC) and alcoholic liver cirrhosis (ALC) was 0.845, 0.757 and 0.931, respectively. In conclusion, our findings demonstrated that kallistatin, a plasma protein produced by the liver, can be a useful and reliable diagnostic indicator of hepatic health status, especially for LC.

Journal article

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