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Pancreatic Neoplasms: HELP
Articles by Harpreet S. Wasan
Based on 12 articles published since 2010
(Why 12 articles?)

Between 2010 and 2020, Harpreet Wasan wrote the following 12 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Review Pancreatic cancer: current management and treatment strategies. 2015

Gall, Tamara M H / Tsakok, Maria / Wasan, Harpreet / Jiao, Long R. ·HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital Campus, London, UK. · Department of Oncology, Imperial College, Hammersmith Hospital Campus, London, UK. ·Postgrad Med J · Pubmed #26243882.

ABSTRACT: The 5-year survival of patients with pancreatic cancer is poor and, despite oncological advances over the past two decades, has not significantly improved. However, there have been several surgical and oncological advances which have improved morbidity and mortality in surgery and more efficacious chemotherapy regimens, resulting in a better patient experience and an increase in survival by a number of months. Most patients have a tumour at the head of the pancreas and those with resectable disease undergo a pancreaticoduodenectomy, which can be performed laparoscopically. Those who have a pancreatic resection have an increased survival in comparison with those receiving oncological treatment only; however, only a quarter of patients have resectable disease at diagnosis. Some centres are now performing venous resections and/or arterial resections in order to increase the number of patients eligible for curative surgery. Innovative techniques using ablation technologies to downstage tumours for resection are also being investigated. After surgery, all patients should be offered adjuvant gemcitabine-based chemotherapy. Those with locally advanced tumours not suitable for surgery should be offered FOLFIRINOX chemotherapy, after which the tumour may be suitable for surgical resection. The use of radiotherapy in this group of patients is controversial but offered by a few centres. Patients with metastatic disease at diagnosis should also be offered FOLFIRINOX chemotherapy, which can improve survival by a few months. As our knowledge of the tumour biology of pancreatic cancer progresses, a number of new agents targeting specific genes and proteins are under investigation and there is hope that median survival will continue to improve over the next decade.

2 Review Pancreatic cancer: current understanding of molecular and genetic aetiologies. 2015

Gall, Tamara M H / Wasan, Harpreet / Jiao, Long R. ·HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, Hammersmith Hospital, London, UK. · Department of Oncology, Imperial College, London, UK. ·Postgrad Med J · Pubmed #26124188.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers where prognosis has not improved over the past few decades. However, there have been several advances in our understanding of the disease leading to earlier detection and targeted therapeutic treatment. It is now understood that specific somatic and germline mutations lead to the development of the disease, and the risk factors associated with this are clearer. Further, several precursor lesions have been identified which, with early detection and surveillance, allows treatment before the development of carcinoma. PDAC can now be diagnosed with a high sensitivity and specificity following advances in radiology, and treatment can be commenced at an earlier stage of the disease. With continued research we are hopeful that the next decade will see an improved survival rate for all patients with pancreatic cancer.

3 Review Opportunities for translation: targeting DNA repair pathways in pancreatic cancer. 2014

Maginn, Elaina N / de Sousa, Camila H / Wasan, Harpreet S / Stronach, Euan A. ·Molecular Therapy Laboratory, Department of Cancer and Surgery, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Electronic address: e.maginn@imperial.ac.uk. · Molecular Therapy Laboratory, Department of Cancer and Surgery, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. ·Biochim Biophys Acta · Pubmed #24727386.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the poorest prognosis neoplasms. It is typified by high levels of genomic aberrations and copy-number variation, intra-tumoural heterogeneity and resistance to conventional chemotherapy. Improved therapeutic options, ideally targeted against cancer-specific biological mechanisms, are urgently needed. Although induction of DNA damage and/or modulation of DNA damage response pathways are associated with the activity of a number of conventional PDAC chemotherapies, the effectiveness of this approach in the treatment of PDAC has not been comprehensively reviewed. Here, we review chemotherapeutic agents that have shown anti-cancer activity in PDAC and whose mechanisms of action involve modulation of DNA repair pathways. In addition, we highlight novel potential targets within these pathways based on the emerging understanding of PDAC biology and their exploitation as targets in other cancers.

4 Clinical Trial Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. 2017

Middleton, Gary / Palmer, Daniel H / Greenhalf, William / Ghaneh, Paula / Jackson, Richard / Cox, Trevor / Evans, Anthony / Shaw, Victoria E / Wadsley, Jonathan / Valle, Juan W / Propper, David / Wasan, Harpreet / Falk, Stephen / Cunningham, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Wadd, Nick / Corrie, Pippa / Hickish, Tamas / Costello, Eithne / Campbell, Fiona / Rawcliffe, Charlotte / Neoptolemos, John P. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London, UK. · Hammersmith Hospital, London, UK. · Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · Royal Marsden, Royal Marsden NHS Foundation Trust, London, UK. · Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Poole Hospital NHS Foundation Trust, Bournemouth University, Poole, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #28259610.

ABSTRACT: BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca.

5 Clinical Trial Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 2017

Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Psarelli, Eftychia E / Valle, Juan W / Halloran, Christopher M / Faluyi, Olusola / O'Reilly, Derek A / Cunningham, David / Wadsley, Jonathan / Darby, Suzanne / Meyer, Tim / Gillmore, Roopinder / Anthoney, Alan / Lind, Pehr / Glimelius, Bengt / Falk, Stephen / Izbicki, Jakob R / Middleton, Gary William / Cummins, Sebastian / Ross, Paul J / Wasan, Harpreet / McDonald, Alec / Crosby, Tom / Ma, Yuk Ting / Patel, Kinnari / Sherriff, David / Soomal, Rubin / Borg, David / Sothi, Sharmila / Hammel, Pascal / Hackert, Thilo / Jackson, Richard / Büchler, Markus W / Anonymous3241111. ·University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. · University of Liverpool, Liverpool, UK; The Clatterbridge Cancer Centre, Wirral, UK. · The Royal Liverpool University Hospital, Liverpool, UK. · University of Liverpool, Liverpool, UK. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. · The Clatterbridge Cancer Centre, Wirral, UK. · Manchester Royal Infirmary, Manchester, UK. · Royal Marsden Hospital, London, UK. · Weston Park Hospital, Sheffield, UK. · Royal Free Hospital, London, UK. · St James's University Hospital, Leeds, UK. · Karolinska Institute, Stockholm, Sweden; Clinical Research Sörmland, Eskilstuna, Sweden. · University of Uppsala, Uppsala, Sweden. · Bristol Haematology and Oncology Centre, Bristol, UK. · University of Hamburg Medical institutions UKE, Hamburg, Germany. · Royal Surrey County Hospital, Guildford, UK. · Guy's Hospital, London, UK. · Hammersmith Hospital, London, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Velindre Hospital, Cardiff, UK. · Queen Elizabeth Hospital, Birmingham, UK. · Churchill Hospital, Oxford, UK. · Derriford Hospital, Plymouth, UK. · Ipswich Hospital, Ipswich, UK. · Skåne University Hospital, Lund, Sweden. · University Hospital Coventry, Coventry, UK. · Hôpital Beaujon, Clichy, France. · University of Heidelberg, Germany. ·Lancet · Pubmed #28129987.

ABSTRACT: BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

6 Clinical Trial Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. 2013

Poplin, Elizabeth / Wasan, Harpreet / Rolfe, Lindsey / Raponi, Mitch / Ikdahl, Tone / Bondarenko, Ihor / Davidenko, Irina / Bondar, Volodymyr / Garin, August / Boeck, Stefan / Ormanns, Steffen / Heinemann, Volker / Bassi, Claudio / Evans, T R Jeffrey / Andersson, Roland / Hahn, Hejin / Picozzi, Vince / Dicker, Adam / Mann, Elaina / Voong, Cynthia / Kaur, Paramjit / Isaacson, Jeff / Allen, Andrew. ·Elizabeth Poplin, Cancer Institute of New Jersey, New Brunswick, NJ · Mitch Raponi, Elaina Mann, Cynthia Voong, and Andrew Allen, Clovis Oncology, San Francisco, CA · Hejin Hahn and Vince Picozzi, Virginia Mason Medical Center, Seattle, WA · Adam Dicker, Radiation Therapy Oncology Group, Philadelphia, PA · Jeff Isaacson, Clovis Oncology, Boulder, CO · Harpreet Wasan, Hammersmith Hospital, London · Lindsey Rolfe and Paramjit Kaur, Clovis Oncology UK, Cambridge · T.R. Jeffrey Evans, University of Glasgow, Glasgow, United Kingdom · Tone Ikdahl, Oslo Universitetssykehus, Oslo, Norway · Ihor Bondarenko, Dnipropetrovsk State Medical Academy, Dnipropetrovsk · Volodymyr Bondar, Donetsk Regional Antitumor Center, Donetsk, Ukraine · Irina Davidenko, Clinical Oncology Center 1, Krasnodar · August Garin, Blokhin Russian Cancer Research Center, Moscow, Russia · Stefan Boeck, Steffen Ormanns, and Volker Heinemann, Ludwig-Maximilians-University of Munich, Munich, Germany · Claudio Bassi, Ospedale Policlinico G.B. Rossi, Verona, Italy · and Roland Andersson, Lund University, Lund, Sweden. ·J Clin Oncol · Pubmed #24220555.

ABSTRACT: PURPOSE: Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. PATIENTS AND METHODS: Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. RESULTS: Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). CONCLUSION: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

7 Clinical Trial Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. 2013

Mukherjee, Somnath / Hurt, Christopher N / Bridgewater, John / Falk, Stephen / Cummins, Sebastian / Wasan, Harpreet / Crosby, Tom / Jephcott, Catherine / Roy, Rajarshi / Radhakrishna, Ganesh / McDonald, Alec / Ray, Ruby / Joseph, George / Staffurth, John / Abrams, Ross A / Griffiths, Gareth / Maughan, Tim. ·Gray Institute for Radiation Oncology and Biology, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford, UK. somnath.mukherjee@oncology.ox.ac.uk ·Lancet Oncol · Pubmed #23474363.

ABSTRACT: BACKGROUND: In the UK, chemotherapy is the standard treatment for inoperable, locally advanced, non-metastatic pancreatic cancer. Chemoradiotherapy is also an acceptable treatment option, for which gemcitabine, fluorouracil, or capecitabine can be used as concurrent chemotherapy agents. We aimed to assess the activity, safety, and feasibility of both gemcitabine-based and capecitabine-based chemoradiotherapy after induction chemotherapy for patients with locally advanced pancreatic cancer. METHODS: In this open-label, randomised, two-arm, phase 2 trial, patients aged 18 years or older with histologically proven, locally advanced pancreatic cancer (with a tumour diameter of 7 cm or less) were recruited from 28 UK centres between Dec 24, 2009 and Oct 25, 2011. After 12 weeks of induction gemcitabine and capecitabine chemotherapy (three cycles of gemcitabine [1000 mg/m(2) on days 1, 8, 15 of a 28-day cycle] and capecitabine [830 mg/m(2) twice daily on days 1-21 of a 28-day cycle]), patients with stable or responding disease, tumour diameter of 6 cm or less, and WHO performance status 0-1 were randomly assigned to receive a further cycle of gemcitabine and capecitabine chemotherapy followed by either gemcitabine (300 mg/m(2) once per week) or capecitabine (830 mg/m(2) twice daily, Monday to Friday only), both in combination with radiation (50·4 Gy in 28 fractions). Randomisation (1:1) was done via a central computerised system and used stratified minimisation. The primary endpoint was 9-month progression-free survival, analysed by intention to treat including only those patients with valid CT assessments. This trial is registered with ISRCTN, number 96169987. FINDINGS: 114 patients were registered and 74 were randomly allocated (38 to the gemcitabine group and 36 to the capecitabine group). After 9 months, 22 of 35 assessable patients (62·9%, 80% CI 50·6-73·9) in the capecitabine group and 18 of 35 assessable patients (51·4%, 39·4-63·4) in the gemcitabine group had not progressed. Median overall survival was 15·2 months (95% CI 13·9-19·2) in the capecitabine group and 13·4 months (95% CI 11·0-15·7) in the gemcitabine group (adjusted hazard ratio [HR] 0·39, 95% CI 0·18-0·81; p=0·012). 12-month overall survival was 79·2% (95% CI 61·1-89·5) in the capecitabine group and 64·2 (95% CI 46·4-77·5) in the gemcitabine group. Median progression-free survival was 12·0 months (95% CI 10·2-14·6) in the capecitabine group and 10·4 months (95% CI 8·9-12·5) in the gemcitabine group (adjusted HR 0·60, 95% CI 0·32-1·12; p=0·11). Eight patients in the capecitabine group had an objective response at 26 weeks, as did seven in the gemcitabine group. More patients in the gemcitabine group than in the capecitabine group had grade 3-4 haematological toxic effects (seven [18%] vs none, p=0·008) and non-haematological toxic effects (ten [26%] vs four [12%], p=0·12) during chemoradiation treatment; the most frequent events were leucopenia, neutropenia, and fatigue. Two patients in the capecitabine group progressed during the fourth cycle of induction chemotherapy. Of the 34 patients in the capecitabine group who received chemoradiotherapy, 25 (74%) received the full protocol dose of radiotherapy, compared with 26 (68%) of 38 patients in the gemcitabine group. Quality-of-life scores were not significantly different between the treatment groups. INTERPRETATION: Our results suggest that a capecitabine-based regimen might be preferable to a gemcitabine-based regimen in the context of consolidation chemoradiotherapy after a course of induction chemotherapy for locally advanced pancreatic cancer. However, these findings should be interpreted with caution because the difference in the primary endpoint was non-significant and the number of patients in the trial was small. FUNDING: Cancer Research UK.

8 Clinical Trial Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. 2011

Kindler, Hedy L / Ioka, Tatsuya / Richel, Dirk J / Bennouna, Jaafar / Létourneau, Richard / Okusaka, Takuji / Funakoshi, Akihiro / Furuse, Junji / Park, Young Suk / Ohkawa, Shinichi / Springett, Gregory M / Wasan, Harpreet S / Trask, Peter C / Bycott, Paul / Ricart, Alejandro D / Kim, Sinil / Van Cutsem, Eric. ·University of Chicago Comprehensive Cancer Center, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu ·Lancet Oncol · Pubmed #21306953.

ABSTRACT: BACKGROUND: Axitinib is a potent, selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. A randomised phase 2 trial of gemcitabine with or without axitinib in advanced pancreatic cancer suggested increased overall survival in axitinib-treated patients. On the basis of these results, we aimed to assess the effect of treatment with gemcitabine plus axitinib on overall survival in a phase 3 trial. METHODS: In this double-blind, placebo-controlled, phase 3 study, eligible patients had metastatic or locally advanced pancreatic adenocarcinoma, no uncontrolled hypertension or venous thrombosis, and Eastern Cooperative Oncology Group performance status 0 or 1. Patients, stratified by disease extent (metastatic vs locally advanced), were randomly assigned (1:1) to receive gemcitabine 1000 mg/m(2) intravenously on days 1, 8, and 15 every 28 days plus either axitinib or placebo. Axitinib or placebo were administered orally with food at a starting dose of 5 mg twice a day, which could be dose-titrated up to 10 mg twice daily if well tolerated. A centralised randomisation procedure was used to assign patients to each treatment group, with randomised permuted blocks within strata. Patients, investigators, and the trial sponsor were masked to treatment assignments. The primary endpoint was overall survival. All efficacy analyses were done in all patients assigned to treatment groups for whom data were available; safety and treatment administration and compliance assessments were based on treatment received. This study is registered at ClinicalTrials.gov, number NCT00471146. FINDINGS: Between July 27, 2007, and Oct 31, 2008, 632 patients were enrolled and assigned to treatment groups (316 axitinib, 316 placebo). At an interim analysis in January, 2009, the independent data monitoring committee concluded that the futility boundary had been crossed. Median overall survival was 8·5 months (95% CI 6·9-9·5) for gemcitabine plus axitinib (n=314, data missing for two patients) and 8·3 months (6·9-10·3) for gemcitabine plus placebo (n=316; hazard ratio 1·014, 95% CI 0·786-1·309; one-sided p=0·5436). The most common grade 3 or higher adverse events for gemcitabine plus axitinib and gemcitabine plus placebo were hypertension (20 [7%] and 5 [2%] events, respectively), abdominal pain (20 [7%] and 17 [6%]), fatigue (27 [9%] and 21 [7%]), and anorexia (19 [6%] and 11 [4%]). INTERPRETATION: The addition of axitinib to gemcitabine does not improve overall survival in advanced pancreatic cancer. These results add to increasing evidence that targeting of VEGF signalling is an ineffective strategy in this disease. FUNDING: Pfizer.

9 Article Combined inhibition of the PI3K/mTOR/MEK pathway induces Bim/Mcl-1-regulated apoptosis in pancreatic cancer cells. 2019

Burmi, Rajpal S / Maginn, Elaina N / Gabra, Hani / Stronach, Euan A / Wasan, Harpreet S. ·a Department of Surgery and Cancer , Imperial College London , London , United Kingdom. · b Clinical Discovery Unit , Early Clinical Development, AstraZeneca , Cambridge , United Kingdom. ·Cancer Biol Ther · Pubmed #30261145.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy insensitivity have been associated with aberrant PI3K/mTOR/MEK signalling. However, cell death responses activated by inhibitors of these pathways can differ - contextually varying with tumour genetic background. Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines. Additionally, a non-caspase dependent decrease in cell viability upon PF384 treatment was observed, and may be attributed to autophagy and G0/G1 cell cycle arrest. Using reverse phase protein arrays, we identify key molecular events associated with the conversion of cytostatic responses (elicited by single inhibitor treatments) into a complete cell death response when PF384 and PD901 are combined. This response was also independent of KRAS mutation, occurring in both BxPC3 (KRAS wildtype) and MIA-PaCa-2 (KRAS

10 Article Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma. 2018

Leen, Edward / Picard, John / Stebbing, Justin / Abel, Mark / Dhillon, Tony / Wasan, Harpreet. ·Department of Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Anaesthetics, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Cancer Medicine, Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London, UK. · Department of Oncology, Royal Surrey County Hospital, Egerton Road, Guildford, Surrey, UK. ·J Gastrointest Oncol · Pubmed #29755766.

ABSTRACT: Background: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. Methods: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. Results: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in-patient stay was 1 day (range, 1-5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. Conclusions: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials.

11 Article Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies. 2016

Modlin, Irvin M / Frilling, Andrea / Salem, Ronald R / Alaimo, Daniele / Drymousis, Panagiotis / Wasan, Harpreet S / Callahan, Stephen / Faiz, Omar / Weng, Lei / Teixeira, Nancy / Bodei, Lisa / Drozdov, Ignat / Kidd, Mark. ·Surgery, Emeritus Prof, Yale University School of Medicine, New Haven, CT. Electronic address: imodlin@optonline.net. · Department of Surgery and Cancer, Imperial College London, London, UK. · Department of Surgery, Yale University School of Medicine, New Haven, CT. · Wren Laboratories, Branford, CT. · Department of Colorectal Surgery, St Mark's Hospital, London, UK. ·Surgery · Pubmed #26456125.

ABSTRACT: BACKGROUND: Surgery is the only curative treatment for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), but the prediction of residual disease/recurrence is limited in the absence of optimal biomarkers. We examined whether a blood-based multianalyte neuroendocrine gene transcript assay (NETest) would define tumor cytoreduction and therapeutic efficacy. METHODS: The NETest is a polymerase chain reaction-based analysis of 51 genes. Disease activity is scaled 0-100%; minimal <14%, low 14-47%, and high >47%. A total of 35 GEP-NETs in 2 groups were evaluated. I: after surgery (R0, n = 15; residual, n = 12); II: nonsurgery (n = 8: embolization with gel-foam alone [bland: n = 3]), transarterial chemoembolization (n = 2), and radiofrequency embolization (n = 3). Measurement (quantitative real-time-polymerase chain reaction) and chromogranin A (CgA; enzyme-linked immunosorbent assay) were undertaken preoperatively and 1 month after treatment. RESULTS: NETest score was increased in 35 (100%) preoperatively; 14 (40%) had increased CgA (χ(2) = 30, P < 2 × 10(-8)). Resection reduced NETest from 80 ± 5% to 29% ± 5, (P < .0001). CgA decrease was insignificant (14.3 ± 1.6 U/L to 12.2 ± 1.7 U/L). NETest decreases correlated with diminished tumor volume (R(2) = 0.29, P = .03). Cytoreduction significantly reduced NETest from 82 ± 3% to 41% ± 6, P < .0001). CgA was not decreased (21.4 ± 5.5 U/L to 18.4 ± 10.1 U/L). Four (36%) of 11 R0s with increased NETest at 1 month developed positive imaging (sensitivity 100%, specificity 20%). One hundred percent (ablated group) were transcript- and image-positive. CONCLUSION: Blood NET transcripts delineate surgical resection/cytoreduction and facilitate identification of residual disease.

12 Article Intraductal tubulopapillary neoplasm of the pancreas as a radiation induced malignancy. 2011

Bhuva, Neel / Wasan, Harpreet / Spalding, Duncan / Stamp, Gordon / Harrison, Mark. ·Oncology Department, Mount Vernon Cancer Centre, Northwood, UK. neel.bhuva@nhs.net ·BMJ Case Rep · Pubmed #22669886.

ABSTRACT: Pancreatic malignancies account for 3% of all cancer diagnoses in the UK and prognosis is poor with overall 1-year survival rates at 20% and 5-year survival rates at 5%. The majority of these cancers (75%-95%) arise from the exocrine part of the gland and are almost all invasive ductal adenocarcinomas. One per cent of all pancreatic tumours are endocrine tumours. There is limited data regarding the management of such rare neoplasms of the pancreas and some evidence suggests that prognoses and risk factors may be different. Therefore, it is important to report experience of this type of malignancy in order to build a knowledge base to guide the practice of future clinicians. The authors report a case of an intraductal tubulopapillary neoplasm of the pancreas. This is very unusual form of intraductal pancreatic tumour, which is now thought to occupy a distinct histological subcategory and has arisen within a previously irradiated field.