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Purpose: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer., Materials and Methods: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (H max /H mean )., Results: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; H mean  = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; H mean : p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; H mean : p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated., Conclusion: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: TG43 does not account for a lack of scatter and tissue and applicator heterogeneities. The advanced collapsed-cone engine (ACE) algorithm available for use in the Oncentra Brachy treatment planning system (Elekta AB, Stockholm, Sweden) can model these conditions more accurately and is evaluated for esophageal and surface mold brachytherapy treatments., Methods and Materials: ACE was commissioned for use then compared against TG43 for five esophageal and five surface mold treatment plans. Dosimetric differences between each algorithm were assessed using superimposed comparisons and dose-volume histogram statistics., Results: Esophagus (6 Gy per fraction): Compared with TG43, ACE demonstrated up to a 0.63% and 0.05 Gy reduction in planning target volume (PTV) V100% and PTV D98, respectively. Lung D2cc and bone D2cc deviated by up to 0.09 Gy and 0.03 Gy, respectively. Lung D0.1 cc and bone D0.1 cc both deviated by up to 0.12 Gy. Surface mold (4.5 Gy per fraction): Compared with TG43, ACE demonstrated up to a 12.5% and 0.18 Gy reduction in PTV V80% and PTV D98, respectively. Bone D2cc and D0.1 cc both reduced by up to 0.2 Gy when modeled with ACE. Increasing mold size laterally increased the dosimetric differences between TG43 and ACE., Conclusions: TG43 generally overestimated dose delivered to the target volume and organs at risk for the sites investigated. Dosimetric differences observed for esophageal treatments were minimal; however, surface mold treatments would benefit from the increased dosimetric accuracy offered by ACE. Implementation should be considered for surface mold 192 Ir treatment planning, but increased calculation time, additional contouring, and mass density assignment requirements should be scrutinized with regard to their potentially negative impact on current clinical practice., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk., Materials and Methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV&#95;R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT)., Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV&#95;R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule., Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.

Radiotherapy is a highly effective anti-cancer treatment commonly used alongside systemic therapies and surgery to achieve long-term cancer-free survival. Conventional radiotherapy uses photon beams to deliver a high dose of radiation to the tumour volume to eradicate cancer cells. This has to be offset against the irradiation of surrounding normal tissues, as increasing this dose causes more treatment-related toxicity. In August 2018, the NHS's first high energy proton beam therapy centre opened at The Christie NHS Foundation Trust in Manchester. A second NHS centre is scheduled to open in 2020 at the University College London Hospitals NHS Trust. Proton beam therapy may offer dosimetric advantages compared to conventional radiotherapy as a result of its characteristic dose deposition - proton beams deliver a comparatively higher proportion of their dose to the target volume relative to normal tissues, without significant exit doses when compared to conventional photon therapy. Therefore proton beam therapy may be indicated for certain tumours situated next to critical organs or in the paediatric population where quality of life and the reduction of secondary effects from radiation are particularly significant. The indications for proton beam therapy and patient outcomes after treatment will be carefully monitored and evaluated in order to provide a robust evidence base for its use.

Bleeding can cause significant morbidity in patients with upper gastrointestinal malignancies. Palliative radiotherapy can palliate bleeding effectively across numerous cancer sites such as the lung and rectum. The data available regarding the role in bleeding from upper gastrointestinal cancers are limited to a single meta-analysis, a phase 2 trial, eleven retrospective cohorts and two case reports, with the majority focusing on gastric cancer. From the data available radiotherapy appears to be a well-tolerated, effective haemostatic agent that should be considered in all patients with bleeding from an upper gastrointestinal malignancy. Questions remain regarding the radiobiology of haemostasis and the optimum fractionation schedule. There is no convincing evidence that protracted higher dose regimens provide additional benefit. Commonly used fractionation schedules use 1, 5 or 10 fractions. Short fractionation schedules have been used in patients with deteriorating performance status.

This literature review clarifies the role of radiotherapy in the management of low-volume haemoptysis. Embase and Medline were interrogated, and PRISMA guidelines were then used to select relevant articles. Seventy-eight articles were considered relevant and manually reviewed. The evidence suggests that external beam radiotherapy is more effective than endobronchial brachytherapy at controlling low-volume haemoptysis. There is no evidence to recommend a combination of the two techniques. Different doses and fractionations appear equally effective, with a potential survival advantage of higher dose regimens for fitter patients. Palliative radiotherapy is effective at controlling low-volume haemoptysis. External beam radiotherapy is the first-line treatment, with endobronchial brachytherapy recommended following external beam radiotherapy failure. Choice of dose and fractionation should take into account the patient's performance status.

Background: Induction chemotherapy followed by chemoradiation is a treatment option for patients with locally advanced pancreatic cancer (LAPC). However, overall survival is comparable to chemotherapy alone and local progression occurs in nearly half of all patients, suggesting chemoradiation strategies should be optimised. SCALOP-2 is a randomised phase II trial testing the role of radiotherapy dose escalation and/or the addition of the radiosensitiser nelfinavir, following induction chemotherapy of gemcitabine and nab-paclitaxel (GEMABX). A safety run-in phase (stage 1) established the nelfinavir dose to administer with chemoradiation in the randomised phase (stage 2)., Methods: Patients with locally advanced, inoperable, non-metastatic pancreatic adenocarcinoma receive three cycles of induction GEMABX chemotherapy prior to radiological assessment. Those with stable/responding disease are eligible for further trial treatment. In Stage 1, participants received one further cycle of GEMABX followed by capecitabine-chemoradiation with escalating doses of nelfinavir in a rolling-six design. Stage 2 aims to register 262 and randomise 170 patients with responding/stable disease to one of five arms: capecitabine with high- (arms C + D) or standard-dose (arms A + B) radiotherapy with (arms A + C) or without (arms B + D) nelfinavir, or three more cycles of GEMABX (arm E). Participants allocated to the chemoradiation arms receive another cycle of GEMABX before chemoradiation begins. Co-primary outcomes are 12-month overall survival (radiotherapy dose-escalation question) and progression-free survival (nelfinavir question). Secondary outcomes include toxicity, quality of life, disease response rate, resection rate, treatment compliance, and CA19-9 response. SCALOP-2 incorporates a detailed radiotherapy quality assurance programme., Discussion: SCALOP-2 aims to optimise chemoradiation in LAPC and incorporates a modern induction regimen., Trial Registration: Eudract No: 2013-004968-56; ClinicalTrials.gov : NCT02024009.

Background: The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC., Aims and Methods: This narrative review aims to explore the potential role and timing for the use of IRE in patients with LAPC., Results: To date, there is limited and inconsistent level I and II evidence available in the literature regarding the use of IRE for the treatment of PDAC., Discussion: Although some of the preliminary experience of the use of IRE in patients with LAPC is encouraging, it should only be used after conventional evidence-based treatments and/or within the research context., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Optimizing the timing of esophageal stent insertion is a challenge, partly due to difficulty predicting survival in advanced malignancy. The Glasgow prognostic score (GPS) is a validated tool for predicting survival in a number of cancers., Goals: To assess the utility of the GPS in predicting 30-day mortality and overall survival postesophageal stent insertion., Study: Patients at a tertiary referral center who had received an esophageal stent for palliation of dysphagia were included if they had a measurement of albumin and C-reactive protein (CRP) in the week preceding the procedure (n=209). Patients with both an elevated CRP (>10 mg/L) and hypoalbuminemia (<35 g/L) were given a GPS score of 2 (GPS2). Patients with only one of these abnormalities were assigned as GPS1 and those with normal CRP and albumin were assigned as GPS0. Clinical and pathologic parameters were also collected to assess for potential confounding factors in the survival analysis., Results: Increasing GPS was associated with 30-day mortality; for patients with GPS0, 30-day mortality was 5% (2/43), for GPS1 it was 23% (26/114), and for GPS2 it was 33% (17/52). The adjusted hazard ratio for overall poststent mortality was 1.6 (95% confidence interval, 1.1-2.4; P=0.02) for GPS1 and 2.4 (95% confidence interval, 1.5-3.8; P<0.001) for GPS2 patients compared with GPS0., Conclusions: GPS is an independent prognostic factor of 30-day mortality and overall survival after esophageal stent insertion. It is a potential adjunct to clinical assessment in identifying those patients at high-risk of short-term mortality poststent.

Background: To assess the feasibility and potential impact on target delineation of respiratory-gated (4D) contrast-enhanced 18 Fluorine fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET-CT), in the treatment planning position, for a prospective cohort of patients with lower third oesophageal cancer., Methods: Fifteen patients were recruited into the study. Imaging included 4D PET-CT, 3D PET-CT, endoscopic ultrasound and planning 4D CT. Target volume delineation was performed on 4D CT, 4D CT with co-registered 3D PET and 4D PET-CT. Planning target volumes (PTV) generated with 4D CT (PTV 4DCT), 4D CT co-registered with 3D PET-CT (PTV 3DPET4DCT) and 4D PET-CT (PTV 4DPETCT ) were compared with multiple positional metrics., Results: Mean PTV 4DCT , PTV 3DPET4DCT and PTV 4DPETCT were 582.4 ± 275.1 cm 3 , 472.5 ± 193.1 cm 3 and 480.6 ± 236.9 cm 3 respectively (no significant difference). Median DICE similarity coefficients comparing PTV 4DCT with PTV 3DPET4DCT, PTV 4DCT with PTV 4DPETCT and PTV 3DPET4DCT with PTV 4DPETCT were 0.85 (range 0.65-0.9), 0.85 (range 0.69-0.9) and 0.88 (range 0.79-0.9) respectively. The median sensitivity index for overlap comparing PTV 4DCT with PTV 3DPET4DCT, PTV 4DCT with PTV 4DPETCT and PTV 3DPET4DCT with PTV 4DPETCT were 0.78 (range 0.65-0.9), 0.79 (range 0.65-0.9) and 0.89 (range 0.68-0.94) respectively., Conclusions: Planning 4D PET-CT is feasible with careful patient selection. PTV generated using 4D CT, 3D PET-CT and 4D PET-CT were of similar volume, however, overlap analysis demonstrated that approximately 20% of PTV 3DPETCT and PTV 4DPETCT are not included in PTV 4DCT , leading to under-coverage of target volume and a potential geometric miss. Additionally, differences between PTV 3DPET4DCT and PTV 4DPETCT suggest a potential benefit for 4D PET-CT., Trial Registration: ClinicalTrials.gov Identifier - NCT02285660 (Registered 21/10/2014).

Background: Oxaliplatin-capecitabine (OxCap) and carboplatin-paclitaxel (CarPac) based neo-adjuvant chemoradiotherapy (nCRT) have shown promising activity in localised, resectable oesophageal cancer., Patients and Methods: A non-blinded, randomised (1:1 via a centralised computer system), 'pick a winner' phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m 2  day 1, 15, 29; capecitabine 625 mg/m 2 bd on days of radiotherapy) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m 2  day 1, 8, 15, 22, 29). Radiotherapy dose was 45 Gy/25 fractions/5 weeks. Both arms received induction OxCap chemotherapy (2 × 3 week cycles of oxaliplatin 130 mg/m 2  day 1, capecitabine 625 mg/m 2 bd days 1-21). Surgery was performed 6-8 weeks after nCRT. Primary end-point was pathological complete response (pCR). Secondary end-points included toxicity, surgical morbidity/mortality, resection rate and overall survival., Statistics: Based on pCR ≤ 15% not warranting future investigation, but pCR ≥ 35% would, 76 patients (38/arm) gave 90% power (one-sided alpha 10%), implying that arm(s) having ≥10 pCR out of first 38 patients could be considered for phase III trials. ClinicalTrials.gov: NCT01843829. Funder: Cancer Research UK (C44694/A14614)., Results: Eighty five patients were randomised between October 2013 and February 2015 from 17 UK centres. Three of 85 (3.5%) died during induction chemotherapy. Seventy-seven patients (OxCapRT = 36; CarPacRT = 41) underwent surgery. The 30-d post-operative mortality was 2/77 (2.6%). Grade III/IV toxicity was comparable between arms, although neutropenia was higher in the CarPacRT arm (21.4% versus 2.6%, p = 0.01). Twelve of 41 (29.3%) (10 of first 38 patients) and 4/36 (11.1%) achieved pCR in the CarPacRT and OxcapRT arms, respectively. Corresponding R0 resection rates were 33/41 (80.5%) and 26/36 (72.2%), respectively., Conclusion: Both regimens were well tolerated. Only CarPacRT passed the predefined pCR criteria for further investigation., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: Margin-directed neoadjuvant radiotherapy for borderline-resectable pancreatic cancer (BRPC) aims to facilitate clear surgical margins. A systematic method was developed for definition of a boost target volume prior to a formal phase-I study., Material and Methods: Reference structures were defined by two oncologists and one radiologist, target structures were submitted by eight oncologist investigators and compared using conformity indices. Resultant risk of duodenal bleed (NTCP) was modelled., Results: For GTV, reference volume was 2.1cm 3 and investigator mean was 6.03cm 3 (95% CI 3.92-8.13cm 3 ), for boost volume 1.1cm 3 and 1.25cm 3 (1.02-1.48cm 3 ). Mean Dice conformity coefficient for GTV was 0.47 (0.38-0.56), and for boost volume was significantly higher at 0.61 (0.52-0.70, p=0.01). Discordance index (DI) for GTV was 0.65 (0.56-0.75) and for boost volume was significantly lower at 0.39 (0.28-0.49, p=0.001). NTCP using reference contours was 2.95%, with mean for investigator contour plans 3.93% (3.63-4.22%). Correlations were seen between NTCP and GTV volume (p=0.02) and NTCP and DI (correlation coefficient 0.83 (0.29-0.97), p=0.01)., Conclusions: Better conformity with reference was shown for boost volume compared with GTV. Investigator GTV volumes were larger than reference, had higher DI scores and modelled toxicity risk. A consistent method of target structure definition for margin-directed pancreatic radiotherapy is demonstrated., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Both oxaliplatin/capecitabine-based chemoradiation (OXCAP-RT) and carboplatin-paclitaxel based radiation (CarPac-RT) are active regimens in oesophageal adenocarcinoma, but no randomised study has compared their efficacy and toxicity. This randomised phase II "pick a winner" trial will identify the optimum regimen to take forward to a future phase III trial against neo-adjuvant chemotherapy, the current standard in the UK., Methods/design: Patients with resectable adenocarcinoma of the oesophagus or Siewert Type 1-2 gastro-oesophageal junction (GOJ), ≥T3 and/or ≥ N1 are eligible for the study. Following two cycles of induction OXCAP chemotherapy (oxaliplatin 130 mg/m2 D1, Cape 625 mg/m(2) D1-21, q 3 wk), patients are randomised 1:1 to OXCAP-RT (oxaliplatin 85 mg/m(2) Day 1,15,29; capecitabine 625 mg/m(2) twice daily on days of RT; RT-45 Gy/25 fractions/5 weeks) or CarPac-RT (Carboplatin AUC2 and paclitaxel 50 mg/m2 Day 1,8,15,22,29; RT-45 Gy/25 fractions/5 weeks). Restaging CT/PET-CT is performed 4-6 weeks after CRT, and a two-phase oesophagectomy with two-field lymphadenectomy is performed six to eight weeks after CRT. The primary end-point is pathological complete response rate (pCR) at resection and will include central review. Secondary endpoints include: recruitment rate, toxicity, 30-day surgical morbidity/mortality, resection margin positivity rate and overall survival (median, 3- and 5-yr OS. 76 patients (38/arm) gives 90% power and one-sided type 1 error of 10% if patients on one novel treatment have a response rate of 35% while the second treatment has a response rate of 15%. A detailed RT Quality Assurance (RTQA) programme includes a detailed RT protocol and guidance document, pre-accrual RT workshop, outlining exercise, and central evaluation of contouring and planning. This trial has been funded by Cancer Research UK (C44694/A14614), sponsored by Velindre NHS Trust and conducted through the Wales Cancer Trials Unit at Cardiff University on behalf of the NCRI Upper GI CSG., Discussion: Following encouraging results from previous trials, there is an interest in neo-adjuvant chemotherapy and CRT containing regimens for treatment of oesophageal adenocarcinoma. NEOSCOPE will first establish the efficacy, safety and feasibility of two different neo-adjuvant CRT regimens prior to a potential phase III trial., Trial Registration: Eudract No: 2012-000640-10. ClinicalTrials.gov: NCT01843829 .

Background: Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER)., Methods: Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated., Results: Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively., Conclusions: The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction.

Although fibromatosis of the mesentery is a very rare locally aggressive benign condition, the uncertain treatment modalities, the natural history of the disease, and the other common differential diagnosis of the condition along with inexperience of the general clinicians with this disease pose a challenge to the professionals. The prolonged periods of stability and even regression in size of the tumor offer a hope for treatment. Accounting for 0.03 % of all neoplasms, it is also known as deep fibromatosis and desmoid tumor. Here, we discuss one case of primary mesenteric fibromatosis in a young male patient who presented to us with chronic abdominal pain after he was treated for acid peptic disease for the same at a local hospital. This case shows how management of this disease can be delayed due to unfamiliarity among clinicians of this condition. In our patient, a palliative surgical management plan was undertaken due to symptomatic mass in the abdomen, owing to unresectability.

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background and Purpose: Standard treatment for rectal cancer which threatens the expected plane of resection on MRI imaging is long-course, pre-operative chemoradiotherapy (1.8-2Gy, 25-28 fractions). Not all patients are suitable for this because of age, poor performance status or co-morbidities. We describe our experience of short-course (5x5Gy) pre-operative radiotherapy with planned, delayed surgery (SCPRT-delay) in this patient group., Materials and Methods: Between April 2001 and October 2007, 43 patients were selected for SCPRT-delay. The clinical records were retrospectively evaluated., Results: Median age was 82 (range 58-87). Forty-one patients had radiotherapy of which 26 (61%) were subsequently able to have surgery. Of these, R0, R1 and R2 resections were performed in 22, 2 and 2 patients, respectively. Treatment was well tolerated, although two patients required hospital admission for management of diarrhoea and one developed significant late small bowel toxicity, attributable to radiotherapy. In those undergoing R0 or R1 resection there have been no local recurrences (median follow-up 18 months). Median survival for the whole group was 23 months, although this was 44 months in those undergoing surgery., Conclusions: SCPRT-delay appears to be a useful alternative to long-course pre-operative chemoradiotherapy in this high-risk group of patients.

Background: The expression of chemokines is central to the recruitment of inflammatory cells for graft rejection, and modulation of chemokine action is of potential in preventing graft rejection. We have examined chemokine expression in a murine model of corneal allograft rejection, and also determined the effect of expressing a broad acting chemokine antagonist, viral macrophage inflammatory protein II (vMIP II), on graft survival., Method: The expression of chemokines in a murine model of corneal transplantation was determined by real time RT-PCR and, in the case of regulated on activation normal T-cell expressed and secreted, by ELISA. The plasmid encoding the virally derived chemokine antagonist, vMIP II, was introduced into the corneal endothelial cells using a non-viral vector consisting of liposomes and transferrin. The expression and activity of vMIP II was determined by ELISA and functional assays, and the effect on graft survival noted., Results: After allotransplantation, there was up-regulation of all 11 chemokines examined. After gene delivery, there was expression of active vMIP II for more than 14 days and considerable prolongation of graft survival. This was associated with a decrease in leukocyte infiltration of the stroma of the cells., Conclusion: As expected there was considerable up-regulation of chemokines during allograft rejection. The expression of vMIP II showed considerable prolongation of graft survival. This is the first time we have observed prolongation of graft survival after a non-viral (as opposed to viral) means of gene delivery and indicates the potential of interfering with chemokine action to prevent corneal graft failure.

The assessment of tissue-specific pharmacodynamics is desirable in the development of tumor-targeted therapies. Plasma deoxyuridine (dUrd) levels, a measure of systemic thymidylate synthase (TS) inhibition, has limited application for studying the pharmacodynamics of novel TS inhibitors targeted to the high affinity alpha-folate receptor (FR). Here, we have evaluated the utility of [(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) for imaging the tissue pharmacodynamics of BGC 945, an FR-targeted antifolate TS inhibitor; the nontargeted antifolate BGC 9331 was used for comparison. TS inhibition by both drugs induced a concentration-dependent increase in [(3)H]thymidine uptake in FR-positive human epidermoid KB cells. Membrane-associated equilibrative nucleoside transporter type 1 levels increased from 55,720 +/- 6,101 to 118,700 +/- 5,193 and 130,800 +/- 10,800 per cell at 100 mug/mL of BGC 9331 and BGC 945, respectively, suggesting this as a potential mechanism of increased nucleoside uptake. In keeping with these in vitro findings, tumor [(18)F]FLT accumulation in KB xenografts increased by >/=2-fold after drug treatment with maximal levels at 1 to 4 hours and 4 to 24 hours after BGC 9331 and BGC 945 treatment, respectively. Of interest to FR targeting, BGC 9331, but not BGC 945, induced accumulation of [(18)F]FLT uptake in intestine, a proliferative and TS-responsive tissue. For both drugs, quantitative changes in tumor [(18)F]FLT uptake were associated with increased tumor dUrd levels. In conclusion, we have validated the utility of [(18)F]FLT-PET to image TS inhibition induced by antifolates and shown the tumor-specific activity of BGC 945. This imaging biomarker readout will be useful in the early clinical development of BGC 945.

Graft rejection is critically dependent on the recruitment of leukocytes via adhesion molecules on the endothelium, and inhibition of these interactions can prolong graft survival. We have therefore developed an approach using siRNA to inhibit the expression of VCAM-1 in endothelial cells. We transfected siRNA constructs into murine corneal and vascular endothelium and looked at expression of VCAM-1 and other surface molecules by flow cytometry. Adhesion assays (both static and under flow) were used to determine the effect of VCAM-1 inhibition. The activation of cellular stress responses was assessed by RT-PCR. Constructs encoding siRNA can block expression of VCAM-1 in both corneal and vascular endothelial cells (in the latter case after cytokine stimulation). Inhibition of VCAM-1 expression reduced the ability of T cells to adhere to endothelium. However, there were non-specific effects of siRNA expression, including upregulation of (Programmed Death Ligand 1) PDL1 and decreased cell growth. Analysis of stress pathways showed that the endothelial cells transfected with siRNA had upregulated molecules associated with cell stress. While these data are supportive of a potential therapeutic role for siRNA constructs in blocking the expression of adhesion molecules, they also highlight potential non-specific effects of siRNA that must be carefully considered in any application of this technology.

Thymidylate synthase (EC 2.1.1.45) is a key enzyme for the de novo synthesis of DNA and as such a target for anticancer drug development. There is a need to develop noninvasive methods for assessing thymidylate synthase inhibition in tumors. The aim of this study was to assess the potential of 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) for early measurement of thymidylate synthase inhibition and to elucidate the cellular mechanisms involved. Radiation-induced fibrosarcoma-1 tumor-bearing mice were injected with a single i.p. dose of the thymidylate synthase inhibitor 5-fluorouracil (5-FU; 165 mg/kg) and imaged by [(18)F]FLT-PET at 1 to 2 hours after treatment. Deoxyuridine, thymidine kinase 1 (cytoplasmic thymidine kinase; EC2.7.1.21), and ATP levels in excised tumors were measured. Cellular assays for membrane transport were also done. There was a 1.8-fold increase in the 60-minute [(18)F]FLT tumor/heart radioactivity ratio in drug-treated mice compared with vehicle controls (P = 0.0016). Plasma and tumor deoxyuridine levels increased significantly but thymidine kinase and ATP levels were unchanged. Whole-cell assays implicated a (low level) functional role for the type-1 equilibrative nucleoside transporter (ENT). There was an increase in type-1 ENT-binding sites per cell from 49,110 in untreated cells to 73,142 (P = 0.03) in cells treated with 10 microg/mL 5-FU for 2 hours, without a change in transporter affinity (P = 0.41). We conclude that [(18)F]FLT-PET can be used to measure thymidylate synthase inhibition as early as 1 to 2 hours after treatment with 5-FU by a mechanism involving redistribution of nucleoside transporters to the plasma membrane.

1. The Rathke's gland secretions of loggerhead (Caretta caretta) and Kemp's ridley (Lepidochelys kempi) sea turtles contain 20 and 10 mg of protein/ml, respectively. The proteins of each species were separated by gel filtration into two major fractions, one (35%) in the excluded volume, and one (50%) with a molecular mass of approximately 55 kDA. 2. The 55 kDa fraction from each species' secretions exhibits a single band on SDS-PAGE (Mr approximately equal to 55,000) and a single amino-terminal sequence. 3. The amino acid compositions of the two 55 kDa proteins are similar, and the first 15 residues of their amino terminus are identical. Both proteins contain glucosamine. 4. Analyses of the amino acid and amino sugar composition of the high molecular weight fractions from the two turtle species also indicate similarities; there are distinct differences between them and their 55 kDa proteins.

Rabbit muscle has been found to contain an activity that catalyzes the specific removal of Ac-Met from acetylated peptides. The activity is associated with free ribosomes and microsomes in the rabbit muscle extract but can be removed from these subcellular fractions by exposure to 0.5 M NaCl in the presence of 2 mM MgCl2; only partial removal was achieved with microsomes, but complete removal with ribosomes. A nearly 200-fold enrichment of the activity was achieved by this simple succession of differential centrifugation and salt extraction. Eighteen 14C-acetylpeptides have been tested as substrates for the partially purified activity assaying for the production of free 14C-acetylamino acid by high performance liquid chromatography. None of the peptides containing N-terminal acetylated Ala, Asp, Ser, or Gly were cleaved at a significant rate. Six of a total of eight peptides containing N-terminal Ac-Met were cleaved by the ribosomal extract at different rates. The active substrates varied in length from tri- to undecapeptides. The activity is inhibited by high concentrations of the protease inhibitor phenylmethylsulfonyl fluoride. Based on these observations, we tentatively conclude that the activity satisfy the criteria of a general N-terminal protein processing enzyme: it can remove Ac-Met from most, but not all, N-terminal sequences and appears to be inactive toward the N-terminal acetylamino acids most commonly found in eukaryotic proteins.

An N-acylaminoacyl-peptide hydrolase has been purified to homogeneity (7,000-fold with 20% yield) from rabbit muscle. This overall enrichment and its general properties as a soluble protein suggest that it is of cytosolic origin and not a component of ribosomes or other cellular organelles. The enzyme has an Mr of 230,000-245,000 and a subunit Mr of 76,000-80,000. An extensive survey of the substrate specificity of the pure enzyme reveals that our earlier conclusions (Radhakrishna, G., and Wold, F. (1986) J. Biol. Chem. 261, 9572-9575) that the enzyme is specific for Ac-Met-peptides are wrong. The enzyme catalyzes the rapid removal of Ac-Thr, Ac-Ala, Ac-Met, Ac-Ser, and more slowly Ac-Gly from peptides of different lengths. Other acetylated amino acids (Cys, Tyr, Asp, Val, Phe, Ile, Leu) may be removed at 1% or less of the rate of the above good substrates from some peptide substrates. The nature of the amino acid in the second position of the acetylated peptide generally has only a minor effect on the reaction rate; however, with charged amino acids (Arg, Asp) in the second position the reaction is retarded, and with proline it is virtually abolished. Except for slow rate of hydrolysis of acetylated dipeptides, the hydrolase does not appear to be severely affected by the peptide length in the range studied (from 2 to 11 amino acid residues). The hydrolase also cleaves formylamino acids from formylated peptides. The biological function of the enzyme is not clear.