Kenneth Bagshawe was a physician, a scientist and an architect of modern oncology. He was first to show that combination chemotherapy can cure a non-haematological cancer, choriocarcinoma. He demonstrated how a tumour marker in blood and urine can give a quantitative representation of the total amount of tumour, providing a monitor of response to treatment or relapse and an indicator of prognosis. He enhanced understanding and treatment of gestational trophoblastic diseases (GTD), a group of which choriocarcinoma is the most lethal member. The most common form of GTD is hydatidiform mole and he developed a national system for management, resulting in a cure rate of virtually 100%. For choriocarcinoma, the figure is today approaching 98%. His system is used in many countries, and over several decades has contributed to the cure and preservation of fertility in hundreds of thousands of women who previously had little or no hope. He used the same principles to treat testicular and ovarian germ cell tumours, again achieving high levels of cure in patients whose disease had spread and would previously have been fatal. He innovated throughout his career, seeking improved tumour specificity in diagnosis and treatment of GTD and inventing antibody-directed enzyme prodrug therapy for more common cancers. He founded the first department of oncology in the UK and devoted much time to developing the speciality, directing research funding organizations and supporting the development of the speciality worldwide. He was a dedicated, original and hugely productive pioneer of oncology.

The 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics international conferences, and the 2012 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 3-6, 2012 in San Diego, CA. The meeting drew over 800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a prelude to the main events, a pre-conference workshop held on December 2, 2012 focused on intellectual property issues that impact antibody engineering. The Antibody Engineering Conference was composed of six sessions held December 3-5, 2012: (1) From Receptor Biology to Therapy; (2) Antibodies in a Complex Environment; (3) Antibody Targeted CNS Therapy: Beyond the Blood Brain Barrier; (4) Deep Sequencing in B Cell Biology and Antibody Libraries; (5) Systems Medicine in the Development of Antibody Therapies/Systematic Validation of Novel Antibody Targets; and (6) Antibody Activity and Animal Models. The Antibody Therapeutics conference comprised four sessions held December 4-5, 2012: (1) Clinical and Preclinical Updates of Antibody-Drug Conjugates; (2) Multifunctional Antibodies and Antibody Combinations: Clinical Focus; (3) Development Status of Immunomodulatory Therapeutic Antibodies; and (4) Modulating the Half-Life of Antibody Therapeutics. The Antibody Society's special session on applications for recording and sharing data based on GIATE was held on December 5, 2012, and the conferences concluded with two combined sessions on December 5-6, 2012: (1) Development Status of Early Stage Therapeutic Antibodies; and (2) Immunomodulatory Antibodies for Cancer Therapy.

The 23rd Annual Antibody Engineering, 10th Annual Antibody Therapeutics international conferences, and the 2012 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, were held December 3–6, 2012 in San Diego, CA. The meeting drew over 800 participants who attended sessions on a wide variety of topics relevant to antibody research and development. As a prelude to the main events, a pre-conference workshop held on December 2, 2012 focused on intellectual property issues that impact antibody engineering. The Antibody Engineering Conference was composed of six sessions held December 3–5, 2012: (1) From Receptor Biology to Therapy; (2) Antibodies in a Complex Environment; (3) Antibody Targeted CNS Therapy: Beyond the Blood Brain Barrier; (4) Deep Sequencing in B Cell Biology and Antibody Libraries; (5) Systems Medicine in the Development of Antibody Therapies/Systematic Validation of Novel Antibody Targets; and (6) Antibody Activity and Animal Models. The Antibody Therapeutics conference comprised four sessions held December 4–5, 2012: (1) Clinical and Preclinical Updates of Antibody-Drug Conjugates; (2) Multifunctional Antibodies and Antibody Combinations: Clinical Focus; (3) Development Status of Immunomodulatory Therapeutic Antibodies; and (4) Modulating the Half-Life of Antibody Therapeutics. The Antibody Society’s special session on applications for recording and sharing data based on GIATE was held on December 5, 2012, and the conferences concluded with two combined sessions on December 5–6, 2012: (1) Development Status of Early Stage Therapeutic Antibodies; and (2) Immunomodulatory Antibodies for Cancer Therapy.

Now in its 23rd and 10th years, respectively, the Antibody Engineering and Antibody Therapeutics conferences are the Annual Meeting of The Antibody Society. The scientific program covers the full spectrum of challenges in antibody research and development from basic science through clinical development. In this preview of the conferences, the chairs provide their thoughts on sessions that will allow participants to track emerging trends in (1) the development of next-generation immunomodulatory antibodies; (2) the complexity of the environment in which antibodies must function; (3) antibody-targeted central nervous system (CNS) therapies that cross the blood brain barrier; (4) the extension of antibody half-life for improved efficacy and pharmacokinetics (PK)/pharmacodynamics (PD); and (5) the application of next generation DNA sequencing to accelerate antibody research. A pre-conference workshop on Sunday, December 2, 2012 will update participants on recent intellectual property (IP) law changes that affect antibody research, including biosimilar legislation, the America Invents Act and recent court cases. Keynote presentations will be given by Andreas Plückthun (University of Zürich), who will speak on engineering receptor ligands with powerful cellular responses; Gregory Friberg (Amgen Inc.), who will provide clinical updates of bispecific antibodies; James D. Marks (University of California, San Francisco), who will discuss a systems approach to generating tumor targeting antibodies; Dario Neri (Swiss Federal Institute of Technology Zürich), who will speak about delivering immune modulators at the sites of disease; William M. Pardridge (University of California, Los Angeles), who will discuss delivery across the blood-brain barrier; and Peter Senter (Seattle Genetics, Inc.), who will present his vision for the future of antibody-drug conjugates. For more information on these meetings or to register to attend, please visit www.IBCLifeSciences.com/AntibodyEng or call 800-390-4078. Members of The Antibody Society and mAbs journal subscribers receive a 20% discount for meeting registration. To obtain this discount, email kdostie@ibcusa.com. mAbs is the official therapeutics journal of The Antibody Society and offers a discounted subscription to Society members for $49.

BACKGROUND:Biology, biomedicine and healthcare have become data-driven enterprises, where scientists and clinicians need to generate, access, validate, interpret and integrate different kinds of experimental and patient-related data. Thus, recording and reporting of data in a systematic and unambiguous fashion is crucial to allow aggregation and re-use of data. This paper reviews the benefits of existing biomedical data standards and focuses on key elements to record experiments for therapy development. Specifically, we describe the experiments performed in molecular, cellular, animal and clinical models. We also provide an example set of elements for a therapy tested in a phase I clinical trial.FINDINGS:We introduce the Guidelines for Information About Therapy Experiments (GIATE), a minimum information checklist creating a consistent framework to transparently report the purpose, methods and results of the therapeutic experiments. A discussion on the scope, design and structure of the guidelines is presented, together with a description of the intended audience. We also present complementary resources such as a classification scheme, and two alternative ways of creating GIATE information: an electronic lab notebook and a simple spreadsheet-based format. Finally, we use GIATE to record the details of the phase I clinical trial of CHT-25 for patients with refractory lymphomas. The benefits of using GIATE for this experiment are discussed.CONCLUSIONS:While data standards are being developed to facilitate data sharing and integration in various aspects of experimental medicine, such as genomics and clinical data, no previous work focused on therapy development. We propose a checklist for therapy experiments and demonstrate its use in the 131Iodine labeled CHT-25 chimeric antibody cancer therapy. As future work, we will expand the set of GIATE tools to continue to encourage its use by cancer researchers, and we will engineer an ontology to annotate GIATE elements and facilitate unambiguous interpretation and data integration.

Now in its 23rd and 10th years, respectively, the Antibody Engineering and Antibody Therapeutics conferences are the Annual Meeting of The Antibody Society. The scientific program covers the full spectrum of challenges in antibody research and development from basic science through clinical development. In this preview of the conferences, the chairs provide their thoughts on sessions that will allow participants to track emerging trends in (1) the development of next-generation immunomodulatory antibodies; (2) the complexity of the environment in which antibodies must function; (3) antibody-targeted central nervous system (CNS) therapies that cross the blood brain barrier; (4) the extension of antibody half-life for improved efficacy and pharmacokinetics (PK)/pharmacodynamics (PD); and (5) the application of next generation DNA sequencing to accelerate antibody research. A pre-conference workshop on Sunday, December 2, 2012 will update participants on recent intellectual property (IP) law changes that affect antibody research, including biosimilar legislation, the America Invents Act and recent court cases. Keynote presentations will be given by Andreas Plückthun (University of Zürich), who will speak on engineering receptor ligands with powerful cellular responses; Gregory Friberg (Amgen Inc.), who will provide clinical updates of bispecific antibodies; James D. Marks (University of California, San Francisco), who will discuss a systems approach to generating tumor targeting antibodies; Dario Neri (Swiss Federal Institute of Technology Zürich), who will speak about delivering immune modulators at the sites of disease; William M. Pardridge (University of California, Los Angeles), who will discuss delivery across the blood-brain barrier; and Peter Senter (Seattle Genetics, Inc.), who will present his vision for the future of antibody-drug conjugates. For more information on these meetings or to register to attend, please visit www.IBCLifeSciences.com/AntibodyEng or call 800-390-4078. Members of The Antibody Society and mAbs journal subscribers receive a 20% discount for meeting registration. To obtain this discount, email kdostie@ibcusa.com. mAbs is the official therapeutics journal of The Antibody Society and offers a discounted subscription to Society members for $49.

During the development cycle of a new antibody therapy, the therapeutic agent will be tested on subsequently more biologically complex models. New experiments’ designs are based upon data gathered from prior models. New researchers who inherit the data and researchers from groups with different cultures or expertise are often called upon to interpret these data. Experiments which are not recorded consistently or employ ambiguous terminology can make interpreting these results difficult. The researcher who had originally collected the data may not be at hand to correct any misunderstanding or offer clarification and data can be unknowingly misused. This introduces an element of risk into the therapy development process. We have developed a reporting guideline for recording therapy experiments. This guideline consists of a checklist of data to be recorded from antibody therapy experiments performed in molecular, cellular, animal and clinical model.

The coincidence of testicular carcinoma and sarcoidosis can result in diagnostic errors and inappropriate treatment unless patients are appropriately investigated. We report 3 such cases; 1 in which sarcoidosis preceded the diagnosis, 1 of coincident diagnoses, and 1 in which the sarcoidosis was diagnosed after testicular carcinoma. We review the investigations that can be used to resolve diagnostic uncertainty and the evidence for an association between the 2 diseases.

The welcome attitude of the 'omics community, journals and funders of research towards data sharing, coupled with successful implementations of data standards, has resulted in resource dissemination and a better understanding of many diseases, including cancer. Sharing experiment data is beneficial in terms of knowledge generation, allowing reproduction and validation of results. An adherence to a reporting guideline enables full-value extraction from costly data; this is an inexpensive method to increased quality without incurring disproportionate costs. For therapy data in particular, easy access to the range of new approaches and the ability to perform valid comparisons between these approaches would be especially useful. We discuss initiatives that support resource sharing and summarize three reporting guidelines for experiment data that have been adopted successfully. Finally, we introduce a new guideline that encompasses the diverse data types in therapeutic experiments, which is intended to be of use to the cancer therapeutics community.

Superparamagnetic iron oxide nanoparticles (SPIONs) can substantially improve the sensitivity of magnetic resonance imaging (MRI). We propose that SPIONs could be used to target and image cancer cells if functionalised with recombinant single chain Fv antibody fragments (scFv). We tested our hypothesis by generating antibody-functionalised (abf) SPIONs using a scFv specific for carcinoembryonic antigen (CEA), an oncofoetal cell surface protein. SPIONs of different hydrodynamic diameter and surface chemistry were investigated and targeting was confirmed by ELISA, cellular iron uptake, confocal laser scanning microscopy (CLSM) and MRI. Results demonstrated that abf-SPIONs bound specifically to CEA-expressing human tumour cells, generating selective image contrast on MRI. In addition, we observed that the cellular interaction of the abf-SPIONs was influenced by hydrodynamic size and surface coating. The results indicate that abf-SPIONs have potential for cancer-specific MRI.

Purpose: In preclinicalmodels, radioimmunotherapy with I-A5B7 anti ^ carcinoembryonic antigen (CEA) antibody (I-A5B7) combined with the vascular disruptive agent combretastatinA4-phosphate (CA4P) produced cures unlike either agent alone.We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. Experimental Design:Patients had CEAof10 to1,000 Ag/L, QTc V450ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry.Tumor was suitable for blood flowanalysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800MBq/m ofI-A5B7onday1and 45mg/mCA4Pgiven 48 and 72 hours post-I-A5B7, thenweekly for up to sevenweeks. Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m, and CA4P escalated to 54 mg/m. Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Singlephoton emission computed tomography confirmed tumor antibody uptake in all10 patients. DCEMRIconfirmed falls in kinetic parameters (K/IAUGC60) in 9 of12 patients.The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient whohad a minor response on computed tomography and a reduced serum tumor marker level. Conclusions:This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy. Carcinoembryonic antigen (CEA) is a membrane-bound glycoprotein that is expressed by most gastrointestinal tumors but the expression of which is normally limited to the luminal surface of the gastrointestinal tract. As such, CEA represents a good target for radioimmunotherapy. I-A5B7 is a CEA-specific mouse monoclonal antibody that has been shown to localize to human colon carcinoma xenografts (1). A previous phase I trial of single-agent I-A5B7, done in patients with advanced colorectal cancer, defined bone marrow suppression as the dose-limiting toxicity (DLT) at a maximum tolerated dose of 2,400 MBq/m. One of ten patients had a partial response. However the efficacy of radioimmunotherapy in solid tumors is limited by low tumor penetration into the poorly perfused central tumor areas (2) and relative radioresistance of hypoxic tissue. By contrast, the tubulinbinding vascular disruptive agent (VDA) combretastatin A4 phosphate (CA4P) causes central tumor necrosis leaving a viable tumor rim (3). Single agent phase I trials of the tubulin-binding VDA CA4P have established the maximum tolerated dose at 60 to 68 mg/m and showed dose-dependent changes in tumor vascular parameters by dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI; ref. 4–6). The lack of objective tumor response in these studies is likely due to the sparing of the tumor rim which continues to grow. Combining radioimmunotherapy with CA4P therefore presents a rational drug combination in which the action of the two agents is complementary in targeting different Cancer Therapy: Clinical Authors’ Affiliations: UCL Cancer Institute, University College London, Department of Medical Oncology, Paul Strickland Scanner Centre, and Gray Cancer Institute, Mount Vernon Hospital, Northwood, Departments of Oncology and Nuclear Medicine, Royal Free Hospital, Hampstead, and Cancer Research UK, London, United Kingdom; and CLiCIR, University of Hertfordshire, Hatfield, Hertfordshire, United Kingdom Received1/9/09; revised3/15/09;accepted4/7/09;publishedOnlineFirst6/23/09. Grant support: Experimental Cancer Medicine Centre grant C34/A7279. CRUKProgrammeGrant C34/A5149. This work was undertaken at University College London Hospital/University College London, which received a proportion of funding from the Department of Health’s NIHRBiomedical Research Centre’s funding scheme. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints:TimMeyer, UCLCancer Institute, Paul O’Gorman Building, University College London, 72 Huntley Street, LondonWC1E 6BT, United Kingdom. Phone: 0207-679-6731; Fax: 0207-679-6731; E-mail: t.meyer@ucl.ac.uk. F2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0035 www.aacrjournals.org Clin Cancer Res 2009;15(13) July1, 2009 4484 Research. on April 13, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from biophysical compartments of the tumor. The combination has been explored in preclinical models using CEA-positive colorectal xenografts (7). In these experiments I-A5B7 delayed tumor growth and CA4P alone was ineffective, but the combination of the two agents achieved cure in five of six animals. We conducted a phase I trial to define the DLT and maximum tolerated regimen of I-A5B7 in combination with CA4P in patients with CEA-expressing tumors refractory to standard therapy. Secondary end points included pharmacokinetic and pharmacodynamic assessments and antitumor effects. For CA4P, an initial dose was given prior to the combined therapy in order that DCE-MRI and pharmacokinetics could be done in nonradioactive patients allowing subsequent correlation with clinical outcome. The trial was sponsored by Cancer Research UK.

Molecular analysis is firmly established as part of everyday practice in modern oncology; for instance, genetic and protein markers are used in the diagnosis and selection of treatment in breast, colorectal, and several other cancers. These applications are the first ripple in a wave of information which, if used effectively, could achieve the holy grail of improving outcomes for people with cancer whilst increasing cost-effectiveness. But there is a major obstacle to realising this vision at the level of handling the volume, diversity, scale, and complexity of relevant information being generated.

We review the current status of imaging as applied to targeted therapy with particular focus on antibody-based therapeutics. Antibodies have high tumor specificity and can be engineered to optimize delivery to, and retention within, the tumor. Whole antibodies can activate natural immune effector mechanisms and can be conjugated to β- and α-emitting radionuclides, toxins, enzymes, and nanoparticles for enhanced therapeutic effect. Imaging is central to the development of these agents and is used for patient selection, performing dosimetry and assessment of response. γ- and positron-emitting radionuclides may be used to image the distribution of antibody-targeted therapeutics While some radionuclides such as iodine-131 emit both β and γ radiation and are therefore suitable for both imaging and therapy, others are more suited to imaging or therapy alone. Hence for radionuclide therapy of neuroendocrine tumors, patients can be selected for therapy on the basis of γ-emitting indium-111-octreotide imaging and treated with β-emitting yttrium-90-octreotate. Positron-emitting radionuclides can give greater sensitivity that γ-emitters but only a single radionuclide can be imaged at one time and the range of radionuclides is more limited. The multiple options for antibody-based therapeutic molecules, imaging technologies and therapeutic scenarios mean that very large amounts of diverse data are being acquired. This can be most effectively shared and progress accelerated by use of common data standards for imaging, biological, and clinical data.

Purpose: There is a need for new treatments for Hodgkin and T-cell lymphoma due to the development of drug resistance in a proportion of patients. This phase I study of radioimmunotherapy used CHT-25, a chimeric antibody to the α-chain of the interleukin-2 receptor, CD25, conjugated to iodine-131 (131I) in patients with refractory CD25-positive lymphomas. Experimental Design: Fifteen patients were treated (Hodgkin lymphoma, 12; angioimmunoblastic T-cell lymphoma, 1; adult T-cell leukemia/lymphoma, 2). Tumor was monitored by computed tomography and in all but two patients by 18F-fluorodeoxyglucose positron emission tomography. Results: There were no grade 3 or 4 infusion reactions. At the maximum tolerated dose of 1,200 MBq/m2, the major side effect was delayed myelotoxicity with the nadir for platelets at 38 days and for neutrophils at 53 days. One patient treated with 2,960 MBq/m2 developed prolonged grade 4 neutropenia and thrombocytopenia and died of Pneumocystis jiroveci pneumonia. Nonhematologic toxicity was mild. Single photon emission computer tomography imaging showed tumor-specific uptake and retention of 131I and no excessive retention in normal organs. Of nine patients receiving ≥1,200 MBq/m2, six responded (three complete response and three partial response); one of six patients with administered radioactivity of ≤740 MBq/m2 had a complete response. Conclusions: CHT-25 is well tolerated with 1,200 MBq/m2 administered radioactivity and shows clinical activity in patients who are refractory to conventional therapies. Phase II studies are justified to determine efficacy and toxicity in a broader range of clinical scenarios. (Clin Cancer Res 2009;15(24):7701–10)

Purpose: In preclinical models, radioimmunotherapy with 131I-A5B7 anti–carcinoembryonic antigen (CEA) antibody (131I-A5B7) combined with the vascular disruptive agent combretastatin-A4-phosphate (CA4P) produced cures unlike either agent alone. We conducted a phase I trial determining the dose-limiting toxicity (DLT), maximum tolerated dose, efficacy, and mechanism of this combination in patients with gastrointestinal adenocarcinomas. Experimental Design: Patients had CEA of 10 to 1,000 μg/L, QTc ≤450 ms, no cardiac arrhythmia/ischaemia, and adequate hematology/biochemistry. Tumor was suitable for blood flow analysis by dynamic contrast enhanced-magnetic resonance imaging (MRI). The starting dose was 1,800 MBq/m2 of 131I-A5B7 on day 1 and 45 mg/m2 CA4P given 48 and 72 hours post-131I-A5B7, then weekly for up to seven weeks. Results: Twelve patients were treated, with mean age of 63 years (range, 32-77). Two of six patients at the first dose level had DLTs (grade 4 neutropenia). The dose was reduced to 1,600 MBq/m2, and CA4P escalated to 54 mg/m2. Again, two of six patients had DLTs (neutropenia). Of ten assessable patients, three had stable disease and seven had progressive disease. Single-photon emission computed tomography confirmed tumor antibody uptake in all 10 patients. DCE-MRI confirmed falls in kinetic parameters (Ktrans/IAUGC60) in 9 of 12 patients. The change of both pharmacokinetic parameters reached a level expected to produce efficacy in one patient who had a minor response on computed tomography and a reduced serum tumor marker level. Conclusions: This is believed to be the first trial reporting the combination of radioimmunotherapy and vascular disruptive agent; each component was shown to function, and myelosuppression was dose-limiting. Optimal dose and timing of CA4P, and moderate improvements in the performance of radioimmunotherapy seem necessary for efficacy.

PURPOSE: This phase I dose-escalation study was undertaken to establish the maximum tolerated dose of the sequence-selective minor groove DNA binding agent SJG-136 in patients with advanced solid tumors. The study also investigated antitumor activity and provided pharmacokinetic and pharmacodynamic data. EXPERIMENTAL DESIGN: Sixteen patients were assigned sequentially to escalating doses of SJG-136 (15-240 microg/m(2)) given as a 10-minute i.v. infusion every 21 days. The dose was subsequently reduced in incremental steps to 45 microg/m(2) due to unexpected toxicity. RESULTS: The maximum tolerated dose of SJG-136 was 45 microg/m(2). The main drug-related adverse event was vascular leak syndrome (VLS) characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema. Other unexpected adverse events included elevated liver function tests and fatigue. The VLS and liver toxicity had delayed onset and increased in severity with subsequent cycles. Disease stabilization was achieved for >6 weeks in 10 patients; in 2 patients this was maintained for >12 weeks. There was no evidence of DNA interstrand cross-linking in human blood lymphocytes with the use of the comet assay. Evidence of DNA interaction in lymphocytes and tumor cells was shown through a sensitive gamma-H2AX assay. SJG-136 had linear pharmacokinetics across the dose range tested. CONCLUSIONS: SJG-136 was associated with dose-limiting VLS and hepatotoxicity when administered by short injection every 21 days. DNA damage was noted, at all dose levels studied, in circulating lymphocytes. The etiology of the …

Chidgey, Leng and Lacey1 review the successes and some outstanding issues facing the UK National Institute for Health and Clinical Excellence (NICE) in improving the routine delivery of care in the National Health Service and similar organizations. The focus of their essay is the NICE programme of guideline development, ‘arguably the largest in the world’, whose objective is to carry out rigorous reviews of the evidence for alternative treatments, develop clinical guidance that ensures clinical decisions are based on the best evidence, target use of resources optimally and maintain ongoing reviews of new evidence. Chidgey et al. point to convincing examples of successes in changing practice, while accepting that overall the record of translating guidance into successful implementation is ‘mixed’. Editorials in the same issue of JRSM discuss this assessment. Iain Chalmers asks ‘How are we to know whether all this work [on guideline development] has led to better patient care in the NHS?’ Gupta and Warner observe that ‘although NICE guidelines can be very helpful in guiding clinicians and patients, they focus on the clinical problem and cannot take into account various other factors (e.g. physical and psychological co-morbidities, social and cultural issues) that make each patient unique’. Finally the editor of the JRSM, Kamran Abbasi, comments that ‘Guidelines have a miserable record in changing clinical practice’ and ‘The central problem for NICE is that too many clinicians view its rationing role with displeasure and each decision and guidance brings its own enemies. … Clinicians feel increasingly isolated from the decision-making process and increasingly resentful of the inflexibility of high level commandments.’ Chidgey et al. suggest a number of ways to improve guideline implementation, ranging from educational and outreach mechanisms to the use of clinical audit and reminders and ‘computer-based decision support’. In this paper we wish to pick up the last remark because it was only mentioned in passing and we believe that Clinical Decision Support (CDS) technology actually offers a major new implementation strategy. Specifically, we wish to draw attention to ways in which CDS can make a significant contribution to the effective dissemination of evidence-based practice. Furthermore we will argue that decision support technology can address a number of issues raised in the editorials: providing clinical guidance in a form that is specific to individual patients; permitting and indeed supporting the exercise of professional clinical judgement if this conflicts with general guidelines, and involving working clinicians in the translation of research into practice. This is not a commentary on NICE, or the UK, but about a strategy for improving the quality and safety of patient care in modern medical services. We will explain these claims in the context of a long-term research programme supported by Cancer Research UK (CRUK) which, while focused on cancer, has resulted in techniques for supporting clinical decision-making which are believed to be applicable across clinical specialties, sectors and countries. CDS technology is a rapidly developing field.2 We have not attempted to write a detailed review of different approaches to CDSs for this paper because several already exist.3–5 Short overviews of many systems can be found at http://www.openclinical.org. In the first section of the paper we briefly overview international efforts to develop and disseminate evidence-based clinical practice guidelines (CPGs), their perceived impact on clinical practice and the issues that have emerged.2 Next we describe advances in the field of decision support, drawing particularly though not exclusively on our own experience. The last part of the paper focuses on how CDS technology can address challenges in implementing clinical guidelines and help clinicians and others to comply with evidence-based recommendations. A novel capability that CDS services can offer is to capture clinicians' experience in using a CPG, thereby informing the treatment policies of the healthcare organization, and feeding back information about CPG use and impact to the authors and reviewers of guidance and clinical researchers.

Introduction: Radioimmunotherapy (RIT) has been shown to be more effective against solid tumor micrometastases, possibly due to an inverse relationship between tumor size and radiolabeled antibody uptake. In this study, the accretion of radiolabeled antibody in intrahepatic micrometastases in an experimental model was investigated using quantitative digital autoradiography, enabling the analysis of antibody uptake in microscopic tumors.Methods: Mice bearing subcutaneous or intrahepatic metastatic models of LS174T colorectal cancer were injected with radiolabeled anti-carcinoembryonic antigen antibody ([I-125]A5B7). Tissues were taken to investigate distribution of radionuclide and tumor uptake. In a therapy Study, mice bearing intrahepatic metastatic tumors were injected with [I-131]A5B7.Results: Subcutaneous tumors and large metastatic deposits had similar uptake (e.g,, similar to 15%ID/g at 24 h). Small metastatic deposits had higher uptake (e.g., similar to 80%ID/g at 24 h) and prolonged retention at later time points. Small deposit uptake was significantly reduced by accompanying large deposits in the same liver. RIT resulted in increased survival time (untreated mean survival of 21.6 +/- 12.9 vs. treated mean Survival of 39.1 +/- 30.8 days), but there was a large range of response within groups, presumably due to variation in pattern and extent of tumor as observed in the biodistribution study. Liver function tests and body weight did not change with tumor growth or therapy response, strongly Supporting the use of in vivo imaging in metastatic tumor therapy studies.Conclusions: Radioimmunodetection and therapy might be greatly influenced by the size and distribution of intrahepatic tumor deposits. (C) 2009 Elsevier Inc. All rights reserved.