The impact of genomic context on outcomes of solid cancer patients treated with genotype-matched targeted therapies: a comprehensive review.

INTRODUCTION: A critical need in the field of genotype-matched targeted therapy in cancer is to identify patients unlikely to respond to precision medicines. This will manage expectations of individualised therapies and avoid clinical progression to a point where institution of alternative treatments might not be possible. We examined the evidence base of the impact of genomic context on which targeted alterations are inscribed to identify baseline biomarkers distinguishing those obtaining the expected response from those with less benefit from targeted therapies. METHODS: A comprehensive narrative review was conducted: scoping searches were undertaken in PubMed, Cochrane Database of Systematic Reviews, and PROSPERO. Outcomes included in meta-analysis were progression-free and overall survival. Data were extracted from Kaplan-Meier and used to calculate hazard ratios. Studies presenting data on two molecular subcohorts (e.g. co-mutation versus no co-mutation) were included in fixed meta-analysis. Other studies were used for descriptive purposes. RESULTS: The presence of concomitant driver mutations, higher tumour mutational burden (TMB), greater copy number burden, and APOBEC signatures significantly reduces benefits of targeted therapy in lung cancers in never smokers (LCINS - less than 100 cigarettes per lifetime) and breast cancer, cancers with low TMB. LCINS have significantly poorer outcomes if their cancers harbour p53 co-mutations, an effect also seen in human epidermal growth factor receptor 2-positive (HER2+) breast cancer patients (trastuzumab) and head and neck cancer patients [phosphoinositide 3-kinase (PI3K) inhibition]. PI3K co-alterations have less impact when targeting epidermal growth factor receptor mutations and anaplastic lymphoma kinase fusions, but significantly reduce the impact of targeting HER2 and MET amplifications. SMARCA4 co-mutations predict for poor outcome in patients treated with osimertinib and sotorasib. In BRAF-mutant melanoma, whilst there are no genomic features distinguishing exceptional responders from primary progressors, there are clear transcriptomic features dichotomising these outcomes. CONCLUSION: To our knowledge, this is the most comprehensive review to date of the impact of genomic context on outcomes with targeted therapy. It represents a valuable resource informing progress towards contextualised precision medicine.

A state-of-the-art review of stratified medicine in cancer: towards a future precision medicine strategy in cancer.

BACKGROUND: Building on the success of targeted therapy in certain well-defined cancer genotypes, three platform studies-NCI-MATCH, LUNG-MAP and The National Lung Matrix Trial (NLMT)-have attempted to discover new genotype-matched therapies for people with cancer. PATIENTS AND METHODS: We review the outputs from these platform studies. This review led us to propose a series of recommendations and considerations that we hope will inform future precision medicine programmes in cancer. RESULTS: The three studies collectively screened over 13 000 patients. Across 37 genotype-matched cohorts, there have been 66/875 responders, with an overall response rate of 7.5%. Targeting copy number gain yielded 5/199 responses across nine biomarker-drug matched cohorts, with a response rate of 2.5%. CONCLUSIONS: The majority of these studies used single-agent targeted therapies. Whilst preclinical data can suggest rational combination treatment to reverse adaptive resistance or block parallel activated pathways, there is an essential need for accurate modelling of the toxicity-activity trade-off of combinations. Agent selection is often suboptimal; dose expansion should only be carried out with agents with clear clinical proof of mechanism and high target selectivity. Targeting copy number change has been disappointing; it is crucial to define the drivers on shared amplicons that include the targeted aberration. Maximising outcomes with currently available targeted therapies requires moving towards a more contextualised stratified medicine acknowledging the criticality of the genomic, transcriptional and immunological context on which the targeted aberration is inscribed. Genomic complexity and instability is likely to be a leading cause of targeted therapy failure in genomically complex cancers. Preclinical models must be developed that more accurately capture the genomic complexity of human disease. The degree of attrition of studies carried out after standard-of-care therapy suggests that serious efforts be made to develop a suite of precision medicine studies in the minimal residual disease setting.

Mechanisms of immunogenicity in colorectal cancer.

BACKGROUND: The immune response in cancer is increasingly understood to be important in determining clinical outcomes, including responses to cancer therapies. New insights into the mechanisms underpinning the immune microenvironment in colorectal cancer are helping to develop the role of immunotherapy and suggest targeted approaches to the management of colorectal cancer at all disease stages. METHOD: A literature search was performed in PubMed, MEDLINE and Cochrane Library databases to identify relevant articles. This narrative review discusses the current understanding of the contributors to immunogenicity in colorectal cancer and potential applications for targeted therapies. RESULTS: Responsiveness to immunotherapy in colorectal cancer is non-uniform. Several factors, both germline and tumour-related, are potential determinants of immunogenicity in colorectal cancer. Current approaches target tumours with high immunogenicity driven by mutations in DNA mismatch repair genes. Recent work suggests a role for therapies that boost the immune response in tumours with low immunogenicity. CONCLUSION: With the development of promising therapies to boost the innate immune response, there is significant potential for the expansion of the role of immunotherapy as an adjuvant to surgical treatment in colorectal cancer.

ANTECEDENTES: La respuesta inmune en el cáncer se considera cada vez más importante por su influencia sobre los resultados clínicos, incluidas las respuestas a las diferentes modalidades de tratamiento. Los nuevos conocimientos sobre los mecanismos implicados en el microambiente inmunitario en el cáncer colorrectal están ayudando a definir el papel de la inmunoterapia y el desarrollo de terapias dirigidas para el tratamiento del cáncer colorrectal en todos los estadios de la enfermedad. MÉTODOS: Se realizó una búsqueda bibliográfica en las bases de datos PubMed, Medline y Cochrane para identificar artículos relevantes. Esta revisión descriptiva discute la comprensión actual de los factores que contribuyen a la inmunogenicidad en el cáncer colorrectal y las posibles aplicaciones en terapias dirigidas. RESULTADOS: La capacidad de respuesta a la inmunoterapia en el cáncer colorrectal no es uniforme. Varios factores, tanto relacionados con la línea germinal, como con el tumor son determinantes potenciales de la inmunogenicidad en el cáncer colorrectal. Los estudios actuales están dirigidos a tumores con alta inmunogenicidad provocada por mutaciones en los genes de reparación de apareamientos erróneos en el ADN. Trabajos recientes sugieren un papel para los tratamientos que estimulan la respuesta inmune en tumores con baja inmunogenicidad. CONCLUSIÓN: Con el desarrollo de tratamientos prometedores para estimular la respuesta inmune innata, existe un potencial significativo para la expansión del papel de la inmunoterapia como adyuvante del tratamiento quirúrgico en el cáncer colorrectal.

Supervised exercise training as an adjunct therapy for venous leg ulcers: a randomized controlled feasibility trial.

BACKGROUND: Venous leg ulcers (VLUs) are typically painful and heal slowly. Compression therapy offers high healing rates; however, improvements are not usually sustained. Exercise is a low-cost, low-risk and effective strategy for improving physical and mental health. Little is known about the feasibility and efficacy of supervised exercise training used in combination with compression therapy patients with VLUs. OBJECTIVES: To assess the feasibility of a 12-week supervised exercise programme as an adjunct therapy to compression in patients with VLUs. METHODS: This was a two-centre, two-arm, parallel-group, randomized feasibility trial. Thirty-nine patients with venous ulcers were recruited and randomized 1 : 1 either to exercise (three sessions weekly) plus compression therapy or compression only. Progress/success criteria included exercise attendance rate, loss to follow-up and patient preference. Baseline assessments were repeated at 12 weeks, 6 months and 1 year, with healing rate and time, ulcer recurrence and infection incidents documented. Intervention and healthcare utilization costs were calculated. Qualitative data were collected to assess participants' experiences. RESULTS: Seventy-two per cent of the exercise group participants attended all scheduled exercise sessions. No serious adverse events and only two exercise-related adverse events (both increased ulcer discharge) were reported. Loss to follow-up was 5%. At 12 months, median ulcer healing time was lower in the exercise group (13 vs. 34·7 weeks). Mean National Health Service costs were £813·27 for the exercise and £2298·57 for the control group. CONCLUSIONS: The feasibility and acceptability of both the supervised exercise programme in conjunction with compression therapy and the study procedures is supported.

Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials.

Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types. Patients and methods: 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status. Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months. Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.

Consensus on precision medicine for metastatic cancers: a report from the MAP conference.

Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.

Brief Report: Implementing a Mediterranean Diet Intervention into a RCT: Lessons Learned from a Non-Mediterranean Based Country.

OBJECTIVE: To examine the participant experiences regarding perceived barriers and facilitators which impact on consuming the Mediterranean diet in the East of England. DESIGN: Qualitative methodology with focus groups. SETTING: A healthy, middle-aged population situated in the East of England. INTERVENTION: An 8-week Mediterranean dietary intervention trial. PARTICIPANTS: Eleven participants (including three co-habiting partners) in three focus groups, ranging between 50-65 yrs with a mean age of 54.3 yrs (±4.0) RESULTS: Thematic analysis from the focus groups revealed that participants considered that the MD intervention had introduced a better quality of food, widening the food-horizon and allowed them to re-define cultural eating habits. They also reported several physical benefits from adapting to this diet and found the experience as positive. Whilst claiming that the MD was an enjoyable and pleasurable, the participants did express difficulty adapting to the eating pattern, finding difficulty in purchasing food items, an increase in food costs and found work, stress and time pressures undermining adherence. CONCLUSION: The participants' experiences suggested that the MD was an encouraging dietary change with a middle aged non-Mediterranean based population group. Future MD interventions should tailor interventions and support participants closely, particularly with the necessary planning, organisation and purchasing involved with implementing this diet in non-Mediterranean countries. Secondly, researchers should also challenge any erroneous assumptions regarding the consumption of Mediterranean food, which may hinder implementation.

The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer.

BACKGROUND: The management of NSCLC has been transformed by stratified medicine. The National Lung Matrix Trial (NLMT) is a UK-wide study exploring the activity of rationally selected biomarker/targeted therapy combinations. PATIENTS AND METHODS: The Cancer Research UK (CRUK) Stratified Medicine Programme 2 is undertaking the large volume national molecular pre-screening which integrates with the NLMT. At study initiation, there are eight drugs being used to target 18 molecular cohorts. The aim is to determine whether there is sufficient signal of activity in any drug-biomarker combination to warrant further investigation. A Bayesian adaptive design that gives a more realistic approach to decision making and flexibility to make conclusions without fixing the sample size was chosen. The screening platform is an adaptable 28-gene Nextera next-generation sequencing platform designed by Illumina, covering the range of molecular abnormalities being targeted. The adaptive design allows new biomarker-drug combination cohorts to be incorporated by substantial amendment. The pre-clinical justification for each biomarker-drug combination has been rigorously assessed creating molecular exclusion rules and a trumping strategy in patients harbouring concomitant actionable genetic abnormalities. Discrete routes of pathway activation or inactivation determined by cancer genome aberrations are treated as separate cohorts. Key translational analyses include the deep genomic analysis of pre- and post-treatment biopsies, the establishment of patient-derived xenograft models and longitudinal ctDNA collection, in order to define predictive biomarkers, mechanisms of resistance and early markers of response and relapse. CONCLUSION: The SMP2 platform will provide large scale genetic screening to inform entry into the NLMT, a trial explicitly aimed at discovering novel actionable cohorts in NSCLC. CLINICAL TRIAL ISRCTN: 38344105.

Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer: a randomized phase II study.

BACKGROUND: Docetaxel/cisplatin/infusional 5-fluorouracil (5-FU; DCF) is a standard chemotherapy regimen for patients with advanced gastric cancer (GC). This phase II study evaluated docetaxel/oxaliplatin (TE), docetaxel/oxaliplatin/5-FU (TEF), and docetaxel/oxaliplatin/capecitabine (TEX) in patients with advanced GC. PATIENTS AND METHODS: Patients with metastatic or locally recurrent gastric adenocarcinoma (including carcinoma of the gastro-oesophageal junction) were randomly assigned (1 : 1 : 1) to TE, TEF, or TEX. Each regimen was tested at two doses before full evaluation at optimized dose levels. The primary end point was progression-free survival (PFS). Overall survival (OS), tumour response, and safety were also assessed. A therapeutic index (median PFS relative to the incidence of febrile neutropenia) was calculated for each regimen and compared with DCF (historical data). RESULTS: Overall, 248 patients were randomly assigned to receive optimized dose treatment. Median PFS was longer with TEF (7.66 [95% confidence interval (CI): 6.97-9.40] months) versus TE (4.50 [3.68-5.32] months) and TEX (5.55 [4.30-6.37] months). Median OS was 14.59 (95% CI: 11.70-21.78) months for TEF versus 8.97 (7.79-10.87) months for TE and 11.30 (8.08-14.03) months for TEX. The rate of tumour response (complete or partial) was 46.6% (95% CI 35.9-57.5) for TEF versus 23.1% (14.3-34.0) for TE and 25.6% (16.6-36.4) for TEX. The frequency and type of adverse events (AEs) were similar across the three arms. Common grade 3/4 AEs were fatigue (21%), sensory neuropathy (14%), and diarrhoea (13%). Febrile neutropenia was reported in 2% (TEF), 14% (TE), and 9% (TEX) of patients. The therapeutic index was improved with TEF versus TEX, TE, or DCF. CONCLUSION: These results suggest that TEF is worthy of evaluation as an arm in a phase III trial or as a backbone regimen for new targeted agents in advanced GC. CLINICALTRIALS.GOV: Identifier Trial registration number: NCT00382720.

Time to adjuvant chemotherapy following colorectal cancer resection is associated with an improved survival.

AIM: Multicentre randomized trials have demonstrated equivalent long-term outcomes for open and laparoscopic resection of colon cancer. Some studies have indicated a possible survival advantage in certain patients undergoing laparoscopic resection. Patients who receive adjuvant chemotherapy in < 8 weeks following surgery can have an improved survival. METHOD: Data were collated for patients having an elective laparoscopic or open resection for non-metastatic colorectal cancer between October 2003 and December 2010 and subsequently having adjuvant chemotherapy. Survival analysis was conducted. RESULTS: In all, 209 patients received adjuvant chemotherapy following open (n = 76) or laparoscopic (n = 133) surgery. Median length of stay was 3 days with laparoscopic resection and 6 days with open resection (P < 0.0005). Median number of days to initiation of adjuvant chemotherapy was 52 with laparoscopic resection and 58 with open resection (P = 0.008). The 5-year overall survival was 89.6% in patients receiving chemotherapy in < 8 weeks after surgery, compared with 73.5% who started the treatment over 8 weeks (P = 0.016). The 5-year overall survival for those patients with a laparoscopic resection was 82.3% compared with 80.3% with an open resection (P = 0.049). CONCLUSION: There is an overall survival advantage when patients receive adjuvant chemotherapy < 8 weeks after surgery. Laparoscopic resection allows earlier discharge and, subsequently, earlier initiation of adjuvant chemotherapy.

Implementing a community-based obesity prevention programme: experiences of stakeholders in the north east of England.

Recent literature indicates the potential of community-based obesity prevention programmes in the endeavour to reduce the prevalence of obesity in developed nations. Considerable suggestion and advocacy come from theoretical standpoints and little is known on actual practical application of this type of multi-component health promotion programme. This article explores the experiences of 'implementation' by stakeholders of a large community-based obesity prevention programme, facilitated by a National Health Service Care Trust in the north-east of England, UK. Three stakeholder groups (senior health officials, public health workers and community members) who had administrated and experienced the programme since its conception in 2006 provide perspectives on the aspects of local delivery and receipt. Semi-structured interviews and focus groups were conducted with stakeholders (28 participants in total). The participants felt there were three broad aspects which shaped and constrained the delivery and receipt of the programme, namely partnership working, integration of services and quality issues. Data indicated that it had taken time to establish working partnerships between the multi-agencies involved in the community-based obesity programme. Strategic management would aid the processes of communication and collaboration between agencies and also the local community involved in the administration, delivery and participation of interventions in the programme. Secondly, the way in which the programme is justified and sustained will have to be reviewed, with the intention of using a suitable evaluative framework or tool for monitoring purposes.

Evaluation of serum lysyl oxidase as a blood test for colorectal cancer.

AIMS: Lysyl oxidase (LOX) expression is elevated in colorectal cancer (CRC) tissue and associated with disease progression. A blood test may form a more acceptable diagnostic test for CRC although LOX has not previously been measured in the serum. We therefore sought to determine the clinical usefulness of a serum LOX test for CRC in a symptomatic population. METHODS: Adult patients referred to a hospital colorectal clinic with bowel symptoms completed a questionnaire and provided a blood sample for serum LOX measurement. Associations between presenting symptoms, serum LOX concentrations and outcomes of investigations were tested by univariate and multivariate analyses to determine if serum LOX was clinically useful in the prediction of CRC. LOX expression in CRC and adjacent colon biopsies was evaluated by ELISA and immunohistochemistry. RESULTS: Thirty-one cases of colorectal cancer and 16 high-risk polyps were identified from a total of 962 participants. There was no association between serum LOX concentration and the presence of CRC, high-risk polyps or cancers at any site. LOX expression was significantly increased in CRC tissue compared to adjacent colon. CONCLUSION: Despite overexpression of LOX in CRC tissue, elevated serum levels could not be demonstrated. Serum LOX measurement is therefore not a clinically useful test for CRC.

A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer.

BACKGROUND: Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients. METHODS: Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4-6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety. RESULTS: All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0-25.1) versus 25.0 weeks (95% CI 20.6-[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected. CONCLUSIONS: The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.

Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials.

BACKGROUND: REAL3 (Randomised ECF for Advanced or Locally advanced oesophagogastric cancer 3) was a phase II/III trial designed to evaluate the addition of panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in untreated advanced oesophagogastric adenocarcinoma, or undifferentiated carcinoma. MAGIC (MRC Adjuvant Gastric Infusional Chemotherapy) was a phase III study which demonstrated that peri-operative epirubicin, cisplatin and infused 5-fluorouracil (ECF) improved survival in early oesophagogastric adenocarcinoma. PATIENTS AND METHODS: Analysis of response rate (RR; the primary end-point of phase II) and biomarkers in the first 200 patients randomised to EOC or modified dose (m) EOC+P in REAL3 was pre-planned to determine if molecular selection for the on-going study was indicated. KRAS, BRAF and PIK3CA mutations and PTEN expression were assessed in pre-treatment biopsies and results correlated with response to mEOC+P. Association between these biomarkers and overall survival (OS) was assessed in MAGIC patients to determine any prognostic effect. RESULTS: RR was 52% to mEOC+P, 48% to EOC. Results from 175 assessable biopsies: mutations in KRAS (5.7%), BRAF (0%), PIK3CA (2.5%) and loss of PTEN expression (15.0%). None of the biomarkers evaluated predicted resistance to mEOC+P. In MAGIC, mutations in KRAS, BRAF and PIK3CA and loss of PTEN (phosphatase and tensin homolog) were found in 6.3%, 1.0%, 5.0% and 10.9%, respectively, and were not associated with survival. CONCLUSIONS: The RR of 52% in REAL3 with mEOC+P met pre-defined criteria to continue accrual to phase III. The frequency of the mutations was too low to exclude any prognostic or predictive effect.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report.

BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

A qualitative exploration of stakeholder perspectives on a school-based multi-component health promotion nutrition programme.

BACKGROUND: Food for Fitness is an on-going multi-component health promotion programme, delivered in primary and secondary schools by community nutrition assistants. The programme uses nutritional interventions aimed at promoting healthier eating practices for children. This service evaluation investigated the receipt and delivery of the programme, as perceived by local stakeholders who had experienced and administered the service. METHODS: Semi-structured interviews and focus groups were carried out with three key stakeholder groups: health professionals (n = 9), school teachers (n = 10) and senior health officials (n = 3). Qualitative data were transcribed verbatim and received thematic analysis with deductive and inductive processes. RESULTS: Stakeholders reported that the programme contributed to the development of food education and healthy-eating practices of children in the local area. Stakeholders considered that the main concern was the limited capacity and size of the service. They described problems with long-term sustainability in supporting schools with maintaining nutritional interventions, highlighting issues regarding contact, planning and organisation of several interventions. CONCLUSIONS: The findings of the service evaluation inform service management, organisation and ground-level delivery. The use of stakeholder opinion provided contextualised information on the factors that impact on the implementation of the programme. The richness of the qualitative results can guide future planning and provision for similar health promotion nutrition programmes delivered in the school environment.

Magnetic resonance imaging of the ligamentous structures of the occipitoatlantoaxial region in the dog.

Our objectives were to establish a magnetic resonance (MR) protocol for the examination of, and then describe, the normal ligaments and the supporting structures of the occipitoatlantoaxial region. This was done in 10 cadaver dogs. In addition, MR images of three patients with cervical pain localized to the occipitoatlantoaxial region are included to provide examples of ligamentous abnormalities. All ligaments were hypointense in all pulse sequences. The apical, dorsal atlantoaxial, and dorsal longitudinal vertebral ligaments were seen best in the sagittal T1W and PD-weighted images. The transverse ligament was best visualized in the transverse plane in all pulse sequences and appeared to be confluent with the dorsal longitudinal vertebral ligament dorsal to the dens in the sagittal plane. A 20° dorsal plane reconstructed image in 0.6-mm slice thickness was necessary to visualize the alar ligaments, which were visible in 9/10 dogs. The dorsal longitudinal vertebral ligament appeared continuous with the apical ligament and tectorial membrane. Abnormalities in clinically affected dogs included thickening of the alar ligaments, absence of transverse ligament and elongation, and irregularity of the apical ligament.

Current status of GV1001 and other telomerase vaccination strategies in the treatment of cancer.

GV1001 is a telomerase-specific, promiscuous class II peptide vaccine which is currently in an advanced stage of clinical development. This article reviews the biological rationale underpinning the design of ongoing studies with the vaccine as well as its immunogenicity and clinical activity. It places GV1001 in the context of other immunotherapeutic approaches targeting telomerase and assesses the chances of the vaccine becoming a future standard of care in the treatment of cancer.

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials.

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand- foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs.

Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy.

Elderly patients are recommended to have a reduced starting dose (300 mg m(-2) once every 3 weeks) of irinotecan monotherapy. The aims of this analysis are to compare toxicity and survival according to age, performance status (PS), gender and prior radical pelvic radiotherapy (RT). The primary end points were overall survival and an irinotecan-specific toxicity composite end point (TCE) defined as the occurrence of grade 3 or 4 diarrhoea, neutropenia, febrile neutropenia, fever, infection or nausea and vomiting. Between 1997 and 2003, 339 eligible patients with advanced colorectal cancer (CRC) progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered in a multicentre randomised trial. All patients commenced irinotecan at 350 mg m(-2) once every 3 weeks. There were no differences in proportions of patients developing TCE by age (<70 vs > or =70 : 37.8 vs 45.8%; P=0.218), PS (0-1 vs 2 : 39.3 vs 41.5%; P=0.793) or prior RT (RT vs no RT : 45.1 vs 38.5%; P=0.377). Males experienced more toxicity than females (44.3 vs 32.6%; P=0.031), but this was not significant after controlling for other co-variates (P=0.06). Patients aged > or =70 had similar objective responses (11.1 vs 9%; P=0.585) and survival (median 9.4 vs 9 months; log rank P=0.74) compared to younger patients. Elderly patients derive the same benefit without experiencing more toxicity with second-line irinotecan treatment for advanced CRC. Our data do not support the recommendation to reduce the starting dose for the elderly patients.