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.

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.

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.

Role of PI 3-kinase, Akt and Bcl-2-related proteins in sustaining the survival of neurotrophic factor-independent adult sympathetic neurons.

By adulthood, sympathetic neurons have lost dependence on NGF and NT-3 and are able to survive in culture without added neurotrophic factors. To understand the molecular mechanisms that sustain adult neurons, we established low density, glial cell-free cultures of 12-wk rat superior cervical ganglion neurons and manipulated the function and/or expression of key proteins implicated in regulating cell survival. Pharmacological inhibition of PI 3-kinase with LY294002 or Wortmannin killed these neurons, as did dominant-negative Class IA PI 3-kinase, overexpression of Rukl (a natural inhibitor of Class IA PI 3-kinase), and dominant-negative Akt/PKB (a downstream effector of PI 3-kinase). Phospho-Akt was detectable in adult sympathetic neurons grown without neurotrophic factors and this was lost upon PI 3-kinase inhibition. The neurons died by a caspase-dependent mechanism after inhibition of PI 3-kinase, and were also killed by antisense Bcl-xL and antisense Bcl-2 or by overexpression of Bcl-xS, Bad, and Bax. These results demonstrate that PI 3-kinase/Akt signaling and the expression of antiapoptotic members of the Bcl-2 family are required to sustain the survival of adult sympathetic neurons.

Cytokine-induced nuclear factor kappa B activation promotes the survival of developing neurons.

Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and interleukin 6 (IL-6) comprise a group of structurally related cytokines that promote the survival of subsets of neurons in the developing peripheral nervous system, but the signaling pathways activated by these cytokines that prevent neuronal apoptosis are unclear. Here, we show that these cytokines activate NF-kappaB in cytokine-dependent developing sensory neurons. Preventing NF-kappaB activation with a super-repressor IkappaB-alpha protein markedly reduces the number of neurons that survive in the presence of cytokines, but has no effect on the survival response of the same neurons to brain-derived neurotrophic factors (BDNF), an unrelated neurotrophic factor that binds to a different class of receptors. Cytokine-dependent sensory neurons cultured from embryos that lack p65, a transcriptionally active subunit of NF-kappaB, have a markedly impaired ability to survive in response to cytokines, but respond normally to BDNF. There is increased apoptosis of cytokine- dependent neurons in p65(-/)- embryos in vivo, resulting in a reduction in the total number of these neurons compared with their numbers in wild-type embryos. These results demonstrate that NF-kappaB plays a key role in mediating the survival response of developing neurons to cytokines.

TNFalpha contributes to the death of NGF-dependent neurons during development.

Many sympathetic and sensory neurons depend on a supply of nerve growth factor (NGF) from their targets during development, and neurons that fail to obtain sufficient NGF die by apoptosis. Here we show that tumor necrosis factor alpha (TNFalpha) is involved in bringing about the death of NGF-deprived neurons. Function-blocking antibodies against either TNFalpha or TNF receptor 1 (TNFR1) rescued many sympathetic and sensory neurons following NGF deprivation in vitro. Fewer sympathetic and sensory neurons died during the phase of naturally occurring neuronal death in TNF-deficient embryos, and neurons from these embryos survived in culture better than wild-type neurons. These neurons coexpress TNFalpha and TNFR1 during this stage of development, suggesting that TNFalpha acts by an autocrine loop.

Bcl-2 influences axonal growth rate in embryonic sensory neurons.

Bcl-2 plays a key role in regulating cell survival in the immune and nervous systems. Mice lacking the bcl-2 gene have markedly reduced numbers of B and T cells as a result of increased apoptosis, whereas mice with a transgene causing high levels of Bcl-2 expression in the immune system show extended survival of B and T cells. Overexpression of Bcl-2 in cultured neurons prevents their death following neurotrophin deprivation, and mice with a bcl-2 transgene under the control of a neuron-specific enolase promoter have increased numbers of neurons in several regions. Cultured neurons expressing antisense bcl-2 RNA have an attenuated survival response to neurotrophins, and neurons of postnatal bcl-2-deficient mice die more rapidly following NGF deprivation in vitro and are present in reduced numbers in vivo. Here, we show that Bcl-2 also plays a role in regulating axonal growth rates in embryonic neurons. Sensory neurons from the trigeminal ganglia of bcl-2-deficient mouse embryos, removed from the embryo on embryonic day 11 or 12, extend axons more slowly in vitro than do neurons from wild-type embryos of the same age. Serial measurements of axonal length in the same neurons revealed that there were marked differences in axonal growth rate between bcl-2-deficient and wild-type neurons, irrespective of whether the neurons were grown with nerve growth factor, brain-derived neurotrophic factor or neurotrophin-3. Because there was no significant difference in the numbers of wild-type and bcl-2-deficient neurons surviving with each neurotrophin at this early stage of development, the effect of Bcl-2 on axonal growth rate is not a consequence of its well documented role in preventing apoptosis.

Impact of protracted venous infusion fluorouracil with or without interferon alfa-2b on tumor response, survival, and quality of life in advanced colorectal cancer.

PURPOSE: The aim of this study was to investigate the effects of adding interferon alfa-2b (IFN) to protracted venous infusion fluorouracil (PVI 5-FU) from the start of treatment in patients with advanced colorectal cancer. PATIENTS AND METHODS: Patients who attended our unit with histologically confirmed advanced colorectal cancer were randomized to receive either PVI 5-FU 300 mg/m2/d via Hickman line, and IFN 5 MU subcutaneously three times weekly, or PVI 5-FU alone. Treatment was given for a maximum of two 10-week blocks, with a 2-week gap for reassessment of all parameters. Quality of life (QL) was measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) pretreatment and every 6 weeks thereafter. RESULTS: A total of 160 patients were randomized, with 155 eligible for assessment. Radiologic response was observed in 43 patients (28%): 17 of 77 (22%) in the 5-FU-plus-IFN arm (all partial responses [PRs]) and 26 of 78 (33%) in the 5-FU-alone group (complete responses [CRs] and 22 PRs) (difference not significant). Symptomatic improvement occurred in the majority of patients, and equally in both arms: 61% to 80% depending on the symptom. There was no significant difference between the two groups in failure-free survival (median, 161 v 193 days) or overall survival (median, 328 v 357 days). However, patients who received IFN did experience significantly more toxicity in the form of leukopenia (P = .001), neutropenia (P = .04), mucositis (P = .008), and alopecia (P = .0002). There were no toxic deaths and few notable differences in QL between the two arms. CONCLUSION: This study confirms that PVI 5-FU is effective in treating the symptoms associated with metastatic colorectal carcinoma, with only mild to moderate toxicity and maintenance of QL. IFN 5 MU three times weekly does not enhance these palliative benefits.

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.

Significant gastric reflux of technetium-99m-MIBI in SPECT myocardial imaging.

We present a case in which significant gastric reflux of 99mTc-methoxy isobutylisonitrile (MIBI) was observed in a patient who underwent stress/rest 99mTc-MIBI SPECT myocardial perfusion imaging for suspected coronary artery disease. The intense gastric activity partially obscured myocardial uptake of 99mTc MIBI, particularly in the inferolateral wall of the left ventricle. The presence of significant gastric activity should be considered when performing SPECT myocardial imaging with 99mTc MIBI, and, where necessary, steps should be taken to minimize this activity prior to commencing acquisition.

Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine.

Eighty-five patients (median age 28 years) with acute myeloid leukemia (AML) in first remission underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings between 1978 and 1987 after cyclophosphamide and single-fraction total body irradiation with cyclosporine for graft-versus-host disease (GVHD) prophylaxis. The actuarial probabilities of development of acute and chronic GVHD were 57% and 47%, respectively. Twenty-six patients died of transplant-related complications at a median of 3.5 months, and two of unrelated causes. Seventeen patients relapsed at a median of 6.5 months. Forty patients were alive and well at 74-197 months (median 157) after BMT; seven (18%) with limited chronic GVHD requiring therapy. The actuarial 10-year probabilities of transplant-related death, relapse, and disease-free survival were 33%, 25% and 48% respectively. In multivariate analysis, infusion of a lower cell dose, development of GVHD, and age > 35 years were associated with increased transplant-related mortality, donor-recipient ABO incompatibility with a lower relapse rate, and age > 35 years and a lower cell dose with poorer disease-free survival. We conclude that with long-term follow-up, allografting in AML after cyclophosphamide-TBI and cyclosporine has resulted in disease-free survival that is comparable to most currently reported series. Patients who are alive and well 3-4 years after BMT have excellent prospects of long-term survival.