Immune Activation following Irbesartan Treatment in a Colorectal Cancer Patient: A Case Study.

Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.

Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

Transfusion in adults: 10-year survival of red cell, plasma and platelet recipients following transfusion.

OBJECTIVE: To determine the long-term survival of adult recipients (>16 years) transfused with red blood cells (RBC), platelets (PLT) and fresh frozen plasma (FFP) in England and Wales. STUDY DESIGN AND METHODS: The EASTR study (Epidemiology and Survival of Transfusion Recipients) was a national multi-centre epidemiological study with cross-sectional sampling from 29 representative hospitals in England supplied by NHS Blood and Transplant (NHSBT). Three separate groups of RBC (n = 9142), FFP (n = 4232) and PLT (3584) recipients were sampled over 1 year (1 October 2001-30 September 2002), with prospective survival monitoring for 10 years. This study presents the data for adult recipients (>16 years of age). RESULTS: The median age interquartile range (IQR) of adult transfusion recipients was RBC 70 (54-79), FFP 66 (51-76), PLT 62 (48-72). The 10-year survival for adult RBC, FFP and PLT recipients was highest for RBC recipients at 36% confidence interval (CI 35-37%, n = 8675), compared with 30% for both FFP (CI 29-32%, n = 3849) and PLT (CI 28-30%, n = 3110) recipients. In all groups, post-transfusion survival decreased with age, and a risk-adjusted analysis showed that reason for transfusion, transfusion type (surgical or medical) and cancer diagnosis (presence or absence) were all significantly associated with survival. Older patients with cancer receiving a medical rather than surgical transfusion had the highest hazard of death. CONCLUSION: This study shows that survival following transfusion in England is broadly similar to that reported in other wealthy nations. More than 70% of recipients die within 10 years of transfusion, but long-term survival is common in younger patients (>80% 10-year survival in RBC recipients aged 16-39 years).

Transfusion in children: epidemiology and 10-year survival of transfusion recipients.

OBJECTIVE: To describe the epidemiology of blood transfusion in children: including the incidence of transfusion, the diagnoses leading to transfusion, donor exposure (DE) and post-transfusion survival. STUDY DESIGN AND METHODS: The Epidemiology and Survival of Transfusion Recipients (EASTR) Study was a multi-centre epidemiological study with prospective survival monitoring. Cross-sectional sampling of adult and paediatric transfusion recipients in 29 hospitals was used to select three separate cohorts of red cell (RBC), platelet (PLT) and fresh frozen plasma (FFP) recipients between October 2001 and September 2002. This paper presents the analysis of results for children <16 years. RESULTS: Children <16 years comprised 449 (5%) of the RBC, 362 (9%) of the FFP and 452 (13%) of the PLT recipients. In children 54% of RBC, 63% FFP and 45% PLT recipients were under 1 year of age and 57% RBC, 60% FFP and 52% PLT were male. Median (IQR) DEduring the study year was 3(2-8); 5(2-13) and 11(6-21) in the RBC, FFP and PLT cohorts, respectively. A total of 20% of RBC, 31% of FFP and 54% of PLT recipients had been exposed to >10 donors. Perinatal conditions were the commonest indication for transfusion in the RBC (36%) and FFP (44%) cohorts and comprised 31% of the PLT cohort. Medical conditions (48%), predominantly malignancy (33%), were the most frequent indication in the PLT cohort. The 10 year (95% CI) survival rates were 81% (77-85%), 72% (67-76%) and 71% (66-75%)for RBC, FFP and PLT cohorts, respectively. CONCLUSIONS: Around half of paediatric transfusion recipients are under 1 year of age. Exposure to components from multiple donors is common. At least 70% of paediatric recipients are long survivors and are at risk for late complications of transfusion.

A clinical governance framework for blood services.

BACKGROUND AND OBJECTIVES: The elements of clinical governance, which ensure excellence in clinical care, can be applied to blood services. In this survey, their application in a range of blood providers was gauged, with the aim of identifying best practice and producing a generalizable framework. MATERIALS AND METHODS: The Medical Directors of members of the Alliance of Blood Operators surveyed how different elements of clinical governance operated within their organizations and developed recommendations applicable in the blood service environment. RESULTS: The recommendations that emerged highlighted the importance of an organization's culture, with the delivery of optimal clinical governance being a corporate responsibility. Senior management must agree and promote a set of values to ensure that the system operates with the patient and donor at its heart. All staff should understand how their role fits into the 'journey to the patient', and a culture of openness promoted. Thus, reporting of errors and risks should be actively sought and praised, with penalties applied for concealment. Systems should exist to collect, analyse and escalate clinical outcomes, safety data, clinical risk assessments, incident reports and complaints to inform organizational learning. CONCLUSION: Clinical governance principles from general health care can be applied within blood services to complement good manufacturing practice. This requires leadership, accountability, an open culture and a drive for continuous improvement and excellence in clinical care.

Strategies for screening blood donors to source convalescent H1N1v plasma for intervention therapy.

BACKGROUND AND OBJECTIVES: During the 1918, pandemic blood components were successfully used to treat severe influenza pneumonia. A Proof of Principle trial investigating the clinical benefit of convalescent plasma was proposed in the 2009 H1N1v epidemic with the aim of screening donors for high titre antibody in order to stockpile plasma packs to be used for treatment for severe pneumonia. MATERIALS AND METHODS: Serum samples were collected from donors. IgG antibody capture format enzyme-linked immunoassays using recombinant proteins (GACELISAs) were compared with microneutralization (MN) and haemagglutination inhibition (HAI). The influence of age and history of influenza-like illness (ILI) on the detection of high titre antibody was examined. RESULTS: 1598 unselected donor sera collected in October and December 2009 were tested by HAI. The HAI and demographic data defined a possible strategy for selective donor screening. One of the GACELISAs was highly specific for recent infection but showed lower sensitivity than HAI. CONCLUSIONS: During the 2009 pandemic screening 17- to 30-year-old donors by HAI delivered around 10% with high antibody levels. The ELISA using a short recombinant H1N1v HA detected fewer reactives but was more specific for high titre antibody (≥1:256). Screening strategies are proposed based on using HAI on serum or GACELISA on plasma.

HIV testing trends among gay men in Scotland, UK (1996-2005): implications for HIV testing policies and prevention.

OBJECTIVE: To examine trends in the HIV testing behaviour of gay men in Scotland over a 10-year period. METHODS: Seven cross-sectional surveys in commercial gay venues in Glasgow and Edinburgh (1996-2005). 9613 men completed anonymous, self-completed questionnaires (70% average response rate). RESULTS: Among 8305 respondents included in these analyses, HIV testing increased between 1996 and 2005, from 49.7% to 57.8% (p<0.001). The proportion of men who had tested recently (in the calendar year of, or immediately before, the survey) increased from 28.4% in 1996 to 33.2% in 2005, when compared with those who have tested but not recently, and those who have never tested (adjusted odds ratio 1.31, 95% CI 1.13 to 1.52). However, among ever testers, there was no increase in rates of recent testing. Recent testing decreased with age: 31.3% of the under 25, 30.3% of the 25-34, 23.2% of the 35-44 and 21.2% of the over 44 years age groups had tested recently. Among men reporting two or more unprotected anal intercourse partners in the previous year, only 41.4% had tested recently. CONCLUSIONS: HIV testing among gay men in Scotland increased between 1996 and 2005, and corresponds with the Scottish Government policy change to routine, opt-out testing in genitourinary medicine clinics. Testing rates remain low and compare unfavourably with near-universal testing levels elsewhere. The limited change and decline across age groups in recent HIV testing rates suggest few men test repeatedly or regularly. Additional, innovative efforts are required to increase the uptake of regular HIV testing among gay men.

AIDS mortality in African migrants living in Portugal: evidence of large social inequalities.

OBJECTIVE: To examine infectious disease and AIDS mortality among African migrants in Portugal, gender and socio-economic differences in AIDS mortality risk, and differences between African migrants to Portugal and to England and Wales. METHODS: Data from death registrations, 1998-2002, and the 2001 Census were used to derive standardised death rates by country of birth, occupational class (men only), and marital status. RESULTS: Compared with people born in Portugal, African migrants had higher mortality for infectious diseases including AIDS. There was considerable heterogeneity among Africans, with those from Cape Verde having the highest mortality. Death rates were more than five times higher among those who were unmarried than those who were. A larger proportion of Africans were unmarried accounting for some excess mortality. Death rates were also higher among men from manual occupational classes than among men from non-manual. A comparison with England and Wales shows that death rates for infectious disease and AIDS in Portugal are much higher and Africans in Portugal also fare worse than Africans in England and Wales. CONCLUSION: AIDS mortality rates were higher among Africans than those born in Portugal and were associated with socio-environmental factors. Further research is required to interpret the excess mortality among Africans and there is a need to ensure the inclusion of relevant data items on ethnicity in national monitoring and surveillance systems.

The EASTR Study: indications for transfusion and estimates of transfusion recipient numbers in hospitals supplied by the National Blood Service.

This study provides data on National Blood Service (NBS) red blood cell (RBC, n = 9142), platelet (PLT, n = 4232) and fresh frozen plasma (FFP, n = 3584) recipients independently sampled by monthly quota from 29 representative hospitals over 12 months in 2001-2002. Hospitals were stratified by size according to total yearly RBC issues. Transfusion indications were chosen from diagnostic and procedural codes, and recipients grouped into Epidemiology and Survival of Transfusion Recipients Case-mix Groups (E-CMGs). The main E-CMGs were digestive [19% of RBC recipients; including 5% gastrointestinal (GI) bleeds and 3% colorectal surgery], musculoskeletal (15%; 12% hip and knee replacement), haematology (13%) and obstetrics and gynaecology (10%). Renal failure, fractured neck of femur, cardiac artery by-pass grafting (CABG) and paediatrics, each accounted for 3-4% recipients. FFP recipients: the main E-CMGs were digestive (21% of FFP recipients; including 7% GI bleeds and 3% colorectal surgery), hepatobiliary (15%; 7% liver disease and 2% liver transplant), cardiac (12%) and paediatrics (9%) The renal, paediatrics, vascular and haematology E-CMGs each had 6-7% of recipients. PLT recipients: the main E-CMGs were haematology (27% of PLT recipients; including 9% lymphoma and 8% acute leukaemia), cardiac (17%), paediatrics (13%), hepatobiliary (10%) and digestive (9%). Back-weighting gave national estimates of 433 000 RBC, 57 500 FFP and 41 500 PLT recipients/year in England and North Wales, median age 69, 64 and 59 years, respectively. Digestive and hepatobiliary indications emerged as the top reason for transfusion in RBC and FFP recipients, and was also a frequent indication in PLT recipients.

The EASTR study: a new approach to determine the reasons for transfusion in epidemiological studies.

Previous studies of blood use have used different methods to obtain and classify transfusion indications. Before undertaking a national study of transfusion recipients, a pilot study was performed over 2 months at two teaching and two district general hospitals to match information from hospital transfusion laboratories with clinical coding data from the hospital's Patients Administration System to determine the indication for transfusion in 2468 recipients. Data analysis revealed major limitations in the conventional use of primary diagnostic International Statistical Classification of Disease and Related Health Problems 10th Revision (ICD-10) or procedure Office of Population, Censuses and Surveys - Classification of Surgical Operations and Procedures - 4th Revision (OPCS-4) codes alone in allocating transfusion indications. A novel algorithm was developed, using both types of code, to select the probable indication for transfusion for each patient. A primary OPCS-4 code was selected for recipients transfused in relation to surgery (43%) and either the primary (36%) or the secondary (12%) ICD-10 code was chosen for recipients transfused for medical reasons. The remaining patients were unclassified. Selected codes were then collated into Epidemiology and Survival of Transfusion Recipients (EASTR) casemix groups (E-CMGs). The most frequent E-CMGs were haematology (15% of recipients), musculoskeletal (14%), digestive system (12%) and cardiac (10%). The haematology E-CMG includes patients with malignant and non-malignant blood disorders and recipients transfused for anaemia where no cause was listed. Recipients undergoing hip and knee replacement and coronary artery bypass grafting are within the musculoskeletal and cardiac E-CMGs. The digestive E-CMG includes recipients transfused for gastrointestinal (GI) bleeds and those undergoing GI surgery. This methodology provides a more useful means of establishing the probable indication for transfusion and arranging recipients into clinically relevant groups.

The dynamics of clot formation in fresh-frozen plasma.

BACKGROUND: Factor VIII (FVIII) levels are used as a quality marker of fresh-frozen plasma (FFP); however, other clotting factors are not routinely measured. METHODS: We assessed additional haemostatic parameters and the dynamics of coagulation using Thrombelastography (TEG) and a thrombin generation test (TGT). FFP was prepared on the day of donation (Day 0) or after overnight hold at 4 degrees C (Day 1). RESULTS: Factor VIII in Day 1 FFP was 18% lower than in Day 0. TEG parameters in Day 1 FFP were consistent with increased coagulability and did not correlate with altered levels of clotting factors, but were consistent with the increased levels of microparticles seen in the Day 1 samples. TGT studies exhibited increased lag time, time to peak and reduced peak thrombin generation, but no change in endogenous thrombin potential (ETP) on Day 1. There was a weak association between FVIII level and both ETP and peak thrombin (ETP r(s)> or = 0.22, P< or = 0.003; peak thrombin r(s)> or = 0.48, P< or = 0.0001), which was influenced by ABO group, with the lowest levels in group O. CONCLUSION: We conclude that levels of FVIII do not predict the haemostatic potential of FFP and that there may be a role for alternative technologies in monitoring the quality of FFP.

Transfusion-associated graft-versus-host disease and its prevention.

Transfusion-associated graft-versus-host disease is a rare but usually fatal complication of transfusion of cellular blood components, caused by multiorgan engraftment and proliferation of donor T lymphocytes. The classical features of skin rash, diarrhoea and hepatitis, along with striking bone-marrow failure, are seen 1-2 weeks after transfusion. Although early reports described the condition only in immunosuppressed individuals, sharing of an HLA haplotype between donor and an immunocompetent recipient can also result in transfusion-associated graft-versus-host disease. The condition is entirely preventable by gamma irradiation of cellular blood components to 25 Gy, although this results in some reduction of red-cell viability and increased loss of red-cell potassium. The major indications for irradiated blood components include bone marrow/stem cell auto- or allografting, Hodgkin's disease, intrauterine transfusions, and transfusions from relatives or HLA-selected platelet donors.

Leucodepletion of blood products by filtration.

The leucocytes present in red cell and platelet components have been implicated in several important immunological and infective complications of blood transfusion. Recent developments in blood filtration technology allow the production of leucodepleted blood products (residual leucocytes < 5 x 10(6) per transfused unit) in the laboratory or at the bedside with the potential to prevent these adverse effects. Quality assurance remains an important problem, particularly for bedside filtration. Prestorage filtration may have significant advantages for red cell and platelet production. There is strong clinical evidence that 3 log10 leucodepletion prevents or delays febrile reactions in patients receiving multiple red cell transfusions and can reduce cytomegalovirus transmission. Leucodepletion to prevent HLA alloimmunisation, platelet refractoriness and febrile reactions in patients receiving red cell and platelet support remains controversial. Transfused leucocytes induce 'immunosuppressive' changes in the recipient, but recent studies cast doubt on the association with cancer recurrence after surgery. However, leucodepleted blood may reduce the incidence of postoperative infection. Leucodepletion by filtration is expensive and there is a requirement for well-designed prospective clinical studies focusing on appropriate filtration technology (and alternatives), clinical outcome and cost-effectiveness.

Leucocyte depletion of blood components.

Universal leucocyte depletion has been implemented in the UK and several other European countries as a precautionary measure against the potential risk of transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Leucocyte depletion had previously only been recommended for a relatively small proportion of transfusion recipients based on clinical and experimental evidence showing clinical benefit. However there is now increasing evidence to support its value in preventing transfusion transmission of infectious agents and in reducing some of the adverse immunomodulatory effects of allogeneic transfusion. The financial costs of providing universal leucocyte depletion are substantial, but, if it transpires that leucocyte depletion has a beneficial effect in reducing, for example, postoperative infection rates, then the health economic gains in this patient group alone may largely or wholly offset these financial costs. The experience in the UK and other European countries in terms of these collateral clinical benefits will help other countries, where the risk of variant Creutzfeldt-Jakob disease may not be so great, to decide whether to similarly adopt universal leucocyte depletion.

Trends in head injury mortality among 0-14 year olds in Scotland (1986-95).

STUDY OBJECTIVE: To examine the trends in childhood head injury mortality in Scotland between 1986 and 1995. DESIGN: Analysis of routine mortality data from the registrar general for Scotland. SETTING: Scotland, UK. SUBJECTS: Children aged 0-14 years. MAIN RESULTS: A total of 290 children in Scotland died as a result of a head injury between 1986 and 1995. While there was a significant decline in the head injury mortality rate, head injury as a proportion of all injury fatalities remained relatively stable. Boys, and children residing in relatively less affluent areas had the highest head injury mortality rates. Although both these groups experienced a significant decline over the study period, the mortality differences between children in deprivation categories 1-2 and 6-7 persisted among 0-9 year olds, and increased in the 10-14 years age group. Pedestrian accidents were the leading cause of mortality. CONCLUSIONS: Children residing in less affluent areas seem to be at relatively greater risk of sustaining a fatal head injury than their more affluent counterparts. While the differences between the most and least affluent have decreased overall, they have widened among 10-14 year olds. The decline in head injury mortality as a result of pedestrian accidents may be partly attributable to injury prevention measures.

Clinical aspects of platelet transfusion.

Several clinical complications of platelet transfusions relate to contaminating donor leucocytes, and a number of strategies have been devised to leucodeplete platelet products before transfusion. Both alloimmunization to class I human leucocyte antigens (HLA), which causes febrile transfusion reactions and refractoriness to transfused platelets, and transmission of cytomegalovirus have been shown to be reduced by 3-log10 leucodepletion by filtration. Lesser degree of leucodepletion, e.g. by platelet preparation from buffy coats, will control febrile transfusion reactions, but will not reliably prevent other complications. The clinical implications and cost-effectiveness of different strategies of platelet production remain a matter of debate.

Effect of feverfew on phagocytosis and killing of Candida guilliermondii by neutrophils.

The in vitro effect of the herbal remedy feverfew on neutrophil function was examined. It was shown that addition of feverfew extract inhibited phagocytosis of Candida guilliermondii and its overall killing. However, intracellular killing was not affected, suggesting that the apparent defect in total killing merely reflected the failure of uptake. The implications for the in vivo effects of feverfew are discussed.

Does bar-based, peer-led sexual health promotion have a community-level effect amongst gay men in Scotland?

This paper evaluates the effectiveness of a bar-based, peer-led community-level intervention to promote sexual health amongst gay men. The intervention consisted of peer education within bars, gay specific genitourinary medicine (GUM) services and a free-phone hotline. Data were collected at baseline (1996) and at follow-up (1999) in gay bars in Glasgow (intervention city) and Edinburgh (control city). During the intervention peer educators interacted with 1484 men and new clients increased at the gay specific GUM service. However, the hotline was under-utilized and abused. The outcome measures were: reported hepatitis B vaccination; HIV testing; unprotected anal intercourse (UAI) with casual partners; negotiated safety; and amongst men reporting UAI with a regular partner, the proportion who knew their own and their partner's HIV status. Significant differences in sexual health behaviours were observed across locations and across time, but the only significant intervention effects were amongst men who had direct contact with the intervention, with higher uptake of hepatitis B vaccination and HIV testing. The intervention did not produce community-wide changes in sexual health behaviours. These results question the replication and transferability of peer-led, community-level sexual health promotion for gay men outwith the USA and across time.

Serious hazards of transfusion (SHOT) initiative: analysis of the first two annual reports.

OBJECTIVE: To receive and collate reports of death or major complications of transfusion of blood or components. DESIGN: Haematologists were invited confidentially to report deaths and major complications after blood transfusion during October 1996 to September 1998. SETTING: Hospitals in United Kingdom and Ireland. SUBJECTS: Patients who died or experienced serious complications, as defined below, associated with transfusion of red cells, platelets, fresh frozen plasma, or cryoprecipitate. MAIN OUTCOME MEASURES: Death, "wrong" blood transfused to patient, acute and delayed transfusion reactions, transfusion related acute lung injury, transfusion associated graft versus host disease, post-transfusion purpura, and infection transmitted by transfusion. Circumstances relating to these cases and relative frequency of complications. RESULTS: Over 24 months, 366 cases were reported, of which 191 (52%) were "wrong blood to patient" episodes. Analysis of these revealed multiple errors of identification, often beginning when blood was collected from the blood bank. There were 22 deaths from all causes, including three from ABO incompatibility. There were 12 infections: four bacterial (one fatal), seven viral, and one fatal case of malaria. During the second 12 months, 164/424 hospitals (39%) submitted a "nil to report" return. CONCLUSIONS: Transfusion is now extremely safe, but vigilance is needed to ensure correct identification of blood and patient. Staff education should include awareness of ABO incompatibility and bacterial contamination as causes of life threatening reactions to blood.

Program descriptions: a positive outcome from change.

1. Major organizational restructuring was the impetus for standardization of occupational health practice at three hospital sites. 2. A generic framework was devised to describe the key occupational health programs. 3. The process of developing these program descriptions yielded obvious quality assurance monitors. 4. Corporate change often is perceived as threatening. The development of a useful tool through cooperative team effort has produced a positive outcome.