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Background Bloodstream infections with antibiotic-resistant Pseudomonas aeruginosa are common and increasingly difficult to treat. Pyocins are naturally occurring protein antibiotics produced by P. aeruginosa that have potential for human use. Objectives To determine if pyocin treatment is effective in a murine model of sepsis with P. aeruginosa. Methods Recombinant pyocins S5 and AP41 were purified and tested for efficacy in a Galleria mellonella infection model and a murine model of P. aeruginosa sepsis. Results Both pyocins produced no adverse effects when injected alone into mice and showed good in vitro antipseudomonal activity. In an invertebrate model of sepsis using G. mellonella, both pyocins significantly prolonged survival from 1/10 (10%) survival in controls to 80%–100% survival among groups of 10 pyocin-treated larvae. Following injection into mice, both showed extensive distribution into different organs. When administered 5 h after infection, pyocin S5 significantly increased survival from 33% (2/6) to 83% (5/6) in a murine model of sepsis (difference significant by log-rank test, P Conclusions Pyocins S5 and AP41 show in vivo biological activity and can improve survival in two models of P. aeruginosa infection. They hold promise as novel antimicrobial agents for treatment of MDR infections with this microbe.

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis., Tuberculosis vaccination: Multi-platform/route BCG boosting in rhesus macaques BCG is the only clinically-approved tuberculosis (TB) vaccine but has highly variable protection against pulmonary manifestations of the disease. JoAnne Flynn and colleagues at the University of Pittsburgh investigate whether heterologous boosting can improve the efficacy of BCG vaccination in a highly susceptible rhesus macaque model. The boosting is performed using a variety of vaccination routes (intramuscular, aerosol) and platforms including multiple Mycobacterium tuberculosis (Mtb) protein subunits in adjuvant and/or expressed in adenovirus vectors. The various platforms and routes are designed to enhance immune responses thought to be involved in protection from Mtb. Despite in certain cases (e.g., aerosol) being able to enhance lung T cell cytokine responses, none of the boosting regimens showed any improved protection over standard intradermal BCG vaccination. This study highlights the formidable challenges facing attempts to elicit robust pulmonary protection against pulmonary Mtb infection.

Background In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. Methods Approval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. Results Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. Conclusions This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia., The rVSV-ZEBOV vaccine was used as postexposure prophylaxis in individuals exposed to Ebola virus in the United Kingdom. It was rolled out rapidly and was generally well tolerated. Side effects correlated with the magnitude of CD8+ T-cell responses.

Introduction: Understanding of how SARS-CoV-2 manifests itself in older adults was unknown at the outset of the pandemic. We undertook a retrospective observational analysis of all patients admitted to older people’s services with confirmed COVID-19 in one of the largest hospitals in Europe. We detail presenting symptoms, prognostic features and vulnerability to nosocomial spread. Methods: We retrospectively collected data for each patient with a positive SARSCoV-2 RT PCR between 18th March and the 20th April 2020 in a department of medicine for the elderly in Glasgow. Results: 222 patients were included in our analysis. Age ranged from 56 to 99 years (mean = 82) and 148 were female (67%). 119 patients had a positive swab for SARS-CoV-2 within the first 14 days of admission, only 32% of these patients presented with primarily a respiratory type illness. 103 patients (46%) tested positive after 14 days of admission – this was felt to represent likely nosocomial infection. 95 patients (43%) died by day 30 after diagnosis. Discussion: This data indicates that older people were more likely to present with non-respiratory symptoms. High clinical frailty scores, severe lymphopenia and cumulative comorbidities were associated with higher mortality rates. Several contributing factors will have led to nosocomial transmission.

Background Septic arthritis (SA) caused by bacterial species, such as Staphylococcus aureus, has high morbidity and mortality. Currently diagnosis is often prolonged and unreliable, with no suitable near-patient biomarkers available. To generate more reliable biomarkers and to understand pathogenesis we sought to develop a novel ex vivo system to explore the effect of pathogenic Staph. aureus strains in promoting cartilage degradation. Methods Human cartilage explants were obtained from femoral heads being surgically removed following trauma. Explants were infected for 48h with 106 cfu bacteria from two Staph. aureus SA-derived patient isolates (28g & 36v strains). In the final 24h of bacterial infection, neutrophils purified from healthy donor blood were added to explant cultures at 3 x 106 cells/well. Chondrocyte viability was assessed using CellTracker green CMFDA and propidium iodide. Images were captured using confocal microscopy (LSM880) and cells counted using Imaris software. Structural damage was measured by glycosaminoglycan (GAG) and a neo-epitope of MMP-mediated degradation of type II collagen (C2M) release. Statistical analysis was performed using GraphPad Prism software. Results When cartilage explants were co-cultured with bacteria +/- neutrophils, cell death was significantly increased compared to the negative control or addition of neutrophils alone, (Friedman multiple comparisons test, N = 3, negative control vs. bacteria - neutrophils p Conclusion A co-culture model of septic arthritis has been developed which allows precise examination of the contribution of the host neutrophil response to cartilage damage. We used this to identify a collagen breakdown product as a biomarker of host response to infected cartilage. This novel model will be a valuable tool in understanding the pathology of joint infection and can be used for the identification of future diagnostic biomarkers. Disclosures K.E. McCall None. C. Atherton None. C. Thudium None. C. Goodyear Grants/research support; C.G. has received funding for research from Celgene, AstraZeneca, MedAnnex, UCB & Jannsen. T. Evans None. N. Millar Grants/research support; Novartis. I. McInnes Consultancies; I.M. has received consultancies fees from BMS, Abbvie, Lilly, GSK & Pfizer. Grants/research support; I.M received research funding from Calgene, Janssen, Novartis, Boehringer Ingelheim & BMS.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver accounting for approximately 90% of cases. Patients often present at an advanced stage when treatment options are limited. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been the first-line treatment in this setting for almost a decade. Several subsequent targeted therapies have failed to demonstrate significant improvement in survival. The results of the REFLECT study suggest that lenvatinib, a multikinase inhibitor, may have promised as a first-line treatment in patients with advanced HCC. This article will review the development of lenvatinib and the evidence behind its potential use in patients with advanced HCC.

Nivolumab; Carcinoma cervical, vaginal o vulvar; Carcinoma metastàtic Nivolumab; Cervical, vaginal, or vulvar carcinoma; Metastatic carcinoma Nivolumab; Carcinoma de cuello uterino, vaginal o vulvar; Carcinoma metastático PURPOSE Nivolumab was assessed in patients with virus-associated tumors in the phase I/II CheckMate 358 trial (ClinicalTrials.gov identifier: NCT02488759). We report on patients with recurrent/metastatic cervical, vaginal, or vulvar cancers. PATIENTS AND METHODS Patients received nivolumab 240 mg every 2 weeks. Although patients with unknown human papillomavirus status were enrolled, patients known to have human papillomavirus–negative tumors were ineligible. The primary end point was objective response rate. Duration of response (DOR), progression-free survival, and overall survival were secondary end points. Safety and patient-reported outcomes were exploratory end points. RESULTS Twenty-four patients (cervical, n = 19; vaginal/vulvar, n = 5) were enrolled. Most patients had received prior systemic therapy for metastatic disease (cervical, 78.9%; vaginal/vulvar, 80.0%). Objective response rates were 26.3% (95% CI, 9.1 to 51.2) for cervical cancer and 20.0% (95% CI, 0.5 to 71.6) for vaginal/vulvar cancers. At a median follow-up of 19.2 months, median DOR was not reached (range, 23.3 to 29.5+ months; + indicates a censored observation) in the five responding patients in the cervical cohort; the DOR was 5.0 months in the single responding patient in the vaginal/vulvar cohort. Median overall survival was 21.9 months (95% CI, 15.1 months to not reached) among patients with cervical cancer. Any-grade treatment-related adverse events were reported in 12 of 19 patients (63.2%) in the cervical cohort and all five patients in the vaginal/vulvar cohort; there were no treatment-related deaths. In the cervical cohort, nivolumab treatment generally resulted in stabilization of patient-reported outcomes associated with health status and health-related quality of life. CONCLUSION The efficacy of nivolumab in patients with recurrent/metastatic cervical and vaginal or vulvar cancers is promising and warrants additional investigation. No new safety signals were identified with nivolumab treatment in this population.

Background: Septic arthritis (SA) is a rheumatological emergency requiring early treatment to prevent lasting joint damage. Treatment outcomes depend on prompt diagnosis, which currently rests on clinical suspicison, riased non-specifc inflammaotry markers and identification of a pathogen from synovial fluid. Objectives: To establish the prevalence of SA in a large University teaching hospital. To review the microbiology results and identified pathogens in each positive case along with subsequent treatment regimes utilising outpatinet parenteral antimicrobial therapy (OPAT) with adherence to local guidelines. Methods: Retrospective data collection of all samples identified as synovial fluid or joint aspiration sent to microbiology lab between 1stJanuary 2016 and 31st December 2016. Electronic review of microbiology results to identify the causal pathogen and case notes to review treatment and outcomes. Results: There were 364 samples identified as joint aspirate or synovial fluid, 54 of these grew a pathogen. Positive aspirates from native joints totaled 35 in 31 patients. Twenty-three of these patients accounting for 25 of the positive samples were treated clinically as SA. Sub analysis of this group revealed Staph.aureus was the most commonly identified pathogen in 14 cases (56%). There were however 8 other pathogens identified in the 25 positive samples. Fifteen patients (65%) underwent a joint washout in theatre, 7 of these patients had multiple washouts. Duration of antibiotic therapy was 5 weeks in 8 cases; 13 cases had therapy for >5 weeks and 2 cases with SA in the upper limb had treatment for Conclusion: In line with known literature, staph.aureus was the most common pathogen1, however there were a number of other bacteria identified which needs to be taken into account when formulating local antimicrobial guidelines. Current literature reports surgical treatment as not superior to medical2, yet 65% of cases here under went joint lavage in theatre. This information will be used to inform local clinical practice, and, guide recruitment targets for a large multi-centre study collecting data and samples from patients presenting with a hot swollen joint, with the aim of identifying a specific biomarker for SA. References [1] Rutherford A I, Kleymann A, Ibrahim F, Galloway J. The increasing incidence of septic arthritis in England between 1998 and 2013. Rheumatology April 2016 55(1):i51-i52 [2] Ravindran V, Logan I, Bourke B E. Medical vs Surgical treatment for the native joint in septic arthritis: A 6 year, single UK academic centre experience. RheumatologyOct200948(10):1320-1322 Disclosure of Interests: Caroline Atherton: None declared, Kathryn McCall: None declared, Neal L Millar: None declared, Yianni Joannidis: None declared, Tom Evans: None declared, Iain McInnes Grant/research support from: AstraZeneca, Celgene, Compugen, Novartis, Roche, UCB Pharma, Consultant for: AbbVie, Celgene, Galvani, Lilly, Novartis, Pfizer, UCB Pharma

TPS3170 Background: Antigen-specific immunotherapy (Sipuleucel-T) is licenced for the treatment for castrate resistant prostate cancer, but has modest clinical efficacy and is complex to administer to patients. New therapeutic antigen-specific approaches are required to generate and sustain therapeutic immune responses against tumour specific antigens in men with early and advanced prostate cancer. We have previously reported immunogenicity and efficacy data of a novel viral vectored vaccines-based immunotherapy based on two replication-deficient viruses, chimpanzee adenovirus (ChAdOx1) and MVA, targeting an oncofetal self-antigen 5T4, administered as a single agent and in combination with anti-PD-1 in mouse tumour models. We tested this immunotherapy alone in a first-in-human trial, VANCE (NCT02390063), in intermediate risk prostate cancer patients. Based on encouraging safety and exceptional T cell immunogenicity of the VANCE study, the phase I/II trial, ADVANCE (NCT03815942) is being undertaken to test the immunotherapy safety and efficacy in combination with PD-1 blockade in intermediate risk disease and metastatic prostate cancer. Methods: Study design: ADVANCE, an open label non-randomised phase I/II study, will recruit 12 patients with intermediate-risk prostate cancer patients (Gleason score ≤ 7, local tumour stage ≤T3c, PSA≤ 20 ng/ml) scheduled to undergo radical prostatectomy (Cohort 1) and 24 mCRPC patients with disease progression on anti-androgen therapy with either enzalutamide or abiraterone (Cohort 2). Cohort 1 will receive one cycle of ChAdOx1-MVA 5T4 immunotherapy and a single nivolumab infusion. Cohort 2 will receive 2 cycles of ChAdOx1-MVA 5T4 vaccination and three nivolumab infusions. Primary endpoint: Cohort 1 - PSA change from baseline to surgery, Cohort 2 – composite response rate measured as either ≥50% reduction of circulating tumour DNA or ≥50% serum PSA decrease from baseline at 24-week assessment and the maximal response rate. Secondary and exploratory endpoints include 5T4-specific immune response in the periphery, progression-free and overall survival and reduction of circulating tumour cells. 23 of planned 24 patients have been enrolled in Cohort 2. Enrolment to the Cohort 1 is ongoing. The data analysis is expected to be completed by Q4 2020 for Cohort 2. Clinical trial information: NCT03815942 .

Streptococcus pneumoniae is the major bacterial cause of community-acquired pneumonia, and the leading agent of childhood pneumonia deaths worldwide. Nasal colonization is an essential step prior to infection. The cytokine IL-17 protects against such colonization and vaccines that enhance IL-17 responses to pneumococcal colonization are being developed. The role of IL-17 in host defence against pneumonia is not known. To address this issue, we have utilized a murine model of pneumococcal pneumonia in which the gene for the IL-17 cytokine family receptor, Il17ra, has been inactivated. Using this model, we show that IL-17 produced predominantly from γδ T cells protects mice against death from the invasive TIGR4 strain (serotype 4) which expresses a relatively thin capsule. However, in pneumonia produced by two heavily encapsulated strains with low invasive potential (serotypes 3 and 6B), IL-17 significantly enhanced mortality. Neutrophil uptake and killing of the serotype 3 strain was significantly impaired compared to the serotype 4 strain and depletion of neutrophils with antibody enhanced survival of mice infected with the highly encapsulated SRL1 strain. These data strongly suggest that IL-17 mediated neutrophil recruitment to the lungs clears infection from the invasive TIGR4 strain but that lung neutrophils exacerbate disease caused by the highly encapsulated pneumococcal strains. Thus, whilst augmenting IL-17 immune responses against pneumococci may decrease nasal colonization, this may worsen outcome during pneumonia caused by some strains., Author summary Streptococcus pneumoniae (the pneumococcus) is an important human pathogen and the commonest cause of community-acquired pneumonia. The bacterial carbohydrate capsule is a key determinant of virulence and host defence. Pneumonia follows colonization of the nasopharynx and can spread systemically. The cytokine IL-17, a key regulator of neutrophil host defence, is important in preventing colonization but its effects on pneumococcal pneumonia are not known. Here, we show that IL-17 has differing roles in host protection against pneumococcal pneumonia that depend on bacterial strain and capsule thickness. Pneumococci with thin capsules invade rapidly and IL-17 is protective; in strains with large capsules that remain in the lungs, IL-17 is detrimental. These strains evade neutrophil killing, and depletion of neutrophils improves outcome following infection. Thus, neutrophil accumulation within the lung is deleterious in pneumonia caused by heavily encapsulated pneumococcal strains. Our study provides fresh insight into the role of IL-17 in host defence against pneumococcal pneumonia, which may also be relevant in other infections caused by encapsulated bacteria that colonize before infection, such as the meningococcus and Haemophilus influenzae.

Sepsis is a common condition with high morbidity and mortality. Although many patients may require critical care, this article considers the features of sepsis that are of most relevance to acute general physicians. Recently updated definitions of sepsis and septic shock have been proposed which better identify patients who are likely to have a poor outcome, and therefore give an opportunity to escalate care. Despite these advances, there is still no molecular signature able to diagnose sepsis. Pathogenesis is complex, with many immune and non-immune mediators involved. Four key areas are endothelial dysfunction, coagulation abnormalities, alterations in cell function and dysregulated cardiovascular responses. No specific therapy targeting the mediators of sepsis has yet proven effective. Prompt administration of appropriate antibiotics is of benefit, together with fluid resuscitation and oxygen.

A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease.

To the Editor: Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuated response to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need for alternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolide antibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy in the treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection after lung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchial hyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma [7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokers with asthma. A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for 12 weeks. All subjects were aged 18–70 years, were current smokers (≥5 pack-years history) with chronic asthma (>1 year duration; defined by international criteria [8]) and had to be free of exacerbation and respiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit was performed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 μg beclometasone ± a long-acting β2-agonist (LABA). Ethical approval was obtained and all subjects provided written informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratory flow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 …

The development of a vaccine for Mycobacterium tuberculosis (Mtb) has been impeded by the absence of correlates of protective immunity. One correlate would be the ability of cells induced by vaccination to recognize the Mtb-infected cell. AERAS-402 is a replication-deficient serotype 35 adenovirus containing DNA expressing a fusion protein of Mtb antigens 85A, 85B and TB10.4. We undertook a phase I double-blind, randomized placebo controlled trial of vaccination with AERAS-402 following BCG. Analysis of the vaccine-induced immune response revealed strong antigen-specific polyfunctional CD4+ and CD8+ T cell responses. However, analysis of the vaccine-induced CD8+ T cells revealed that in many instances these cells did not recognize the Mtb-infected cell. Our findings highlight the measurement of vaccine-induced, polyfunctional T cells may not reflect the extent or degree to which these cells are capable of identifying the Mtb-infected cell and correspondingly, the value of detailed experimental medicine studies early in vaccine development.

To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C ss,max, 36 for AUCss. gMean AUCss and C ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C ss,max and 41 for AUCss. gMean AUCss and C ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUCss and C ss,max were >1 for ketoconazole and

Objectives: Lyme borreliosis (LB) is the most common human tick-borne infection in Europe and the USA. In this study we set out to analyse the outcome of patients treated for Lyme disease via outpatient parenteral antibiotic therapy (OPAT) and the appropriateness of this treatment using current guidelines. Methods: This was a retrospective review of all patients with suspected LB managed via OPAT in Glasgow in 2000–11. Results: Of 72 patients treated for suspected LB, 35 patients (49%) were treated in accordance with guidelines and 36 (50%) were treated with no specific guidelines. A definite improvement was seen in 20 patients (28%). Adverse reactions were documented in 29 (40%) patients with neutropenia, and mild liver function derangement was most commonly observed. Conclusions: These results show the complexity of translating well-substantiated regimens from clinical trials to actual clinical practice. OPAT was an effective way of administering parenteral therapy for Lyme disease but should not be undertaken lightly due to the rate of adverse events and low rates of success in certain patient groups seen in this study. In view of this, stricter criteria for inclusion to OPAT in line with published guidance should be applied to minimize patient harm and optimize success.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for38 months, and 12 patients had disease stabilization (8 for ≥3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year (with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months (patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 micro g of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies.

Interferon-gamma (IFN-gamma) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-gamma gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma.Patients were enrolled at four successive dose levels: 10(7) infectious units (iu) (n=3), 10(8) iu (n=3), 10(9) iu (n=3), and 10(10) iu (n=2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated.A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n=8), and grade 1 fatigue (n=5) patients. Clinical changes observed at the local injected tumor site included erythema (n=5), a minor decrease in size of the injected lesion (n=5) and significant central necrosis by histopathology (n=1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity.Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma.

BACKGROUND—Nitric oxide (NO) and prostanoids are mediators of vascular and bronchial tone that are postulated to be involved in asthma. Increased levels of both are found in asthmatic subjects and are synthesised by enzymes that have cytokine inducible forms: inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2), respectively. We hypothesised that the in vivo expression of iNOS and COX-2 in the airways would be increased in asthma, and that these cytokine inducible enzymes may represent targets for regulation by corticosteroid treatment. METHODS—Bronchial biopsy specimens were obtained from three groups of subjects: atopic asthmatics treated with β2 agonists alone (n=7), atopic asthmatics additionally receiving regular treatment with corticosteroids (n=8), and non-asthmatic control subjects (n=10). Expression of iNOS and COX-2 mRNA and immunoreactive protein was studied using in situ hybridisation and quantitative immunohistochemistry. RESULTS—Immunoreactivity and the hybridisation signal for iNOS and COX-2 were mainly localised in the airway epithelium. The proportion of epithelium immunostained was significantly greater in the non-steroid treated asthmatic subjects (iNOS 8.6 (1.8)%; COX-2 26.3 (4.6)%) than either the steroid treated asthmatics (iNOS 3.4 (1.0)%, p=0.009; COX-2 13.0 (0.6)%, p=0.0015) or the non-asthmatic controls (iNOS 4.2 (0.9)%, p=0.018; COX-2 11.6 (0.6)%, p=0.0003). Similarly, the hybridisation signal was stronger in the non-steroid treated group of asthmatic subjects than in the other two groups. CONCLUSIONS—These findings highlight the potential role of the airway epithelium both as a contributor to the inflammatory process in asthma and as a target for inhaled corticosteroid treatment in this disease.

OBJECTIVES To describe prospectively the evolution of liver abnormalities in cystic fibrosis (CF), and to assess their impact on nutritional status. STUDY DESIGN 124 children (61 boys) with CF (median age, 5.4 years; range, 0.1–13.9) were followed longitudinally for a median of four years. Annual clinical examination, biochemistry, and ultrasound assessment were performed. Chrispin-Norman score, anthropometry, and bacterial colonisation of airway secretions were measured at each assessment. RESULTS At initial assessment, 45% of the patients had no liver abnormalities, 42% had biochemical abnormality, 35% ultrasound abnormality, and 6% had clinical abnormality of the liver. In this cross sectional analysis, abnormal biochemistry was present in 40% of children with ultrasound or clinical abnormalities, but when longitudinal follow up data were analysed, abnormal biochemistry preceded or coincided with abnormal ultrasound or clinical hepatosplenomegaly in three quarters of 53 children developing new abnormalities. Eighty four of 124 children (68%) showed ultrasound or clinical evidence of liver abnormality at some point during the four years of follow up. No association was found between liver disease and nutritional status. CONCLUSIONS Hepatic abnormality was common in this group of children with CF, was often predicted by intermittent biochemical abnormalities, and was not associated with deterioration in nutritional status.

In the 1890s, William B. Coley started to treat cancer patients with inoculations of bacterial extracts (Coley's toxins) to activate general systemic immunity, some of which might be directed against the tumour.1,,2 Subsequent efforts to enhance our understanding of the molecular basis of immune recognition and immune regulation of cancer cells have led to the identification of potential new targets on tumour cells, and the potential to create potent, specific cancer vaccines. In this review, we discuss the principles of tumour immunity, the tumour antigens that can be recognized by the immune system, the different types of vaccines that have been evaluated, and the potential clinical applications of these approaches. Unlike most vaccines for infectious agents, the goal of cancer vaccination is therapeutic and this can be achieved by activating immune responses against tumour antigens. The immune response can be crudely divided into either antibody responses or T-cell responses. Antibodies recognize and bind to conformational determinants on cell surface proteins, and can kill the cell by either antibody-dependent cellular cytotoxicity or complement-mediated cell lysis. Conversely, T cells recognize small proteins presented on the cell surface on major histocompatibility (MHC) antigens, and T-cell activation requires a co-stimulatory signal which is usually present on the cell surface of antigen-presenting cells. However, attempts to exploit the immune system as a therapeutic strategy in cancer treatment have to overcome the host's inability to develop effective endogenous immunity against cancer. Several mechanisms have been proposed to explain this phenomenon, including generation of tumour variants lacking certain tumour antigens,3–,5 loss of MHC expression,6–,9 downregulation of the antigen processing mechanism10 and also expression of inhibitory molecules which may promote escape from immune surveillance including TGF β 11 and Fas ligand.12 A further significant contributor to escape … Dr T.R.J. Evans, CRC Department of Medical Oncology, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD. e-mail: trjelv{at}udcf.gla.ac.uk

To assess the efficacy and toxicity of an outpatient combination chemotherapy in small-cell lung cancer (SCLC), we treated 70 consecutive patients with epirubicin 80 mg m(-2) i.v. on day 1 and etoposide 200 mg o.d. p.o. on days 1-4 (EE) at 3-weekly intervals. The median age of patients was 64 years (range 39-84). The male-female ratio was 42:28 and 35 (50%) had metastatic disease. Fifty-seven patients were evaluable for response. The overall response rate was 64.4%, including 14 (23.7%) complete responses and 24 (40.7%) partial responses. Median time to progression was 7 months in responders and 8 months in patients with limited disease. The median survival in patients with limited disease was 10.5 months (range 0.5-70 +) and 7 months (range 0.5-24) in those with extensive disease. Improvement of symptoms occurred in 79% of patients with shortness of breath, 80% with cough, 81% with haemoptysis and 68% with pain. In 19 patients an increase in body weight was noted. Major (WHO grade 3/4) toxicities were neutropenia in 13 (18.5%) patients, alopecia in 33 (47.1%) patients, mucositis in 15 (21.4%) patients, anorexia in eight patients (11.4%), nausea and vomiting in six patients (8.5%) and diarrhoea in 4 (5.7%) patients. In conclusion, EE is an active and well-tolerated outpatient regimen in the treatment of SCLC. The survival data in this unselected group of patients were disappointing and the possible explanations for this are discussed.

BACKGROUND--While there are reports on the outcome in adults and teenagers with cystic fibrosis of colonisation with Burkholderia (Pseudomonas) cepacia, there is little information in children. METHODS--In December 1991 only one of 115 children with cystic fibrosis attending a paediatric centre was colonised with B cepacia. Over the next 12 months there was a rapid increase with 23 (20%) becoming colonised; eighteen (79%) of these became colonised in hospital at a time that overlapped with the admission of a B cepacia positive child. Three different bacteriocin types were isolated, with one type (S22/PO) being present in 17 (74%) patients. The outcome for children who became colonised with B cepacia was compared with that in 33 children who continued to be colonised with Pseudomonas aeruginosa alone. RESULTS--Children colonised with B cepacia were older and more poorly nourished than those colonised with P aeruginosa, but did not have poorer pulmonary function. After colonisation, the forced expiratory volume in one second (FEV1) deteriorated between consecutive annual tests, with the average deterioration being greater in those with higher initial levels. Five children with B cepacia died from respiratory failure although none showed a fulminant deterioration. Introduction of segregation measures within hospital led to a dramatic decrease in the number of newly colonised patients. CONCLUSIONS--This study provides further evidence for person-to-person spread of B cepacia and confirms the effectiveness of simple isolation measures in interrupting spread. Colonisation with B cepacia and P aeruginosa in children is associated with a more rapid decline in lung function and a significantly increased mortality compared with cases colonised with P aeruginosa alone.

Sir, We appreciate Dr Stricker et al. ’s interest in our article describing the use of outpatient parenteral antibiotic therapy in the treatment of Lyme disease.1 They highlight the finding that, of the 47 patients for whom intravenous antibiotic therapy was recommended, the 13 that received prolonged antibiotics appeared to do better than those who received the currently recommended duration of therapy (14–28 days) and then provide a statistical analysis to demonstrate that this difference was statistically significant. Of these 13 patients, 7 received 2–4 weeks of parenteral ceftriaxone followed by a …

BACKGROUND: VCL-CB01, a candidate cytomegalovirus (CMV) DNA vaccine that contains plasmids encoding CMV phosphoprotein 65 (pp65) and glycoprotein B (gB) to induce cellular and humoral immune responses and that is formulated with poloxamer CRL1005 and benzalkonium chloride to enhance immune responses, was evaluated in a phase 1 clinical trial. METHODS: VCL-CB01 was evaluated in 44 healthy adult subjects (22 CMV seronegative and 22 CMV seropositive) 18-43 years old. Thirty-two subjects received 1- or 5-mg doses of vaccine on a 0-, 2-, and 8-week schedule, and 12 subjects received 5-mg doses of vaccine on a 0-, 3-, 7-, and 28-day schedule. RESULTS: Overall, the vaccine was well tolerated, with no serious adverse events. Local reactions included mild to moderate injection site pain and tenderness, induration, and erythema. Systemic reactions included mild to moderate malaise and myalgia. All reactions resolved without sequelae. Through week 16 of the study, immunogenicity, as measured by enzyme-linked immunosorbant assay and/or ex vivo interferon (IFN)-gamma enzyme-linked immunospot assay, was documented in 45.5% of CMV-seronegative subjects and in 25.0% of CMV-seropositive subjects who received the full vaccine series, and 68.1% of CMV-seronegative subjects had memory IFN-gamma T cell responses at week 32. CONCLUSION: The safety and immunogenicity data from this trial support further evaluation of VCL-CB01.

Purpose To evaluate effects of a 6-month social marketing campaign on awareness of, attitudes toward and use of female as well as male condoms for 15–25 year-old-women. Methods Using a time-space sampling methodology, we conducted a cross-sectional survey of 3407 women at pre-campaign in 12 western U.S. neighborhoods on female and male condom awareness, attitudes, and use. Six of the 12 study neighborhoods were randomly selected to receive the POWER social marketing campaign designed to impact condom knowledge, attitudes, and use. The campaign was followed with another cross-sectional survey of 3,003 women in all 12 study neighborhoods on condom knowledge, attitudes, use and awareness of POWER materials. We compared pre-and post-campaign surveys to determine the efficacy of POWER and conducted post hoc analyses on post-campaign data to determine if exposure to POWER was related to higher levels of positive condom attitudes and norms and condom use. Results We found no differences between neighborhoods with and without the POWER campaign with regard to our primary outcomes. To diagnose reasons for this null effect, we examined outcomes post hoc examining the influence of POWER exposure. Post hoc analyses show some evidence that exposure to POWER was associated with condom use. In the context of the nested trial, this raises concerns that post test only evaluations are limited. Conclusions Establishing the efficacy of a social marketing campaign is challenging. This group randomized trial showed a null effect. Social marketing campaigns may need to have more media channels and saturation before they can show behavioral effects. Using a nested design with randomization at the community level and probability sampling introduces rigor not commonly seen in evaluations of social marketing campaigns.

Sepsis and multiple organ failure are common causes of death in patients admitted to intensive care units. The incidence of sepsis and associated mortalities has been steadily increasing over the past 20 years. Sepsis is a complex inflammatory condition, the precise causes of which are still poorly understood. Animal models of sepsis have the potential to cause substantial suffering, and many of them have been poorly representative of the human syndrome. However, a number of non-animal approaches, including in vitro, in silico and clinical studies, show promise for addressing this situation. This report is based on discussions held at an expert workshop convened by Focus on Alternatives and held in 2004 at the Wellcome Trust, London. It provides an overview of some non-animal approaches to sepsis research, including their strengths and weaknesses, and argues that they should be prioritised for further development.

Neutropenia is frequently observed in the practice of oncology, usually resulting from the use of cytotoxic drugs. Less frequently, neutropenia is due to infiltration of the bone marrow by malignant disease. Both of these usually cause some depletion of all haematopoietic linages. True isolated neutropenia is, in contrast, a less frequent phenomenon. We report a case of auto-immune neutropenia occurring in a patient with metastatic melanoma, and discuss the differential diagnosis and implications for patient management.

After the publication of the 10-year survival data from Milan on the adjuvant use of the block sequential regimen consisting of four cycles of adriamycin followed by eight cycles of intravenous CMF, many centres adopted this as standard of care for high risk, multiple node-positive breast cancer. For this reason it was identified as the standard arm for the Anglo-Celtic adjuvant high-dose chemotherapy trial. This study reports on the experience of this regimen in 329 women with early breast cancer involving at least four axillary nodes, who were treated outside any adjuvant chemotherapy trial. At a median follow-up of 3 years, the overall 5-year disease-free survival is 61%, and the overall survival is 70%. These data confirm the efficacy of this regimen in non-trial patients, and, for the same high risk subgroup, indicate that this approach offers an outcome at least as good as that seen in the CALGB 9344 AC-Taxol arm, and the NCIC days 1 and 8 CEF. British Journal of Cancer (2002) 87, 1365–1369. doi:10.1038/sj.bjc.6600660 www.bjcancer.com © 2002 Cancer Research UK

MALIGNANT hyperthermia (MH) is a potentially fatal hypermetabolic response to volatile inhalation agents and succinylcholine that may have variable presentations. The authors describe an unusual presentation with late onset of malignant hyperthermia after laparoscopic cholecystectomy, with rhabdomyolysis as the principal sign.

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10–15 μg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82–532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states. British Journal of Cancer (2002) 86, 680–685. DOI: 10.1038/sj/bjc/6600162 www.bjcancer.com © 2002 Cancer Research UK

The Brownlee Centre for Infectious Diseases, Tropical Medicine and Counselling, Gartnaval General Hospital, 1053 Great Western Road, Glasgow G12 3YN, UK; The Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; Division of Inflammation, Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8QQ, UK

Background—Two clinical formulae (CF conference formula and estimation based on 120% of average requirement for energy) have been recommended for the estimation of energy requirements in cystic fibrosis but their accuracy is unknown. Aim—To compare the accuracy of estimates of energy requirement derived from the two formulae. Methods—Energy requirement, defined as total daily energy expenditure, was measured using the doubly labelled water method in 15 patients (six girls, nine boys; mean (SD) age, 10.0 (2.4) years) who were well and clinically stable. The accuracy of the formulae was assessed using calculation of biases and limits of agreement relative to measured energy requirement. Results—Estimates from the CF conference formula were lower than measured values (mean paired diVerence, 0.52 MJ/ day; 95% confidence interval (CI), ˛1.10 to 0.10), but this bias was not significant, and was smaller than that from the alternative formula (mean paired diVerence, 0.77 MJ/day; 95% CI, ˛0.20 to 1.74). Limits of agreement relative to measured total daily energy expenditure were narrower for the CF conference formula (˛2.72 to 1.68 MJ/ day) than for that based on 120% of estimated average requirement (˛2.75 to 4.29 MJ/day), but with both formulae errors in estimation at the individual level were large. Conclusions—The CF conference formula oVers improved prediction of energy requirements, but the accuracy of both formulae at the individual level is not sufficiently good for clinical purposes. (Arch Dis Child 1999;81:120‐124)

Acute respiratory exacerbations have been proposed to contribute to the negative energy balance which causes undernutrition in cystic fibrosis. However, no studies have measured their effect on all components of energy balance. The aim of this study was to measure the effect of an acute respiratory exacerbation on energy balance. Fourteen children (six females, eight males, mean+/-SD age 9.9+/-2.4 yrs) were studied when well and during the course of an acute respiratory exacerbation treated with intravenous antimicrobial therapy. The total energy expenditure was measured using the doubly-labelled water method, resting energy expenditure by ventilated hood indirect calorimetry, energy intake by household measures records, and fat malabsorption from measurements of dietary fat intake and faecal fat output. The exacerbation was associated with a significant reduction in energy intake (mean paired difference 47 kJ x kg of body weight(-1) x day(-1), p

Abstract —Inflammation appears to have a major role in the development of atherosclerotic lesions affecting native and transplanted coronary arteries. The subsequent risk of plaque rupture and acute ischemic events correlates with the degree of inflammation and may be modified by aspirin, an anti-inflammatory cyclooxygenase inhibitor. Cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) are involved in the inflammatory response via the rapid and exaggerated production of prostanoids and nitric oxide, both of which may have proatherosclerotic effects. These effects may be mediated by the formation of peroxynitrite in the case of nitric oxide and involve “cross talk” between the two enzyme systems. This study aimed to investigate native and transplant atherosclerosis for the presence and distribution of Cox-2 and iNOS. Immunocytochemical studies were performed on atherosclerotic lesions from patients with native (n=12) and transplant (n=5) coronary disease by using antibodies to Cox-2, iNOS, and nitrotyrosine (an indicator of peroxynitrite production). Control tissue was obtained from unused donor hearts and at the time of autopsy. Cox-2 and iNOS colocalized predominantly in macrophages/foam cells in both types of atherosclerosis. Cox-2 expression was also detected in medial smooth muscle cells and endothelial cells, including those of the vasa vasorum. Nitrotyrosine was found in the same distribution as that of iNOS and was colocalized with Cox-2 in macrophages. Cox-2 and iNOS are coexpressed in native and transplant atherosclerosis, possibly allowing for interaction between the enzymes and suggesting an alternative mechanism for the benefits of aspirin via inhibition of Cox-2 activity.

But: Etudier la reponse systemique des cytokines a une chirurgie hepatique majeure pour evaluer de nouveaux traitements potentiels. Type d'etude: Ouverte, prospective. Provenance : Hopital universitaire, Royaume-Uni. Patients: Treize patients ayant eu une resection hepatique programmee avec exclusion vasculaire. Methodes: Des prelevements sanguins ont ete realises en preoperatoire, pendant l'intervention et au cours des quatre premiers jours postoperatoires pour mesurer les concentrations d'endotoxine, d'interferon gamma (INF-γ), de facteur de necrose tumoral α (FNT α), d'interleukine-1 (IL-1), et d'interleukine-6 (IL-6). Resultats: Les concentrations d'endotoxine etaient elevees chez 3 patients sur 13 avant l'intervention et chez 6 patients au cours de la periode postoperatoire. Les concentrations de TNF-α etaient nulles. Les doses d'INF-γ et d'IL-1 etaient faibles et leurs variations difficilement interpretables. Les concentrations d'IL-6 etaient augmentees de maniere significative de la sixieme heure au troisieme jour postoperatoire, avec un maximum de 699 (277) pg/ml a la vingtquatrieme heure (p

Introduction and Objectives Pseudomonas aeruginosa (PA) colonisation is a hallmark of cystic fibrosis (CF) resulting in damaging neutrophilic inflammation. Patients with CF produce anti-pseudomonal antibodies but the role of CD4 + T cell responses to PA remains unclear. Novel T helper cell subsets, Th17 and Th22 cells, have important roles in host defense but may also enhance tissue damage. We aimed to define the antigen-specific memory T helper cell responses to Pseudomonas aeruginosa in healthy humans and patients with cystic fibrosis. Methods CD14 + monocytes and memory CD4 + CD45RO + T cells were isolated from peripheral blood of CF patients with PA colonisation (n = 8) and healthy controls (n = 10). Monocyte-derived dendritic cells (DCs) were stimulated with live Pseudomonas strain PA103 and PA isolates derived from CF patients. Autologous T cells were co-cultured with activated DCs. The resultant T helper response was determined by measuring proliferation, immunoassay of cytokine output, and immunostaining of intracellular cytokines. Lavage samples from explanted CF lungs were assayed for IL-22 secretion. Results Healthy individuals andpatients with cystic fibrosis had robust antigen-specific memory CD4 + T cell responses to Pseudomonas aeruginosa that not only contained a Th1 and Th17 component but also Th22 cells. In contrast to previous descriptions of human Th22 cells, these Pseudomonal-specific Th22 cells lacked the skin homing markers CCR4 or CCR10, although they did express the chemokine receptor CCR6 that would direct migration to damaged epithelial surfaces. Furthermore, IL-22 production was evident in the lungs of CF patients colonised with PA. Healthy individuals and patients with cystic fibrosis had similar levels of Th22 and Th1 cells, but the patient group had significantly fewer Th17 cells in peripheral blood. Conclusions MemoryTh22 cells specific to Pseudomonas aeruginosa are induced in both healthy individuals and patients with CF, with IL-22 secretion being demonstrated in the CF lung. These Th22 cells do not express tissue specificity for gut or skin sites and we thus hypothesise may have a role in respiratory defense. Along with Th17 cells, they may play an important role in the pathogenesis of pulmonary infection with this microbe in patients with cystic fibrosis.

Amongst the many mediators that have been implicated in the pathophysiological changes seen in sepsis and septic shock, nitric oxide (NO) is one of the most recent to be described. Its role in mammalian cell biology is enormous (reviewed in Nathan 1992; Bredt and Snyder 1994), but this chapter focuses on its role in sepsis. While the functions of NO are legion, we concentrate on a few central roles that NO plays in sepsis. In particular, we discuss its hypotensive, cytotoxic, immunomodulatory, cardiovascular, and cerebral effects. In common with other mediators in sepsis there are problems in extending the results obtained in animal models to humans. We therefore discuss the clinical data pertaining to the role of NO in sepsis separately. NO is one example of a potentially toxic oxygen compound, and many others have been identified as possible mediators in sepsis which we do not have space to review. However, it is clear that NO can react with a number of these compounds to generate very toxic molecules, which are described here.

s / Pancreatology 13 (2013) e1–e20 e8 University College London, Institute of Liver and Digestive Health, Royal Free Hospital Guy's and St Thomas’ NHS Foundation Trust, London, Department of Gastroenterology King's College London and King's Health Partners, Division of Women's Health University College London, Department of Pathology University College London, HPB & Liver Transplant Unit, Royal Free Hospital Category: Benign and Inflammatory Background and aims: Some 35% of women of reproductive age are obese. Emerging evidence suggests that maternal obesity(MO) may predispose offspring to an increased risk of obesity and its related disorders, including Non-Alcoholic Fatty Pancreas Disease(NAFPD), a newly described disease entity which may link obesity and pancreatic adenocarcinoma. We have investigated the impact of MO on the pathogenesis of NAFPD using a pathophysiologically relevant model and mechanistically explored a role for altered expression of circadian genes(CG). Methods: Female C57BL6 mice were fed standard or obesogenic diet(OD) for 6 weeks prior to and throughout pregnancy and lactation. Litters were standardised to a minimum of 6 pups and offspring then weaned onto either standard or OD to produce 4 groups before sacrifice at 6 months. We assessed biochemical, histological and pro-inflammatory/profibrogenic markers associated with the NAFPD phenotype and the expression of CG in the pancreas. Results and Interpretation: Offspring exposed to MO and OD had increased bodyweights (p

s / Pancreatology 13 (2013) e1–e20 e5 Conclusion: Components of the metabolic syndrome, which are associated with insulin resistance, namely elevated diastolic blood pressure, elevated serum HbA1c and decreased serum HDL were positively associated with large increases in the risk of pancreatic cancer. Factors influencing these parameters should be measured in future aetiological work and may suggest mechanisms for carcinogenesis, but support an aetiological role for insulin resistance in pancreatic cancer. Take-home message: Metabolic factors and serum HDL may be predicitve of the risk of developing pancreatic cancer. Abstract previously presented? yes (BSG) Any disclosures? no ()

The occurrence of viridans streptococcal bacteraemia (VSB) in a London postgraduate teaching hospital was analysed retrospectively. Over a 30-month period, 39 patients with VSB were identified, and the clinical significance of VSB was assessed for each, based upon clinical and laboratory information. Endocarditis accounted for only 13% of the total patients with apparent VSB. A greater proportion of patients with VSB originated from the haematology unit (21%) and in particular, the bonemarrow transplantation unit (15%). VSB also occurred in patients with solid epithelial malignancies and in children aged

10000 Background: Pts with sarcomas, a family of >70 types of cancer, have limited options once cytotoxic agents fail. Brivanib (B) is an oral once daily selective dual inhibitor of FGF and VEGF signaling currently in phase III. Data from a phase II trial were analyzed to evaluate the potential utility of biomarkers and STS subtypes in predicting response to B. Methods: Pts aged ≥18 y with unresectable STS and no other treatment options received open-label B 800 mg qd for a 12-wk lead-in period and were assessed by CT/MRI. Pts with RECIST response continued on open-label B, those with progressive disease (PD) went off study. Pts with stable disease (SD) were randomized 1:1 to B or placebo (P), stratified by FGF2 expression (IHC + or -), until PD or unacceptable toxicity. Pts with PD on P could crossover to resume open-label B. The primary endpoint was PFS for B vs P in FGF2+ pts; secondary endpoints included ORR, DCR (ORR+SD), and exploratory biomarkers. Results: Of 251 pts (52% with ≥2 prior systemic reg...

8527 Background: E7080 is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of E7080, DLTs were hypertension and proteinuria and common toxicities included grade 1-2 fatigue, anorexia, nausea, weight loss and diarrhea. MTD for E7080 once daily (QD) is 25 mg and for twice daily (BID) is 20 mg (i.e.10 mg BID). Methods: From 7/2005 to 10/2008, 82 patients (pts) with advanced solid tumors including 14 with advanced melanoma were enrolled into a phase I study of escalating doses of E7080 QD. From 7/2005 to 8/2009, 77 pts with advanced solid tumors including 29 with advanced melanoma were enrolled into a second phase I study of escalating doses of E7080 BID. 25/29 pts receiving E7080 BID underwent pretreatment biopsy for molecular analysis of tumor vascular and melanoma cell components. Those results are reported separately. Clinical outcomes for melanoma pts treated with E7080 in phase I trials are reported. Results: 35/43 pts received E7080 doses of ≥ 20 mg...

3079 Background: Brivanib (B) is an oral once daily selective dual inhibitor of FGF and VEGF signaling currently in phase III development for advanced hepatocellular carcinoma and colorectal cancer...

3063 Background: CXR1002, an ammonium salt of perfluorooctanoic acid, is a lipid mimetic that causes ER stress and inhibits PIM kinases. Aims of this study were to assess the tolerability, safety and pharmacokinetics (PK) and to identify the recommended phase II dose (RP2D) of CXR1002 administered orally once weekly. Methods: Sequential cohorts of pts with advanced refractory solid tumors were enrolled. Cohort 1 received a single dose of CXR1002 followed by once weekly dosing commenced 6 weeks (wks) later. Subsequent cohorts received CXR1002 once wkly. Dose escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. Plasma levels of CXR1002 were determined by LC-MS/MS at the following time-points: pre-dose, 2, 3, 4, 24 hours post-dose for the first 6 wks then 6 wkly. Exploratory PD analyses included: serum leptin; plasma lipids, glucose and insulin. Results: 41 pts have been enrolled (23M / 18F); median age 63 (range 36-75); PS < 2; colorectal (n=16); pancreatic...