Mature autologous dendritic cell vaccines in advanced non-small cell lung cancer: a phase I pilot study

Background

Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients.

Methods

Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5 × 10⁷ DC cells administered subcutaneous and intravenously two times at two week intervals. The immunologic response, safety and tolerability to the vaccine were evaluated by the lymphoproliferation assay and clinical and laboratorial evolution, respectively.

Results

The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.005). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together.

Conclusion

Despite the small sample size, the results on the immune response, safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment.

Trial Registration

Current Controlled Trials: ISRCTN45563569     

ARC--augmented renal clearance

In-hospital and intensive care unit mortality rates for sepsis remain un-acceptably high, and have prompted the publication of international guidelines on best practice. Crucial to this is the application of early appropriate antibacterial therapy, in the correct dose. However, antibacterial regimes in this setting have largely been extrapolated from those in healthy volunteers, and fail to consider the unique pathophysiology and treatment provided to this population. As such, augmented renal clearance (ARC) - the enhanced renal elimination of circulating solute - is likely to be one of the more common physiological changes encountered in this setting, although to date remains largely under-appreciated. Significantly this may alter the pharmacokinetics of many routinely prescribed agents in this setting, pre-disposing to subtherapeutic levels or treatment failure. This review paper examines this phenomenon in detail, providing a summary of the likely underlying mechanisms, those patients at greatest risk, and the implications for antibacterial dosing in the critically ill.     

Physiological changes in the critically ill patient with sepsis

Intensive care medicine deals with the critically ill; these patients usually have multiple organ failure, and complex medical conditions. The mortality in Australia and New Zealand among this population is approximately 16.1%, with approximately 24.2% having existing co-morbidities, and 23.4% of these patients experiencing sepsis or septic shock. Sepsis is a clinical syndrome that traditionally was regarded as a physiological maladaptive response to a foreign pathogen and ranges in disease severity from simple sepsis to septic shock, a life threatening condition, associated with multiple organ failure. Sepsis has profound effects on all systems of the body, and most notably the cardiovascular, renal and hepatic systems. There has been much research into the septic critically ill patient and recent developments in basic pharmacology and physiology has yielded results applicable to clinical practice. Sepsis may induce a state of increased cardiac output, which has significant effects on drug pharmacokinetics and pharmacodynamics. This increased cardiac output increases both renal and hepatic blood flow, and alters rates of antibiotic metabolism, and excretion. There are also alterations in the fluid compartments of the septic critically ill, that results in an altered volume of distribution, and ultimately decreased antibiotic concentrations at their site of action. This article will examine and review in detail the septic critically ill patient, and the effects that sepsis has on physiology and the resulting altered antibiotic pharmacokinetics and pharmacodynamics. Current knowledge suggests that the medical prescriber should be weary of antibiotic dosing in the septic critically ill, and consider alternative dosing regimes that are individualized to the patient in order to maximize efficacy.     

The growing impact of HIV infection on the epidemiology of tuberculosis in England and Wales: 1999 2003

BACKGROUND: Previous studies have estimated the prevalence of tuberculosis and HIV infection in population subgroups in the UK. This study was undertaken to describe recent trends in the proportion of individuals with HIV infection among reported cases of tuberculosis in England and Wales, and to review the implications for clinical and public health care. METHODS: A population-based matching study using national surveillance databases was used to investigate all persons aged 15 years and over reported with a diagnosis of tuberculosis to the Health Protection Agency in England and Wales in 1999-2003. Record linkage was used to match the national tuberculosis and HIV/AIDS surveillance databases to identify all cases of tuberculosis and determine the proportion of patients with tuberculosis co-infected with HIV. The distribution and characteristics of the cases were determined and the trend examined by year. RESULTS: Of 30,670 cases of tuberculosis reported in England and Wales between 1999 and 2003, an estimated 1743 (5.7%) were co-infected with HIV. There was a year on year increase in the proportion from 3.1% (169/5388) in 1999 to 8.3% (548/6584) in 2003 (p for trend <0.0001). Co-infected patients contributed to almost a third of the increase in the number of cases of tuberculosis during the 5 year period. Patients co-infected with HIV were predominantly those born abroad. 18.5% (n = 323) of co-infected patients had not been reported as active cases of tuberculosis on the national tuberculosis database. CONCLUSION: The proportion of patients with tuberculosis co-infected with HIV in England and Wales is increasing, with the greatest impact on those born abroad regardless of their ethnic origin. With HIV infection contributing substantially to the increase in the number of cases of tuberculosis, close cooperation in the clinical management and accurate notification of patients is vital if appropriate care and public health action is to be achieved.     

Child well-being in single-mother families.

OBJECTIVES: Children from single-mother families are at increased risk of psychosocial morbidity. This article examines the strength of association between single-mother family status and child outcome, both alone and controlling for other sociodemographic and personal (maternal/family) variables. METHOD: Data from the Canadian National Longitudinal Survey of Children and Youth Cycle 1 (1994-1995) were used. Children aged 6 to 11 years in single-mother and two-parent families were included (n = 9,398). Child functioning measures included social impairment, psychiatric problems, and math score. RESULTS: Single-mother family status on its own is a significant predictor of all child difficulties, but the explained variance is limited and the effect size decreases when other variables known to influence child functioning are included. Household income, a sociodemographic variable, is inversely associated with social impairment and positively associated with math score. Hostile parenting and maternal depression are the personal variables most strongly associated with social impairment and psychiatric problems. Children in single-mother families where there is hostile parenting are at significantly increased risk of psychiatric problems. CONCLUSIONS: The results suggest that children from single-mother families develop difficulties for the same reasons as children from two-parent families. Specific interventions for single-mother families may be warranted in the areas of parenting and other areas of concentrated risk.     

A comparison of epinephrine and norepinephrine in critically ill patients

Objective  To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients. Design  Prospective, double-blind, randomised-controlled trial. Setting  Four Australian university-affiliated multidisciplinary ICUs. Patients and participants  Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately. Interventions  Blinded infusions of epinephrine or norepinephrine to achieve a MAP ≥70 mmHg for the duration of ICU admission. Measurements  Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8–70.4 h) with epinephrine compared to 40.0 h (IQR 14.5–120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69–1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59–1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62–1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality. Conclusions  Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients. This study was presented at the Annual Congress of the European Society of Intensive Care Medicine in Berlin on October 10 2007. The presentation received the International Sepsis Forum prize for best abstract and paper. This study has been published in abstract form: Myburgh J.A., Higgins A., Jovanovska A., Lipman J., Ramakrishnan N., Santamaria J and the CAT Study Investigators. (2007). A comparison of epinephrine and norepinephrine on reversal of shock. Intensive Care Medicine 33 (Supplement 2): S197. Trial registration: The study was registered with Current Controlled Studies: ISRCTN number 92846592.     

Acute respiratory distress in a bleomycin primed patient: a new use for nitric oxide

We describe the use of nitric oxide as an oxygen-sparing strategy in the context of prior bleomycin exposure. A 27-year-old male, previously treated with bleomycin for a testicular germ cell tumour presented with severe acute respiratory distress syndrome on the second postoperative day following an extensive retroperitoneal dissection. The mechanism of bleomycin toxicity and potential benefits of nitric oxide in this situation are considered.     

Amoxicillin-clavulanic acid and trimethoprim- sulfamethoxazole in rodent feed and water: effects of compounding on antibiotic stability.

We assessed the concentrations of 2 antibiotic combinations, amoxicillin-clavulanic acid and trimethoprim-sulfamethoxazole when compounded in reverse osmosis [RO] (pH 6.0), tap (pH 6.7), and acidified water (pH 2.6) over 7 d, and pre- and post-pelleting, post-gamma irradiation and shipping, and monthly until 180 d post-milling in feed. Amoxicillin concentrations in RO and tap water varied between 1.18 and 1.29 mg/ml, and 1.09 and 1.22 mg/ml, respectively. The concentration of amoxicillin declined immediately and remained between 0.43 and 0.50 mg/ml in acidified water. Clavulanic acid exhibited a slow time-dependent decrease in concentration to 0.05 mg/ml at day 7 in RO water, immediately declined and varied from 0.02 to 0.05 mg/ml in tap water, and was undetectable in acidified water. Trimethoprim and sulfamethoxazole concentrations were near expected in RO, tap, and acidified water. In food, amoxicillin, trimethoprim, and sulfamethoxazole concentrations were each reduced to approximately 60% of expected after pelleting, but remained stable thereafter for 180 d. The initial clavulanic acid concentration in feed was less than 10% of expected and was undetectable after 1 mo. Plasma drug concentrations were determined in C57BL/6NCrl mice at 4 h after commencement of the dark and light cycles following administration of antibiotic food for at least 72 h. Plasma amoxicillin and sulfamethoxazole concentrations were 3- and 10-fold greater, respectively, during the dark period. Plasma levels of clavulanic acid and trimethoprim were consistent at both time points. These results indicate that the antibiotic concentration can be influenced by compounding in feed and water, and differs in plasma during the light and dark phases of the photoperiod.