Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients

BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.     

Permeant lipophilicity and vehicle composition influence accumulation of dyes in hair follicles of human skin

In skin and hair research drug targeting to the hair follicle is of great interest. Therefore the influence of permeant lipophilicity and vehicle composition on local accumulation has been examined using confocal laser scanning microscopy (CLSM). Formulations saturated with either Oregon Green^® 488, Bodipy^® FL C₅ or Bodipy^® 564/570 C₅ were prepared. The dyes were applied in citric acid buffer, 8% (w/v) surfactants in citric acid buffer or 8% (w/v) surfactants/20% (w/v) propylene glycol in citric acid buffer. Flow-through diffusion experiments were performed with fresh human scalp skin, after which the skin was imaged using CLSM. Diffusion studies showed for Oregon Green^® 488 (low lipophilicity) a higher flux when applied in citric acid buffer compared to surfactants. In contrast the fluxes of the more lipophilic dyes (Bodipy^® FL C₅ and Bodipy^® 564/570 C₅) are highest when applied in surfactants/propylene glycol. CLSM studies revealed that follicular accumulation increased with (i) a lipophilic dye and (ii) application of lipophilic dyes in surfactants–propylene glycol. Therefore we conclude that targeting to the hair follicle can be increased by the use of lipophilic drugs in combination with surfactant solutions and propylene glycol.     

Osseointegrated Oral Implants in Head and Neck Cancer Patients

After cancer treatment in the head and neck area, mastication and speech are often affected. Some of the problems encountered can be solved by adequate dental rehabilitation. However, dental rehabilitation is often compromised for various reasons. The change in anatomy due to surgery often results in lack of denture-bearing mucosa. The effects of radiotherapy on the salivary glands and the mucosa result in dry oral tissue and diminished retention of removable dentures. Osseointegrated oral implants can help to solve these problems. Although implant treatment for patients with cancer of the head and neck is covered by the Dutch national health insurance, and there is therefore no financial obstacle, implants have not, so far, been widely used with these patients. In order to establish the possible reasons for this, an analysis was performed. Retrospective data on 95 consecutive patients were collected from records. The indication for the use of oral osseointegrated implants was reviewed. Analysis of the data showed that 45% did not need specific prosthetic rehabilitation. An indication for the use of osseointegrated implants was found in 25% of the patients. For various reasons, only 3% actually received implants. In striving to completely rehabilitate a cancer patient, the possible use of osseointegrated oral implants should be evaluated before the initial oncological treatment begins. The insertion of implants during the initial surgical procedure should be considered more often, with a view to reducing the number of surgical procedures.     

Detection of human papillomavirus DNA in urine. A review of the literature

The detection of human papillomavirus (HPV) DNA in urine, a specimen easily obtained by a non-invasive self-sampling method, has been the subject of a considerable number of studies. This review provides an overview of 41 published studies; assesses how different methods and settings may contribute to the sometimes contradictory outcomes; and discusses the potential relevance of using urine samples in vaccine trials, disease surveillance, epidemiological studies, and specific settings of cervical cancer screening. Urine sampling, storage conditions, sample preparation, DNA extraction, and DNA amplification may all have an important impact on HPV DNA detection and the form of viral DNA that is detected. Possible trends in HPV DNA prevalence in urine could be inferred from the presence of risk factors or the diagnosis of cervical lesions. HPV DNA detection in urine is feasible and may become a useful tool but necessitates further improvement and standardization.     

Novel membrane frizzled‐related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds

Purpose: We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds. Methods: Ophthalmological examination, general paediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings. Results: Clinical analysis showed high hyperopia (+11 D and +12 D), short axial lengths (15 mm) and the presence of macular folds and optic nerve head drusen. Autofluorescence of the retina was generally normal with subtle macular abnormalities. Sequence analysis showed compound heterozygosity for severe MFRP mutations in both sisters: a previously reported p.Asn167fs (c.498dupC) and a novel stop codon mutation p.Gln91X (c.271C>T). Conclusion: These are the youngest nanophthalmos patients in the literature identified with severe loss of MFRP function, showing already the known structural abnormalities for this disease. Adult patients affected by homozygous or compound heterozygous MFRP mutations generally show signs of retinal dystrophy, with ERG disturbances and RPE abnormalities on autofluorescence imaging. ERG examination could not be performed in these children, but extensive RPE abnormalities were not seen at this young age.     

Cationic Liposomes Loaded with a Synthetic Long Peptide and Poly(I:C): a Defined Adjuvanted Vaccine for Induction of Antigen-Specific T Cell Cytotoxicity

For effective cancer immunotherapy by vaccination, co-delivery of tumour antigens and adjuvants to dendritic cells and subsequent activation of antigen-specific cytotoxic T cells (CTLs) is crucial. In this study, a synthetic long peptide (SLP) harbouring the model CTL epitope SIINFEKL was encapsulated with the TLR3 ligand poly(inosinic-polycytidylic acid) (poly(I:C)) in cationic liposomes consisting of DOTAP and DOPC. The obtained particles were down-sized to about 140 nm (measured by dynamic light scattering) and had a positive zeta-potential of about 26 mV (according to laser Doppler electrophoresis). SLP loading efficiency was about 40% as determined by HPLC. Poly(I:C) loading efficiency was about 50%, as assessed from the fluorescence intensity of fluorescently labelled poly(I:C). Immunogenicity of the liposomal SLP vaccine was evaluated in vitro by its capacity to activate dendritic cells (DCs) and present the processed SLP to SIINFEKL-specific T cells. The effectiveness of the vaccine to activate CD8⁺ T cells was analysed in vivo after intradermal and subcutaneous immunisation in mice, by measuring antigen-specific T cells in blood and spleens and assessing their functionality by cytokine production and in vivo cytotoxicity. The liposomal formulation efficiently delivered the SLP to DCs in vitro and induced a functional CD8⁺ T cell immune response in vivo to the CTL epitope present in the SLP. The SLP-specific CD8⁺ T cell frequency induced by the poly(I:C)-adjuvanted liposomal SLP formulation showed an at least 25 fold increase over the T cell frequency induced by the poly(I:C)-adjuvanted soluble SLP. In conclusion, cationic liposomes loaded with SLP and poly(I:C) have potential as a powerful therapeutic cancer vaccine formulation.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9686-4) contains supplementary material, which is available to authorized users.KEY WORDS: cancer immunotherapy, cationic liposomes, CTL epitope, peptide antigen, Poly(I:C)     

Physical activity, dipping and haemodynamics

OBJECTIVE: To determine the effect of physical activity on diurnal blood pressure (BP) and haemodynamic variation. METHODS: Ambulatory measurements were performed during 24 h in 36 subjects (18 hypertensive, 13 male), aged 49.7 +/- 13.5 years. BP was recorded in the brachial artery. Physical activity and posture were measured with five acceleration sensors. RESULTS: Of the subjects 50% were dippers (nocturnal decrease in systolic or diastolic BP >/= 10%). Dippers and non-dippers had similar daytime BP, daytime, night-time, and day-night difference in physical activity, subjective sleep quality, and nocturnal cardiac output decrease (14.9 +/- 9.6 and 16.0 +/- 5.9%). In non-dippers vascular resistance increased from day to night by 9.7 +/- 8.3%, while it remained unchanged (-1.0 +/- 13.9%) in dippers. Day-night changes in heart rate and cardiac output were correlated with day-night changes in physical activity (r = 0.39 and 0.43), whereas day-night changes in systolic BP were correlated with night-time activity (r = -0.34). By selection of the active (i.e. walking) and inactive (i.e. not walking) periods during the day, we showed that physical activity has a large potential effect on dipping status and diurnal haemodynamic variation underlying BP variation. Depending on the BP taken (systolic or diastolic, respectively) the proportion of dippers increased to 81% or decreased to 25% if only the walking period was considered, whereas it decreased to 36% or increased to 53% if only the non-walking period was considered. CONCLUSIONS: Non-dippers differ from dippers by an increase of vascular resistance during the night. The degree of physical activity normally encountered during ambulatory monitoring has little influence on the diurnal BP profile or dipping status, but significantly influences underlying haemodynamics. Related to the different effects of posture and activity on systolic and diastolic BP, dipping classification may vary with the BP index taken.