Anakinra for palmoplantar pustulosis: results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, debilitating, chronic inflammatory skin disease that affects the hands and feet. Clinical, immunological and genetic findings suggest a pathogenic role for interleukin (IL)-1. OBJECTIVES: To determine whether anakinra (an IL-1 receptor antagonist) delivers therapeutic benefit in PPP. METHODS: This was a randomized (1 : 1), double-blind, two-staged, adaptive, UK multicentre, placebo-controlled trial [ISCRTN13127147 (registered 1 August 2016); EudraCT number: 2015-003600-23 (registered 1 April 2016)]. Participants had a diagnosis of PPP (> 6 months) requiring systemic therapy. Treatment was 8 weeks of anakinra or placebo via daily, self-administered subcutaneous injections. Primary outcome was the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) at 8 weeks. RESULTS: A total of 374 patients were screened; 64 were enrolled (31 in the anakinra arm and 33 in the placebo arm) with a mean (SD) baseline PPPASI of 17·8 (10·5) and a PPP investigator's global assessment of severe (50%) or moderate (50%). The baseline adjusted mean difference in PPPASI favoured anakinra but did not demonstrate superiority in the intention-to-treat analysis [-1·65, 95% confidence interval (CI) -4·77 to 1·47; P = 0·30]. Similarly, secondary objective measures, including fresh pustule count (2·94, 95% CI -26·44 to 32·33; favouring anakinra), total pustule count (-30·08, 95% CI -83·20 to 23·05; favouring placebo) and patient-reported outcomes, did not show superiority of anakinra. When modelling the impact of adherence, the PPPASI complier average causal effect for an individual who received ≥ 90% of the total treatment (48% in the anakinra group) was -3·80 (95% CI -10·76 to 3·16; P = 0·285). No serious adverse events occurred. CONCLUSIONS: No evidence for the superiority of anakinra was found. IL-1 blockade is not a useful intervention for the treatment of PPP.

The Intestinal Tumour Microenvironment.

The tumour microenvironment (TME) of intestinal tumours is highly complex and comprises a network of stromal cells, tumour cells, immune cells and fibroblasts, as well as microorganisms. The tumour location, environmental factors and the tumour cells themselves influence the cells within the TME. Immune cells can destroy tumour cells and are associated with better patient prognosis and response to therapy; however, immune cells are highly plastic and easily influenced to instead promote tumour growth. The interaction between local immune cells and the microbiome can lead to progression or regression of intestinal tumours. In this chapter, we will discuss how tumour development and progression can influence, and be influenced by, the microenvironment surrounding it, focusing on immune and fibroblastic cells, and the intestinal microbiota, particularly in the context of colorectal cancer.

Perspectives of oncology health workers in Flanders on caring for patients of non-Western descent.

This study was undertaken to gain insight in the views and experiences of oncology healthcare providers in Flanders, the Dutch-speaking part of Belgium, on caring for patients of non-Western descent. A qualitative research design with the constant comparative method was used. Data were collected through five focus group interviews, with 23 oncology health workers as participants. Barriers and difficulties were paramount in the provision of care to patients of non-Western descent. Participants want to act according to their professional standards, which call for treating all patients equally and providing appropriate care. However, a focus on medical aspects occurs, wherein 'cure' takes precedence over 'care', when participants were not willing or not fully able to overcome barriers. This results in feelings of inadequacy in those participants who equate professional standards to care of equal quality. Participants who interpreted their professional standard as equivalent care were irritated by 'these' patients who restrained them from providing appropriate care. The findings indicate that professional standards provide protection against possible discrimination that may result from personal beliefs. Extending professional standards from 'treating all patients equally' to 'care attuned to each patient' might be a way to prevent 'cure' taking precedence over 'care'.

Balancing truth-telling: relatives acting as translators for older adult cancer patients of Turkish or northwest African origin in Belgium.

The first generation of Turkish and Northwest African immigrants in Belgium are ageing and at risk for developing cancer. Relatives play an important role and provide both emotional and practical care, including mental support and acting as a contact person and/or a translator for improving access to healthcare, as most patients and their spouses have only a limited command of the language. Although access to professional interpreters has shown to be the best guarantee for qualitative healthcare, oncology health providers working with relatives as interpreters is much more common than professional interpreters. The aim of this study was to provide insight into the process wherein relatives balance truth-telling in translating for an older family member diagnosed with cancer. This was a qualitative research study, with elements of constructivist grounded theory. Twenty-eight loosely structured interviews were conducted. Most relatives consider it their responsibility to contribute to a positive attitude of the patient. Relatives decided to what extent they inform the patient, based on several motives and embedded in their assessment of the patient's emotional strength, understanding and need to be informed. What they decide influences the way they act as a translator and/or a contact person between the patient and health professional(s). Some considered it best to omit medical information while others considered it best to inform the patient fully. The results emphasise the importance for healthcare providers to take into account the complexity and unpredictable character of the process of balancing truth-telling when family members translate for their ill older relative.

Sequential use of biologics in the treatment of moderate-to-severe plaque psoriasis.

A number of biologic agents, including the tumour necrosis factor (TNF) antagonists etanercept, adalimumab and infliximab, and the interleukin (IL)-12/IL-23 antagonist ustekinumab, are available for the treatment of moderate-to-severe plaque psoriasis in the U.K. Currently, the selection of the first biologic, and the choice of sequential biologics in the event of efficacy/tolerability concerns, is made using a limited evidence base. The efficacy of biologics, the potential mechanisms of primary and secondary failure and the evidence for sequencing therapy among TNF antagonists and between TNF antagonists and IL-12/IL-23 blockade are reviewed. As psoriasis biologics registers begin to produce long-term safety and efficacy data, therapy decisions in plaque psoriasis may become more objective, and it may be possible to individualize treatment based on clinical or pharmacogenetic information.

Alzheimer CSF biomarkers in routine clinical setting.

OBJECTIVES: Our work was aimed to evaluate Alzheimer's disease diagnosis improvement using cerebrospinal fluid biomarkers (CSF) in neurological daily practice. MATERIALS AND METHODS: For this purpose, 150 patients clinically and neurochemically classified as having AD or cognitive impairment with or without other dementia type were included in the study. The following CSF peptides were studied, blindly to the clinical diagnosis: beta-amyloid(1-42) peptide (Aß(1-42)), Tau (T-tau), threonine-181 hyperphosphorylated tau protein (P-tau(181)), and beta-amyloid(1-40) peptide (Aß(1-40)). From these measurements, Innotest® Amyloid Tau Index (IATI) was calculated for each patient. RESULTS: This assessment allowed to separate 83 biochemical profiles of AD and 67 non-Alzheimer's disease (non-AD), both AD and non-AD categories match with clinical data amounting to 73% and 90%, respectively. Among mild cognitive impairment (MCI) patients, CSF biomarkers led to discriminate those who are likely to be AD. We devoted a special section to Aß(1-40) which is not a routine parameter but can help to confirm a pathological amyloid process as Aß(1-42)/Aß(1-40) ratio underlining the real decline of the Aß(1-42). CONCLUSIONS: The interest of biomarkers and their ability to solve awkward cases were carefully noticed all the more when a discrepancy between clinical and CSF biological data was involved. The final proposed algorithm allowed to identify pathogenic forms of AD according to the prevailing role of hyperphosphorylated tau or amyloid beta peptide.

Lovesick: immunological costs of mating to male sagebrush crickets.

A growing body of evidence suggests that resources invested in reproduction often come at the expense of the ability to mount an immune response. During mating, female sagebrush crickets, Cyphoderris strepitans, consume the ends of the male's hind wings and ingest his haemolymph. Previous research has shown that this behaviour impairs the ability of males to secure additional matings. One hypothesis to account for this effect is that wing wounding triggers an energetically costly immune response, such that nonvirgin males are unable to sustain the costly acoustical signalling needed to attract additional females. To test this hypothesis, we injected virgin males with lipopolysaccharides (LPS) to provoke an immune response, and monitored their mating success in the field. LPS-injected virgin males took significantly longer to mate than sham-injected virgin males, and spent significantly less time calling. We also compared virgin, nonvirgin and experimentally wing-wounded virgin males with respect to: (1) their ability to encapsulate a foreign invader via the accumulation of haemocytes and deposition of melanin and (2) baseline levels of phenoloxidase (PO), a key enzyme in the biochemical cascade leading to the production of melanin. Although encapsulation ability did not differ with reproductive experience, virgin males had significantly higher levels of PO than either nonvirgin or experimentally wing-wounded virgin males. These results suggest that wing-wounding alone is sufficient to impair male immunity, and that males trade-off investment in reproduction and immunity.

Cutaneous mucinosis associated with dermatomyositis and nephrogenic fibrosing dermopathy: fibroblast hyaluronan synthesis and the effect of patient serum.

BACKGROUND: Dermal mucin is an amorphous gelatinous substance composed primarily of hyaluronan (HA) and sulphated glycosaminoglycans (GAGs). In primary cutaneous mucinosis, accumulation of mucin is a characteristic feature of lichen myxoedematosus, scleromyxoedema and reticular erythematous mucinosis. Secondary mucinoses are disorders where mucin deposition is an additional finding, and deposition is associated with lupus erythematosus, dermatomyositis, scleroderma and granuloma annulare. The underlying cause of the abnormal mucin deposition is unknown. An increasing number of cases of a fibromucinous scleromyxoedema-like disorder associated with renal dysfunction, recently termed nephrogenic fibrosing dermopathy (NFD), is being reported. OBJECTIVES: To examine the synthesis of sulphated GAGs and HA by fibroblasts derived from uninvolved and involved skin of a patient with dermatomyositis and two patients with NFD, and the effect of patient serum. METHODS: GAGs were quantified by a radiometric assay and HA was determined by an enzyme-linked HA-binding protein assay. RESULTS: We found that fibroblasts derived from active lesions of NFD synthesize elevated levels of GAGs, and in particular HA, compared with normal controls, while serum from the patient with dermatomyositis and the two patients with NFD stimulates GAG synthesis, including HA synthesis, by both control and patient fibroblasts. CONCLUSIONS: Fibroblasts from patients with active NFD are either activated to synthesize elevated levels of HA or contain another cell type, possibly derived from circulating fibrocytes. In both disorders, there is additionally a serum-derived factor that stimulates production of sulphated GAGs and HA by fibroblasts.

Outcomes and pathological review of a cohort of children with melanoma.

BACKGROUND: Prepubertal malignant melanoma is rare, pathological criteria are difficult and follow-up data on patients are lacking in the literature. OBJECTIVES: To review prepubertal cases of melanoma diagnosed in the West of Scotland 1979-2002. METHODS: Twenty cases were identified in whom melanoma was diagnosed before the age of 15. Pathological review was possible for 13 of 20 cases, and current follow-up information is available for all 20. Three pathologists not responsible for the original diagnosis reviewed the slides independently, in every case without knowledge of the outcome. RESULTS: Of the 13 cases reviewed, there was concordance of diagnosis between the three pathologists in 12 cases. Eight of the 13 cases reviewed were considered to be unusual naevi rather than melanoma. One child has died of melanoma and all three pathologists agreed with the original pathological diagnosis. One patient has experienced nodal metastases but is alive and disease-free 12 years later. The remaining 18 cases have had no recurrence since primary surgery 2-21 years ago. CONCLUSIONS: There may be a tendency to overdiagnose prepubertal melanoma. Good communication between clinician and pathologist and the use of an expert pathology panel is recommended before making the diagnosis.

Screening of SLC26A4 (PDS) gene in Pendred's syndrome: a large spectrum of mutations in France and phenotypic heterogeneity.

Sensorineural hearing defect and goiter are common features of Pendred's syndrome. The clinical diagnosis of Pendred's syndrome remains difficult because of the lack of sensitivity and specificity of the thyroid signs. The identification of PDS as the causative gene allowed molecular screening and enabled a re-evaluation of the syndrome to identify potential diagnostic characteristics. This report presents the clinical and genotypic findings of 30 French families, for whom a diagnosis of Pendred's syndrome had been made. Twenty-seven families had at least one mutated allele. Twenty-eight different mutations were identified, 11 of which had never been previously reported. The main clinical characteristics were: early hearing loss, fluctuation in terms of during deafness evolution, and the presence of an enlarged vestibular aqueduct.

A Crohn's disease-associated insertion polymorphism (3020insC) in the NOD2 gene is not associated with psoriasis vulgaris, palmo-plantar pustular psoriasis or guttate psoriasis.

A C-insertion polymorphism in the NOD2 gene (3020insC) on chromosome 16 is a rare mutation associated with Crohn's disease. Crohn's disease and psoriasis are more commonly observed together than expected by chance. Furthermore a susceptibility locus for psoriasis has been identified on chromosome 16q which overlaps the recently identified susceptibility locus for Crohn's disease. Thus, NOD2 may potentially be important as a candidate susceptibility gene for psoriasis. We tested this hypothesis by genotyping psoriasis patients for the C-insertion polymorphism using the Taqman ABI 7700 sequencing system. No statistically significant differences were observed between psoriasis vulgaris (n = 216), palmo-plantar pustular psoriasis (PPP) (n = 100), guttate psoriasis (n = 118) and the control group (n = 283). In both patient and control groups, no mutant homozygotes were observed and approximately 4% were heterozygotes. This particular insertion mutation in the NOD2 gene does not appear to contribute to the genetic susceptibility of psoriasis vulgaris, PPP or guttate psoriasis. However, other mutations exist in the NOD2 gene, which may potentially have a role in psoriasis susceptibility.