45 research outputs found
The influence of sentinel lymph node tumour burden on additional lymph node involvement and disease-free survival in cutaneous melanoma – a retrospective analysis of 392 cases
Twenty per cent of sentinel lymph node (SLN)-positive melanoma patients have positive non-SLN lymph nodes in completion lymph node dissection (CLND). We investigated SLN tumour load, non-sentinel positivity and disease-free survival (DFS) to assess whether certain patients could be spared CLND. Sentinel lymph node biopsy was performed on 392 patients between 1999 and 2005. Median observation period was 38.8 months. Sentinel lymph node tumour load did not predict non-SLN positivity: 30.8% of patients with SLN macrometastases (⩾2 mm) and 16.4% with micrometastases (⩽2 mm) had non-SLN positivity (P=0.09). Tumour recurrences after positive SLNs were more than twice as frequent for SLN macrometastases (51.3%) than for micrometastases (24.6%) (P=0.005). For patients with SLN micrometastases, the DFS analysis was worse (P=0.003) when comparing those with positive non-SLNs (60% recurrences) to those without (17.6% recurrences). This difference did not translate into significant differences in DFS: patients with SLN micrometastasis, either with (P=0.022) or without additional positive non-SLNs (P<0.0001), fared worse than patients with tumour-free SLNs. The 2-mm cutoff for SLN tumour load accurately predicts differences in DFS. Non-SLN positivity in CLND, however, cannot be predicted. Therefore, contrary to other studies, no recommendations concerning discontinuation of CLND based on SLN tumour load can be deduced
Density-Dependent Mortality of the Human Host in Onchocerciasis: Relationships between Microfilarial Load and Excess Mortality
Human onchocerciasis (River Blindness) is a parasitic disease leading to visual impairment including blindness. Blindness may lead to premature death, but infection with the parasite itself (Onchocerca volvulus) may also cause excess mortality in sighted individuals. The excess risk of mortality may not be directly (linearly) proportional to the intensity of infection (a measure of how many parasites an individual harbours). We analyze cohort data from the Onchocerciasis Control Programme in West Africa, collected between 1974 and 2001, by fitting a suite of quantitative models (including a ‘null’ model of no relationship between infection intensity and mortality, a (log-) linear function, and two plateauing curves), and choosing the one that is the most statistically adequate. The risk of human mortality initially increases with parasite density but saturates at high densities (following an S-shape curve), and such risk is greater in younger individuals for a given infection intensity. Our results have important repercussions for programmes aiming to control onchocerciasis (in terms of how the benefits of the programme are calculated), for measuring the burden of disease and mortality caused by the infection, and for a better understanding of the processes that govern the density of parasite populations among human hosts
Brugia malayi Microfilariae Induce a Regulatory Monocyte/Macrophage Phenotype That Suppresses Innate and Adaptive Immune Responses
Background Monocytes and macrophages contribute to the dysfunction of immune
responses in human filariasis. During patent infection monocytes encounter
microfilariae in the blood, an event that occurs in asymptomatically infected
filariasis patients that are immunologically hyporeactive. Aim To determine
whether blood microfilariae directly act on blood monocytes and in vitro
generated macrophages to induce a regulatory phenotype that interferes with
innate and adaptive responses. Methodology and principal findings Monocytes
and in vitro generated macrophages from filaria non-endemic normal donors were
stimulated in vitro with Brugia malayi microfilarial (Mf) lysate. We could
show that monocytes stimulated with Mf lysate develop a defined regulatory
phenotype, characterised by expression of the immunoregulatory markers IL-10
and PD-L1. Significantly, this regulatory phenotype was recapitulated in
monocytes from Wuchereria bancrofti asymptomatically infected patients but not
patients with pathology or endemic normals. Monocytes from non-endemic donors
stimulated with Mf lysate directly inhibited CD4+ T cell proliferation and
cytokine production (IFN-γ, IL-13 and IL-10). IFN-γ responses were restored by
neutralising IL-10 or PD-1. Furthermore, macrophages stimulated with Mf lysate
expressed high levels of IL-10 and had suppressed phagocytic abilities.
Finally Mf lysate applied during the differentiation of macrophages in vitro
interfered with macrophage abilities to respond to subsequent LPS stimulation
in a selective manner. Conclusions and significance Conclusively, our study
demonstrates that Mf lysate stimulation of monocytes from healthy donors in
vitro induces a regulatory phenotype, characterized by expression of PD-L1 and
IL-10. This phenotype is directly reflected in monocytes from filarial
patients with asymptomatic infection but not patients with pathology or
endemic normals. We suggest that suppression of T cell functions typically
seen in lymphatic filariasis is caused by microfilaria-modulated monocytes in
an IL-10-dependent manner. Together with suppression of macrophage innate
responses, this may contribute to the overall down-regulation of immune
responses observed in asymptomatically infected patients