The complement system plays an important role in mediating tissue injury after oxidative stress. The role of mannose-binding lectin (MBL) and the lectin complement pathway (LCP) in mediating ...complement activation after endothelial oxidative stress was investigated. iC3b deposition on hypoxic (24 hours; 1% O(2))/reoxygenated (3 hours; 21% O(2)) human endothelial cells was attenuated by N-acetyl-D-glucosamine or D-mannose, but not L-mannose, in a dose-dependent manner. Endothelial iC3b deposition after oxidative stress was also attenuated in MBL-deficient serum. Novel, functionally inhibitory, anti-human MBL monoclonal antibodies attenuated MBL-dependent C3 deposition on mannan-coated plates in a dose-dependent manner. Treatment of human serum with anti-MBL monoclonal antibodies inhibited MBL and C3 deposition after endothelial oxidative stress. Consistent with our in vitro findings, C3 and MBL immunostaining throughout the ischemic area at risk increased during rat myocardial reperfusion in vivo. These data suggest that the LCP mediates complement activation after tissue oxidative stress. Inhibition of MBL may represent a novel therapeutic strategy for ischemia/reperfusion injury and other complement-mediated disease states.
Summary
Background
Mycosis fungoides (MF) and Sézary Syndrome (SS) are the most common cutaneous T‐cell lymphomas. MF/SS is accompanied by considerable morbidity from pain, itching and disfigurement.
...Aim
To identify factors associated with poorer health‐related quality of life (HRQoL) in patients newly diagnosed with MF/SS.
Methods
Patients enrolled into Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI; an international observational study in MF/SS) had their HRQoL assessed using the Skindex‐29 questionnaire. Skindex‐29 scores were analysed in relation to patient‐ and disease‐specific characteristics.
Results
The study population consisted of 237 patients 60·3% male; median age 60 years, (interquartile range 49–70), of whom 179 had early MF and 58 had advanced MF/SS. In univariate analysis, HRQoL, as measured by Skindex‐29, was worse in women, SS, late‐stage MF, those with elevated lactate dehydrogenase, alopecia, high modified Severity Weighted Assessment Tool and confluent erythema. Linear regression models only identified female gender (β = 8·61; P = 0·003) and alopecia (β = 9·71, P = 0·02) as independent predictors of worse global HRQoL. Item‐level analysis showed that the severe impairment in symptoms odds ratio (OR) 2·14, 95% confidence interval (CI) 1·19–3·89 and emotions (OR 1·88, 95% CI 1·09–3·27) subscale scores seen in women was caused by more burning/stinging, pruritus, irritation and greater feelings of depression, shame, embarrassment and annoyance with their diagnosis of MF/SS.
Conclusions
HRQoL is significantly more impaired in newly diagnosed women with MF/SS and in those with alopecia. As Skindex‐29 does not include existential questions on cancer, which may cause additional worry and distress, a comprehensive validated cutaneous T‐cell lymphoma‐specific questionnaire is urgently needed to more accurately assess disease‐specific HRQoL in these patients.
What's already known about this topic?
Cross‐sectional studies of mixed populations of known and newly diagnosed patients with mycosis fungoides (MF)/Sézary syndrome (SS) have shown significant impairment in health‐related quality of life (HRQoL).
Previous studies on assessing gender‐specific differences in HRQoL in MF/SS are conflicting.
More advanced‐stage disease and pruritus is associated with poorer HRQoL in patients with MF/SS.
What does this study add?
This is the first prospective study to investigate HRQoL in a homogenous group of newly diagnosed patients with MF/SS.
In patients newly diagnosed with MF/SS, HRQoL is worse in women and in those with alopecia and confluent erythema.
MF/SS diagnosis has a multidimensional impact on patient HRQoL, including a large burden of cutaneous symptoms, as well as a negative impact on emotional well‐being.
Linked Comment: Talpur. Br J Dermatol 2020; 182:541–542.
Plain language summary available online
Particle concentrations and size distributions have been measured from different heights inside and above a boreal forest during three BIOFOR campaigns (14 April-22 May 1998, 27 July-21 August 1998 ...and 20 March-24 April 1999) in Hyytiälä, Finland. Typically, the shape of the background distribution inside the forest exhibited 2 dominant modes: a fine or Aitken mode with a geometric number mean diameter of 44 nm and a mean concentration of 1160 cm
−3
and an accumulation mode with mean diameter of 154 nm and a mean concentration of 830 cm
−3
. A coarse mode was also present, extending up to sizes of 20 μm having a number concentration of 1.2 cm
−3
, volume mean diameter of 2.0 μm and a geometric standard deviation of 1.9. Aerosol humidity was lower than 50% during the measurements. Particle production was observed on many days, typically occurring in the late morning. Under these periods of new particle production, a nucleation mode was observed to form at diameter of the order of 3 nm and, on most occasions, this mode was observed to grow into Aitken mode sizes over the course of a day. Total concentrations ranged from 410-45 000 cm
−3
, the highest concentrations occurring on particle production days. A clear gradient was observed between particle concentrations encountered below the forest canopy and those above, with significantly lower concentrations occurring within the canopy. Above the canopy, a slight gradient was observed between 18 m and 67 m, with at maximum 5% higher concentration observed at 67 m during the strongest concentration increases.
Summary
Background
Survival in mycosis fungoides (MF) is varied and may be poor. The PROCLIPI (PROspective Cutaneous Lymphoma International Prognostic Index) study is a web‐based data collection ...system for early‐stage MF with legal data‐sharing agreements permitting international collaboration in a rare cancer with complex pathology. Clinicopathological data must be 100% complete and in‐built intelligence in the database system ensures accurate staging.
Objectives
To develop a prognostic index for MF.
Methods
Predefined datasets for clinical, haematological, radiological, immunohistochemical, genotypic, treatment and quality of life are collected at first diagnosis of MF and annually to test against survival. Biobanked tissue samples are recorded within a Federated Biobank for translational studies.
Results
In total, 430 patients were enrolled from 29 centres in 15 countries spanning five continents. Altogether, 348 were confirmed as having early‐stage MF at central review. The majority had classical MF (81·6%) with a CD4 phenotype (88·2%). Folliculotropic MF was diagnosed in 17·8%. Most presented with stage I (IA: 49·4%; IB: 42·8%), but 7·8% presented with enlarged lymph nodes (stage IIA). A diagnostic delay between first symptom development and initial diagnosis was frequent 85·6%; median delay 36 months (interquartile range 12–90). This highlights the difficulties in accurate diagnosis, which includes lack of a singular diagnostic test for MF.
Conclusions
This confirmed early‐stage MF cohort is being followed‐up to identify prognostic factors, which may allow better management and improve survival by identifying patients at risk of disease progression. This study design is a useful model for collaboration in other rare diseases, especially where pathological diagnosis can be complex.
What's already known about this topic?
Mycosis fungoides (MF) is a rare skin cancer that may closely mimic common inflammatory dermatoses in early‐stage disease.
There is no singular diagnostic test for MF.
Diagnosis of early‐stage MF requires close clinical, pathological and genotypic correlation.
What does this study add?
This study reports on the clinical characteristics of a large international cohort of patients with early‐stage MF whose diagnosis has been confirmed following clinicopathological review.
The median age of presentation is 57 years, which is significantly younger than those presenting with advanced‐stage MF (66 years).
This study confirmed a worldwide male predominance in early‐stage MF (1·7 males : 1 female).
A diagnostic delay is frequent (median 3 years).
Linked Editorial: Alhusayen and Piguet. Br J Dermatol 2019; 181:231–232.
Respond to this article
Background/Aims Fatty infiltration initiates alcohol-induced liver changes and complement component C3 affects lipid metabolism. We recently observed that ethanol-induced steatosis seen in normal ...(C3+/+ ) mice was absent in livers of C3-deficient (C3−/− ) mice. To understand the underlying molecular mechanisms we analyzed lipid parameters and liver gene expression profiles in these mice. Methods A Western-type high-fat diet with ethanol or carbohydrates (control) was fed for 6 weeks to C3+/+ and C3−/− mice. Serum and liver lipid parameters were analyzed and liver mRNA expression patterns studied by micro-array analysis and RT-PCR. Results In both genotypes ethanol markedly reduced serum cholesterol, apolipoprotein A-I, phospholipid transfer protein activity and hepatic mRNA levels of fatty acid-binding proteins and fatty acid β-oxidation enzymes. In contrast, exclusively in C3−/− mice, ethanol treatment increased serum and liver adiponectin levels but down-regulated transcripts of lipogenic enzymes, adiponectin receptor 2 and adipose differentiation-related protein and up-regulated phospholipase D1. Conclusions We propose that these ethanol-induced alterations observed exclusively in C3−/− mice contribute to protection against fatty infiltration and subsequent inflammatory processes in the liver of these mice. The results suggest important cross-talk between complement factor C3 and lipid regulators in ethanol-induced steatosis.
Summary
Background
The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front‐line treatments and ...quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF).
Objectives
To identify (i) differences in first‐line approaches according to tumour‐nodes‐metastasis‐blood (TNMB) staging; (ii) parameters related to a first‐line systemic approach and (iii) response rates and QoL measures.
Methods
In total, 395 newly diagnosed patients with early‐stage MF (stage IA–IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review.
Results
The most common first‐line therapy was skin‐directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA–IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first‐line SDT was 73%, while the ORR to first‐line systemic treatments was lower (57%) (P = 0·027). Health‐related QoL improved significantly both in patients with responsive disease and in those with stable disease.
Conclusions
Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early‐stage MF need to address these issues.
What is already known about this topic?
Early‐stage mycosis fungoides is characterized by a good prognosis.
The first‐line treatment approach is typically stage based and is usually skin‐directed therapy.
What does this study add?
This multicentre prospective international study reports that real‐life treatment decisions are not limited to a stage‐based approach but are also influenced by the presence of plaques and folliculotropic mycosis fungoides.
Approximately half of the patients with early‐stage disease experienced a moderate or severe impact on their quality of life at diagnosis.
This study suggests that treatment guidelines in patients with early‐stage disease should incorporate high‐risk features and quality‐of-life evaluation.
Linked Comment: Porcu and Nikbakht. Br J Dermatol 2021; 184:594–595.
Summary
Mycosis fungoides (MF) is the commonest type of skin lymphoma and is part of a group of conditions known as cutaneous T‐cell lymphomas (CTCL). MF can appear as flat/raised, smooth/scaly red ...lesions known as patches and plaques, making it difficult to tell apart from eczema or psoriasis. Raised “lumps” called tumours can appear and the disease can become more serious.
Sézary syndrome (SS) is a leukaemic form of CTCL and has an extensive red, itchy rash over most of the body, the presence of cancerous cells in the blood, and enlarged lymph glands.
MF/SS can reduce patient quality of life (QoL) due to symptoms including itch and pain, poor self‐esteem secondary to cosmetic disfigurement, and can impair interpersonal relationships. In this article, we examine QoL in patients with MF/SS in a large international research study called PROCLIPI, using a questionnaire called Skindex‐29 which asks patients to comment on skin related questions which may affect their life enjoyment.
We identified a number of important determinants of worse QoL in MF/SS including: female gender, patients diagnosed with SS and those with more widespread disease. Disease features which were associated with more impaired QoL included alopecia (hair loss) and confluent erythema (red patches and plaques merging together to form larger areas of affected skin). Combining all these factors together, we found that female patients, alopecia and confluent erythema were the most important.
Given that females had worse QoL, we examined more closely which items in the Skindex‐29 questionnaire differed between males and females. Female patients experienced more burning, stinging, itch and irritation on their skin and greater feelings of depression, shame, embarrassment and annoyance with their diagnosis of MF/SS.
Our research study has highlighted important aspects of QoL in MF/SS and emphasizes the urgent need for a more comprehensive QoL questionnaire to address not only the skin related aspects of the disease, but also the effects of cancer and its treatment on patient QoL.
This is a summary of the study: Characteristics associated with significantly worse quality of life in mycosis fungoides/Sézary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study
Linked Article: Molloy et al. Br J Dermatol 2020; 182:770–779
In the present study we determined whether the cystatin c gene (CST3) is genetically associated with late-onset Alzheimer's disease (AD).
Two informative flanking single nucleotide polymorphisms ...(SNP), rs2424577 and rs3827143, of the CST3 gene and apolipoprotein E (APOE) gene were assessed in 568 Finnish AD patients and 688 cognitively healthy controls. Samples were genotyped with the TaqMan technique, and we conducted a single allele and genotypic distribution comparison as well as an estimation of haplotype frequencies between cases and controls.
The APOE genotype distribution differed as expected between the AD cases and controls (p < 0.001). On the whole, any significant differences in AD risk were not found in single SNP and haplotype analyses for the CST3 gene between the whole study cohorts or in the stratified subgroups. Interestingly, AG-genotype carriers of rs3827143 showed a significant difference (p = 0.04) between cases and controls when compared to AA-genotype carriers, but this finding remained insignificant in the adjusted model.
Although flanking SNP cover the whole gene transcript with strong linkage disequilibrium, our data show that the CST3 gene is not associated with AD risk in the Finnish population.
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