British Journal of Dermatology最新文献

Background: Large and giant congenital melanocytic nevi present a risk for developing melanoma or neurocutaneous melanosis. Most are caused by NRAS or, less commonly, BRAF mutations.

Objectives: We present a series of patients with large to giant congenital melanocytic nevi with BRAF fusion genes as driver alterations and describe their unique clinical presentation.

Methods: We retrospectively identified five patients with giant congenital melanocytic nevi harboring BRAF fusion genes, from three academic institutions. We analyzed tumor DNA using capture-based next-generation sequencing.

Results: Four of five patients with giant congenital melanocytic nevi harboring a BRAF fusion gene exhibited thousands of satellite nevi, many with significant pruritus, nodularity and firmness. One patient developed neurocutaneous melanosis. Histopathology showed marked stromal desmoplasia, akin to the changes observed in acquired melanocytic nevi with BRAF fusion genes. Notably, one case responded to the MEK inhibitor trametinib, demonstrating the potential therapeutic advantage of genetic characterization of these lesions.

Conclusion: Congenital melanocytic nevi with BRAF fusion genes appear to have unique clinical features and may be associated with numerous satellite lesions. Marked desmoplasia is a histopathologic feature that can point towards an underlying BRAF fusion gene.

Background: Outcomes for advanced melanomas have improved following the advent of immunotherapy and targeted therapy. This heralds a need for reconsideration of future research agendas. Patients can, and are keen to help identify and prioritise research topics to ensure future research benefits patients. No previous peer-reviewed research has reported patient research priorities for melanoma.

Objectives: To determine melanoma patients' prioritised research topics in England.

Methods: Patients ≥18 years, diagnosed with melanoma within the past ten years were recruited across England by skin cancer charities. Pre-interview questionnaires obtained demographic, tumour and treatment information. Semi-structured interviews were conducted where patients were asked what they thought were important topics to research in melanoma. Using a grounded theory approach, transcripts were analysed in an iterative process to identify themes for patient research priorities.

Results: Twenty patients were individually interviewed from 8/9 English regions. Five key themes were identified. (1) Risk factors and prevention of melanoma. Patients voiced desire for research into modifiable risk factors and public campaigns to prevent melanoma. (2) Diagnostic delay and misdiagnosis of melanoma. Patients felt diagnostic delays could be reduced through research to support non-specialists and integrating technology such as teledermatology or artificial intelligence. (3) Indications, outcomes, side effects and interactions of treatments for melanoma. Novel treatments inspired patients to encourage future research into the indications, outcomes and side effects of therapeutic options. (4) Optimising follow-up for melanoma. With increased survivorship, research to support the delivery of a personalised approach to follow-up was valued. (5) Factors that influence survival from melanoma. Patients prioritised research to accurately predict recurrence and survival based on patient-specific factors.

Conclusions: This is the first peer-reviewed study to report patient research priorities in melanoma. Many of the themes identified align with NICE research recommendations. Additionally, novel themes were identified which provides rationale to develop a James Lind Alliance Priority Setting Partnership for melanoma. If research addresses topics relevant to patients, decision-makers will be equipped to deliver services which meet patient needs.

Background: Prognosis and quality of life of advanced cutaneous T cell lymphoma (CTCL) patients, in particular those with Sézary syndrome (SS) and advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody-drug conjugates (ADCs) have been implemented into CTCL therapy algorithms, but the spectrum of antibody-targetable cell-surface antigens on T cell non-Hodgkin lymphomas (T-NHL) is limited.

Objectives: To evaluate expression of the MHC-II chaperone CD74 across common subtypes of CTCL by various methods, and to explore the efficacy of CD74-targeting of CTCL cells by anti-CD74 antibody-drug conjugate (ADC) in vitro and in vivo.

Methods: We comprehensively investigate expression of CD74 in well-defined CTCL cell lines by PCR analyses, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common entities are analyzed by immunohistochemistry, flow cytometry, immunofluorescence and 'co-detection by indexing' (CODEX) multiplexed tissue imaging as well as single-cell RNAseq analyses. DNA methylation of CTCL cell lines is interrogated by generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 is investigated on CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull (NSG) mice.

Results: We demonstrate by different experimental approaches in CTCL cell lines and a broad collection of primary CTCL samples that CD74 is widely and robustly expressed in CTCL cells. Additionally, CD74 expression in SS and MF is confirmed by analyses of single cell (sc)RNA-seq data, and correlates in CTCL cell lines with CD74 gene DNA hypomethylation. CD74 is rapidly internalized in CTCL cells, and CD74 targeting by the ADC STRO-001 efficiently kills CTCL-derived cell lines. Finally, CD74 targeting synergizes with conventional chemotherapy in vitro, and eradicates murine xenotransplants of CTCL cell lines in vivo.

Conclusions: CD74 is expressed across common CTCL subtypes, and CD74-targeting efficiently kills CTCL cells in vitro and in vivo. Our data thus identify CD74-targeting as highly promising treatment strategy for CTCL.

Background: Understudied the association between exposure to fine particulate matter (PM2.5) from conception to one year after birth and later development of atopic dermatitis (AD) has not been completely elucidated.

Objective: To investigate the effects of PM2.5 exposure during pregnancy and infancy on AD and explore sensitive time windows to identify biological pathways of the effects of PM2.5 on AD.

Methods: A birth cohort study comprising 564,869 term births born between 2004-2013 and followed up until 5 years after birth. A satellite-based model was used to calculate PM2.5 exposure for each child. A Cox proportional hazard model combined with a distributed lag non-linear model was performed to examine the associations of AD with PM2.5, as well as the dose-response relationship.

Results: The birth cohort comprised of 76,944 cases diagnosed with AD. Increased cumulative exposure to PM2.5 from 34 weeks of gestation until birth, as well as from 33 weeks after birth during infancy, was significantly associated with a higher incidence of AD. In the dose-response relationship, exposure to PM2.5 more than 65 μg/m3 might sharply increase the risk of AD.

Conclusions: Both prenatal and postnatal exposures to PM2.5 were related to later development of AD. The susceptible time windows may be late gestation and early life after birth.

Background: Vitiligo and autoimmune alopecia (AA) are caused by T-cell mediated autoimmunity in genetically predisposed individuals. Studies in vitiligo have reported reduced risks for melanoma (MM), some also for keratinocyte skin cancer (KC). In AA, reduced risks for KC (and also MM) have been reported. The driving mechanisms (genetic predisposition, immunological or other effects of the disease phenotypes, or environmental) remains unclear. Whether the immune-related genetic predisposition in vitiligo and AA offers "inherent" protection against other types of cancer remains unresolved.

Objectives: To investigate the incidence and outcome of MM, squamous cell skin cancer (SCC) and non-cutaneous cancers in vitiligo and alopecia, vs. that in the general population, and to investigate the corresponding risks in their siblings.

Methods: We performed a population-based matched cohort study using data from linkage of Swedish registers. We used Cox proportional hazards regression to calculate hazard ratios (HR) contrasting patients with vitiligo or AA and the general population, and contrasting their siblings.

Results: Between 2006 to 2021, we included 15,030 patients with vitiligo, 18,541 with alopecia, and 17,853 and 21,821 of their siblings. Based on 17 MM events (crude incidence per 100,000, IR: 16), 23 SCC events (IR: 22) in vitiligo, and, 20 MM (IR: 15) and 24 SCC (IR: 18) in AA, the HR for MM was 0.53 (95%CI 0.32-0.86) in vitiligo and 0.53 (95%CI 0.34-0.83) in AA. Regarding SCC, HRs were 0.81 (95%CI 0.53-1.24) in vitiligo and 0.65 (95%CI 0.43-0.98) in AA. Stage at diagnosis of MM didn't differ substantially between patients and the general population. Among siblings, HRs for MM and SCC were not statistically significantly altered (0.82 ≤ HR ≤ 1.10). In patients and their siblings, HRs for non-cutaneous solid or hematological cancers were not reduced.

Conclusion: In vitiligo and in AA the decreased risk of cutaneous cancers extends beyond the cell-type targeted by the autoimmune reaction. The general tendency towards somewhat reduced skin cancer risks among their siblings suggests a role for other factors than the disease phenotypes per se. Neither the vitiligo and AA phenotypes nor their immune-related genetic predispositions seem to offer any "inherent"protection against non-cutaneous malignancies.

Background: Desmocollin-3 (DSC3) is a calcium-dependent desmosomal cadherin that plays an essential role in cell-cell adhesion. IgG antibodies (Abs) directed against the extracellular (EC) domain of DSC3 have occasionally been detected in rare types of pemphigus. Investigations into the prevalence of anti-EC-DSC3 IgG Abs and those targeting the intracellular (IC) domain of DSC3 in pemphigus vulgaris and pemphigus foliaceus sera, and their potential pathogenic activity, have yielded conflicting results.

Objectives: To assess the prevalence and pathogenicity of Abs directed against the EC and IC domains of DSC3 in patients with pemphigus.

Methods: Anti-DSC3 IgG and IgA directed against the EC and IC domains of DSC3 were assayed in 146 patients with pemphigus using a newly developed addressable laser bead immunoassay. The pathogenicity of these autoAbs was first tested in vitro using a keratinocyte dissociation assay with patients' sera or from C57BL/6 mice immunized with recombinant IC-DSC3. In vivo pathogenicity was tested by passive transfer of an anti-IC-DSC3 monoclonal Ab (mAb) derived from a hybridoma (A9) into neonatal mice.

Results: Anti-EC-DSC3 or anti-IC-DSC3 IgG and/or IgA Abs were detected in 21.2% of sera from patients with pemphigus vs. 4.0% (P < 0.001) and 5.0% (P < 0.001) of sera from healthy donors, respectively. Most anti-DSC3 Abs corresponded to IgA. Anti-IC-DSC3 Abs were detected in 44% of patients with pemphigus whose serum anti-desmoglein (DSG) 1-3 Ab profile was inconsistent with their clinical and histological features, according to compensation theory. Anti-IC-DSC3 IgG and IgA Abs induced a dissociation of the keratinocyte monolayer in vitro, which was abolished by preadsorption of these IgG or IgA fractions with recombinant IC-DSC3. In addition, IgG from mice immunized with recombinant IC-DSC3 induced acantholysis in vitro. Finally, in neonatal mice, the passive transfer of an anti-IC-DSC3 mAb in combination with anti-DSG1-3 Abs exacerbated blister formation.

Conclusions: Our findings suggest that anti-IC-DSC3 Abs are pathogenic and explain the discordance seen in some patients with regard to their clinical phenotype and their anti-DSG1-3 Ab profile.