Cancer-Associated Fibroblasts in Mycosis Fungoides Promote Tumor Cell Migration and Drug Resistance through CXCL12/CXCR4.

Cancer cells are known to reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs) to act as tumor supporters. The presence and role of CAFs in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, are unknown. This study sought to characterize CAFs in MF and their cross talk with the lymphoma cells using primary fibroblast cultures from punch biopsies of patients with early-stage MF and healthy subjects. MF cultures yielded significantly increased levels of FAPα, a CAF marker, and CAF-associated genes and proteins: CXCL12 (ligand of CXCR4 expressed on MF cells), collagen XI, and matrix metalloproteinase 2. Cultured MF fibroblasts showed greater proliferation than normal fibroblasts in ex vivo experiments. A coculture with MyLa cells (MF cell line) increased normal fibroblast growth, reduced the sensitivity of MyLa cells to doxorubicin, and enhanced their migration. Inhibiting the CXCL12/CXCR4 axis increased doxorubicin-induced apoptosis of MyLa cells and reduced MyLa cell motility. Our data suggest that the fibroblasts in MF lesions are more proliferative than fibroblasts in normal skin and that CAFs protect MF cells from doxorubicin-induced cell death and increase their migration through the secretion of CXCL12. Reversing the CAF-mediated tumor microenvironment in MF may improve the efficiency of anticancer therapy.

The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.

A novel ablative radiofrequency microplasma nonsurgical blepharoplasty for dermatochalasis.

Dermatochalasis (DC) is part of the aging process of the eyelids, characterized by lax, redundant, and overhanging excess eyelid skin. Mostly, it is treated by surgical blepharoplasty. Lately alternative nonsurgical blepharoplasty technologies have been introduced. In this study, we evaluated the efficacy and safety of a novel noninvasive RF microplasma technology for upper eyelid DC. A prospective single center study included 17 patients with moderate to severe upper eyelid DC. Subjects were treated by controlled micro-plasma sparks via a single tip leading to superficial ablation and coagulation at the treatment area. One to three treatment sessions at 2 months interval were performed. Three blinded observers evaluated the photographs taken at baseline and at 6 to 8 months follow-up visit following the final treatment session. Treatment efficacy was assessed using a 4-point grading scale. Seven out of 17 patients (41%) treated for DC by the single microplasma spark exhibited a 2 grade improvement on a 4 point DC scale. 10 out of 17 (59%) patients showed a single grade improvement on a 4 point DC scale. No adverse side effects were observed. Noninvasive ablative microplasma may offer safe and effective therapy for upper eyelid DC.

Radio Peel-Synergism Between Nano-fractional Radiofrequency and 20% Trichloroacetic Acid Chemical Peeling.

BACKGROUND: Microneedling fractional radiofrequency (FRF) and chemical peels are widely used for skin rejuvenation. OBJECTIVE: The authors aimed at evaluating the efficacy and safety of FRF and trichloroacetic acid 20% (TCA20%) peel in different combinations for determining the optimal treatment protocol. METHODS: In this prospective clinical comparison of 4 protocols (FRF alone, TCA20% alone, TCA20% before FRF [TCA→FRF], and TCA20% following FRF [FRF→TCA]), the patients underwent 3.8 ± 1.2 successive treatments of one protocol at 4- to 6-week intervals. The patients and 2 dermatologists evaluated improvement of pigmentation and dyschromia, erythema and blood vessels, laxity and wrinkling, and skin imperfections using a global aesthetic improvement scale (GAIS) and a 1 to 5 scoring system. The patients rated their satisfaction and reported adverse effects and reduced activity. Skin impedance and histological changes following the different protocols were also evaluated on 3 additional volunteers. RESULTS: Sixty-seven patients (age range 22-80 years) were studied. TCA→FRF caused skin impedance to decrease, yielding a more superficial and less-efficient penetration of FRF energy. FRF→TCA produced more significant improvement in overall facial skin appearance (GAIS) and most evaluated skin parameters. Adverse effects and satisfaction rates were similar for all approaches. CONCLUSION: FRF→TCA had the best synergistic effect on skin rejuvenation compared with FRF or TCA20% alone and TCA→FRF.

Melanoma-associated leukoderma - immunology in black and white?

Melanoma is an 'immunogenic tumor', often highly infiltrated with lymphocytes, which are capable of inducing regression of the primary tumor. The commonly observed phenomenon of regression suggests substantial cross-talk between immune cells and transformed melanocytes. An immune response to melanocyte differentiation antigens common to transformed and normal melanocytes manifests clinically at distant sites as melanoma-associated vitiligo or halo nevi. Despite similar antigenic targets, the pathogenesis and prognosis differ between the different melanoma-associated leukodermas. Understanding immunologic cross-talk between melanocytes and the immune system will aid the development of approaches to combat melanoma.

Cellular immunity induced by a recombinant adenovirus- human dendritic cell vaccine for melanoma.

BACKGROUND: Human Adenoviral vectors (HAdV) are immunogenic vectors which have been tested in many vaccination and gene therapy settings. Dendritic cells (DC) transduced by genetically engineered HAdV-5 (HAdV-5/DC), are investigational cancer vaccines being tested clinically. We have previously examined immune responses to HAdV-5 -encoded melanoma tumor antigens. Here, we determined whether the HAdV-5/DC also present immunogenic HAdV-5 vector-derived antigens, and characterized the cellular immune response to the viral as well as encoded melanoma tumor antigens. METHODS: Both CD4(+) and CD8(+) HAdV-5-specific T cell responses were examined in vitro, with cells from both 8 healthy donors (HD) and 2 melanoma patients. PBMC were stimulated weekly with HAdV-5/DC and responses were examined after each stimulation. We also tested HAdV-5 neutralizing antibody levels and natural killer (NK) cell and regulatory T cell (Treg) activation and expansion in vitro. RESULTS: HAdV-5/DC rapidly induced a high frequency of type 1 cytokine producing HAdV-5-specific CD8(+) and CD4(+) T cells. IFNγ and TNFα-producing T cells predominate. Those with pre-existing cellular memory to HAdV-5 had more robust responses to the HAdV-5 as well as tumor-associated antigens. NK cells are activated while Treg are only minimally and transiently expanded. CONCLUSIONS: This study demonstrates that HAdV-5/DC promote strong type I cellular immunity to viral vector-derived antigens as well as to the encoded tumor antigens. The cytokine and chemokine milieu produced by HAdV-5/DC and the activated HAdV-5-specific T cells may enhance responses to encoded tumor antigens as well. These properties make HAdV-5/DC a cancer vaccine capable of activating type 1 virus and tumor antigen-specific immunity in a cooperative way.

[Acute generalized exanthematous pustulosis (AGEP) following intake of furosemide].

INTRODUCTION: Acute generalized exanthematous pustulosis (AGEP) is an acute pustular eruption with unique clinical features, a rapid clinical course and a typical histopathology. The causative agents are mostly drugs but other triggers have also been described. CASE REPORT: A 52 year-old woman with a history of diabetes mellitus type II, dyslipidemia and osteomyelitis was treated for about a year with metformin (Glucophage) and simvastatin (Simovil) tablets. Due to the osteomyelitis, the patient was started on a regimen of intravenous vancomycin as well as furosemide tablets (Fusid) for pedal edema. About seventeen days after beginning treatment with vancomycin and a week after starting furosemide the patient was hospitalized due to an acute pruritic pustular eruption, involving most of her body surface area. Both vancomycin and furosemide treatment were discontinued, and topical treatment was provided. The clinical course was rapid with spontaneous resolution of the pustules followed by a characteristic pin-point post-pustular desquamation. The morphological, clinical and histological findings suggested a definite case of AGEP based on the EuroSCAR scoring system. The latent period between the initiation of medication intake and the appearance of AGEP, as well as a literature search, suggest that furosemide might be the incriminated drug. CONCLUSION: We have described a rare case of typical AGEP most probably induced by furosemide.