Intracranial hemorrhage caused by dabrafenib and trametinib therapy for metastatic melanoma.

Although generally well tolerated compared with chemotherapy, molecular targeted therapy used in metastatic melanoma may be associated with life-threatening toxicity. We report the case of a patient with metastatic melanoma treated by dabrafenib plus trametinib who developed intracranial hemorrhage. Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. However, they should be also careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.

Areal bone mineral density, trabecular bone score and 3D-DXA analysis of proximal femur in psoriatic disease.

Objectives: To evaluate bone mineral density (BMD) and bone quality, with assessment of the cortical and trabecular compartments, in patients with psoriasis (PsO) alone or with psoriatic arthritis (PsA). Methods: Patients with PsA and patients with PsO alone were evaluated and compared to control subjects matched for age, sex and body mass index category. Areal BMD (aBMD) was determined for the lumbar spine, femoral neck, total hip and total body using dual-energy X-ray absorptiometry (DXA). Bone quality was evaluated by using trabecular bone score (TBS) at the lumbar spine, and by 3D DXA-based analysis (3D Shaper) for the proximal femur. Results: One hundred ninety-six subjects including 52 patients with PsA and 52 patients with PsO and their respective paired controls were analyzed. Patients with PsA had comparable aBMD, TBS and 3D DXA analysis parameters compared to their paired controls. After adjustment for confounders, patients with PsO alone were characterized by a higher aBMD at the left femur and higher cortical 3D DXA derived parameters (total hip cortical surface BMD and total hip cortical thickness) than their paired controls. TBS was decreased in PsO compared to their controls. Conclusion: Patients with PsA had normal bone mass and bone quality parameters. Patients with PsO were characterized by higher femoral neck bone density by DXA and cortical parameters by 3D DXA-based analysis, supporting no increased risk for hip fracture. Conversely, bone texture by TBS assessment was decreased in patients with PsO, which may be associated with impaired vertebral bone resistance.

Detection of wildtype Merkel cell polyomavirus genomic sequence and VP1 transcription in a subset of Merkel cell carcinoma.

AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.

Perception and Experience of Dupilumab in Atopic Dermatitis: A Real-Life Study.

Purpose: There are few data on the practical use of dupilumab by the patients and on the patients' experience with this treatment. Objective: The objective of our study was to describe the experience and perception of dupilumab treatment in patients with atopic dermatitis (AD). Patients and Methods: We conducted a multicenter retrospective observational study including adult patients with moderate to severe AD treated with dupilumab between January 2017 and December 2021. Clinical characteristics were collected and a questionnaire was sent to all patients. It consisted of different parts including the injection method and different numeric rating scales (NRS) evaluating the patient's satisfaction and the constraints related to the treatment. Results: Eighty-two patients were included and the information was available for 77 patients who responded to the questionnaire. Injection of dupilumab was performed by a nurse in 47% (n=36) of patients and 43% (n=33) were autonomous. Injections were performed by a family member for 7 patients or by the general practitioner (1 patient). A wearing-off of the beneficial effect of dupilumab was reported by 47% of patients leading to shorten the dosing interval. In contrast, dose spacing was reported by 9 patients (11%). After a mean follow-up time of 29.7 ± 10.7 months (median: 27 months), drug survival was 72%. From the patients' perspective, the mean patient's satisfaction NRS score was 7.5 ± 1.8, and the constraints related to the treatment were scored at 3.1 ± 2.1 on NRS. Conclusion: Although AD treatments may contribute to the burden of the disease, dupilumab was associated with a lower burden score, likely reflecting both treatment efficacy and easy of use and patient satisfaction.

Efficacy of Immune Checkpoint Inhibitor (ICI) Rechallenge in Advanced Melanoma Patients' Responders to a First Course of ICI: A Multicenter National Retrospective Study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée, GCC).

BACKGROUND: The long-term effectiveness of immune checkpoint inhibitor (ICI) rechallenge for progressive or recurrent advanced melanoma following previous disease control induced by ICI has not been thoroughly described in the literature. PATIENTS AND METHODS: In this retrospective multicenter national real-life study, we enrolled patients who had been rechallenged with an ICI after achieving disease control with a first course of ICI, which was subsequently interrupted. The primary objective was to evaluate tumor response, while the secondary objectives included assessing the safety profile, identifying factors associated with tumor response, and evaluating survival outcomes. RESULTS: A total of 85 patients from 12 centers were included in the study. These patients had advanced (unresectable stage III or stage IV) melanoma that had been previously treated and controlled with a first course of ICI before undergoing rechallenge with ICI. The rechallenge treatments consisted of pembrolizumab (n = 44, 52%), nivolumab (n = 35, 41%), ipilimumab (n = 2, 2%), or ipilimumab plus nivolumab (n = 4, 5%). The best overall response rate was 54%. The best response was a complete response in 30 patients (35%), a partial response in 16 patients (19%), stable disease in 18 patients (21%) and progressive disease in 21 patients (25%). Twenty-eight adverse events (AEs) were reported in 23 patients (27%), including 18 grade 1-2 AEs in 14 patients (16%) and 10 grade 3-4 AEs in nine patients (11%). The median progression-free survival (PFS) was 21 months, and the median overall survival (OS) was not reached at the time of analysis. Patients who received another systemic treatment (chemotherapy, targeted therapy or clinical trial) between the two courses of ICI had a lower response to rechallenge (p = 0.035) and shorter PFS (p = 0.016). CONCLUSION: Rechallenging advanced melanoma patients with ICI after previous disease control induced by these inhibitors resulted in high response rates (54%) and disease control (75%). Therefore, ICI rechallenge should be considered as a relevant therapeutic option.

Efficacy, safety and acceptability of a benzalkonium chloride spermicide cream in women aged 40 years and over needing contraception: A prospective multicentre study.

OBJECTIVE: This multicenter prospective study (BZK40+) aims to determine the efficacy and tolerance of a benzalkonium chloride-containing spermicide as contraceptive among women aged 40 and over. PROCEDURE: Fertile women enrolled in this open single-arm study were instructed to systematically use the benzalkonium chloride spermicide before each intercourse. At the end of a 6-month mandatory period, participants were given the option of continuing the study for a further 6 months. The primary endpoint for contraceptive efficacy was the Pearl Index (PI) up to 12 months of typical use. MAIN FINDINGS: A total of 151 women (mean age: 45.9 years) were enrolled, 144 (95.4%) completed the initial 6-month period and 63 (41.7%) completed the optional 6-month period. The median number of intercourses ranged from 3 to 5 per month. The spermicide was applied before 96.3% of the 5,895 sexual intercourses. The PI up to 12 months of typical use was 0 pregnancies (95% confidence interval: 0-2.88). The cumulative treatment exposure was 1249.7 women-months. CONCLUSION: This first study in women aged 40 years and over shows that benzalkonium chloride spermicide (Pharmatex®) is effective, well tolerated and well accepted in this population. Although very interesting, these results with a PI equal to zero are surprising and not in accordance with the low efficacy of spermicides in the overall population according to the WHO. So, our results should be interpreted with caution and confirmed by future research. Clinical trial registration number (EudraCT): 2016-004,188-38.

Resolved Psoriasis with Abundant Oleic Acid in Stratum Corneum Exhibits Lower T-Cell-Driven IL-17 Signature.

Relapses of psoriasis involve T cells that stem and survive in the skin. Inherited from previous flares, the tissue-resident memory T cells are epidermal IL-17-producing CD8+ and IL-22-producing CD4+ T cells. Because the capacity of resident memory T cells to take in fatty acids is essential for their residence and function, the surface composition of fatty acids may affect underlying T-cell populations. In patients treated with biologics, we used gas chromatography/mass spectrometry to decipher the fatty acid composition in both resolved and nonlesional sites. Skin T cells were activated by OKT-3 in explants from the same body sites to perform bulk transcriptomic analysis (Nanostring). The fatty acid composition differed between skin from healthy donors and normal-looking skin of patients with psoriasis but not further between nonlesional and resolved skin. Patients in whom the resolved skin was rich in oleic acid had lower T-cell-driven IL-17 epidermal transcriptomic signature upon activation of T cells in skin explants. The skin lipid composition is linked with the functions of the underlying epidermal T cells. Testing the modulating effect of custom fatty acids on skin resident T cells could help with coming closer to disease oblivion in inflammatory skin diseases.

Distinct Regulation of EZH2 and its Repressive H3K27me3 Mark in Polyomavirus-Positive and -Negative Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.

Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study.

BACKGROUND: Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS: In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS: From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION: Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING: French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

Human papilloma virus-16-specific CD8+ T-cell expansions characterize different clinical forms of lichen planus and not lichen sclerosus et atrophicus.

Lichen planus (LP) is a cutaneomucosal chronic inflammatory disease characterized by a CD8+ cytotoxic T-lymphocytes (CTL) infiltrate. In erosive oral LP, we found HPV16-specific activated CTL in lesions, supporting a pathogenic contribution of HPV16. Here, we investigated whether a similar scenario occurs in other clinical forms of LP and in lichen sclerosus et atrophicus (LSA), another chronic disease also affecting the mucosa and/or the skin. Blood CTL from LP and LSA patients expressed significant higher levels of granzyme B, perforin and CD107a proteins than healthy donors. Expansions of TCRVß3+ CTL, with presence of TCR clonotypes identical to those previously detected in erosive oral LP, were found both in blood and mucosal/skin lesions of LP, and not of LSA patients. These expansions were enriched with HPV16-specific CD8+ T-cells as shown by their recognition of the E711-20 immunodominant epitope. In LSA patients, the peripheral repertoire of CTL was oligoclonal for TCRVß6+ CTL. Finally, although patients with LP and LSA have developed antibodies against HPV16 capsid L1, antibodies against HPV16 E6 were only observed in patients with LP. Overall, our data collectively suggest an involvement of HPV16-specific CTL in different clinical forms of LP, not only in erosive oral LP, while a different scenario operates in LSA.