Selim Aractingi

BACKGROUND AND OBJECTIVES: Prognosis of melanoma with leptomeningeal disease (LMD) is poor (median overall survival of 5.1 months). Intrathecal (IT) nivolumab appears safe, although its efficacy remains uncertain. We investigated the feasibility, safety, and efficacy of continuous IT nivolumab. METHODS: This was a retrospective analysis of 11 melanoma patients with progressive LMD (MelBase; NCT02828202) treated as part of the patients' care with continuous IT nivolumab administered through spinal (n = 10) or ventricular catheter (n = 1). RESULTS: Patients (5 women, median age 52) with Eastern Cooperative Oncology Group ≤1 (except for 1) and stable extracranial disease (except for 4) were treated over a median duration of 1.5 months and followed for 2.5 months. Seven presented symptomatic LMD. Primary tumors were mostly cutaneous (n = 8) and BRAF-mutated (n = 10). All patients had progressed on systemic immunotherapy; 7 had received brain radiotherapy (whole brain radiotherapy [n = 3]; stereotactic radiosurgery [n = 4]). Concomitant therapies included corticosteroids >10 mg (n = 5), intravenous nivolumab (first 3 months of IT therapy, n = 1), and targeted therapies (n = 7). The median overall survival was 2.5 months, with 3 patients surviving for more than a year. Reversible treatment-related adverse events occurred in 5 patients: meningoencephalitis (grade 3, n = 1), intracranial hemorrhage (grade 1, n = 1), intracranial hypotension (grade 2, n = 2; grade 1, n = 1). Baseline levels of nivolumab in the cerebrospinal fluid (CSF) were <2 µg/mL, even among patients with plasma detection. CSF concentrations of nivolumab at steady state varied from 36 to 97 µg/mL, with clearances of 4.3-15.7 mL/h. Next-generation sequencing identified CSF genomic profiles correlating with clinical progression in 4 patients. CONCLUSION: These findings warrant further trials on IT nivolumab.

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and is most often caused by cumulative UV exposure. However, cSCC may also arise independently of UV exposure, on sites of sustained skin damage like chronic ulcers, scars, Recessive Dystrophic Epidermolysis Bullosa (RDEB), and inflammatory skin diseases such as hidradenitis suppurativa (HS). Little is known about non‐UV‐induced skin carcinomas. We aimed to describe the clinical, pathological, and genetic features, of non‐UV‐induced cSCC. We collected clinical and pathologic data corresponding to 31 patients with non‐UV‐induced cSCC, including 5 cSCC on HS, 4 on chronic leg ulcers and 8 on RDEB. DNA was extracted from FFPE samples and analysed using a NGS assay targeting 523 cancer genes. A comparison was performed with published genetic data obtained in non‐UV‐induced and UV‐induced cSCC. We found that the Tumour Mutational Burden (TMB) of non‐UV‐induced cSCC was 6‐times lower than the published TMB of UV‐induced cSCC. The predominant mutational signature was a clock‐wise signature. By comparing the frequency of driver mutations, we found TP53 and NOTCH1 to be significantly less frequently mutated than in UV‐mutated cSCC. Interestingly, KMT2B (a histone methyl transferase) was mutated in 11/31 non‐UV‐induced cSCC and this proportion was significantly higher than in UV‐mutated cSCC. These mutations were high impact loss‐of‐function mutations. We found that knocking down KMT2B expression using siRNA did not affect cell proliferation of SCC‐13 and A‐431 cell lines, however, it significantly increased cell migration in vitro . Taken together, this study provides a comprehensive description of non‐UV‐induced cSCC and identifies that KMT2B is mutated and involved in non‐UV‐induced cSCC carcinogenesis. © 2025 The Pathological Society of Great Britain and Ireland.

Background: Pregnant women and their fetuses are particularly susceptible to respiratory pathogens. How they respond to SARS-CoV-2 infection is still under investigation. Methods: We studied the transcriptome and phenotype of umbilical cord blood cells in pregnant women infected or not with SARS-CoV-2. Results: Here we show that symptomatic maternal COVID-19 is associated with a transcriptional erythroid cell signature as compared with asymptomatic and uninfected mothers. We observe an expansion of fetal hematopoietic multipotent progenitors skewed towards erythroid differentiation that display increased clonogenicity. There was no difference in inflammatory cytokines levels in the cord blood upon maternal SARS-CoV-2 infection. Interestingly, we show an activation of hypoxia pathway in cord blood cells from symptomatic COVID-19 mothers, suggesting that maternal hypoxia may be triggering this fetal stress hematopoiesis. Conclusions: Overall, these results show a fetal hematopoietic response to symptomatic COVID-19 in pregnant mothers in the absence of vertically transmitted SARS-CoV-2 infection which is likely to be a mechanism of fetal adaptation to the maternal infection and reduced oxygen supply.

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Fetal microchimeric cells (FMC) are fetal progenitor cells transferred to the mothers during pregnancy that niche into bone marrow, where they pe | POSTER