In silico study of heterogeneous tumour-derived organoid response to CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients' T-cells to directly target antigen-presenting cancer cells. One of the barriers to the development of this type of therapies, is target antigen heterogeneity. It is thought that intratumour heterogeneity is one of the leading determinants of therapeutic resistance and treatment failure. While understanding antigen heterogeneity is important for effective therapeutics, a good therapy strategy could enhance the therapy efficiency. In this work we introduce an agent-based model (ABM), built upon a previous ABM, to rationalise the outcomes of different CAR T-cells therapies strategies over heterogeneous tumour-derived organoids. We found that one dose of CAR T-cell therapy should be expected to reduce the tumour size as well as its growth rate, however it may not be enough to completely eliminate it. Moreover, the amount of free CAR T-cells (i.e. CAR T-cells that did not kill any cancer cell) increases as we increase the dosage, and so does the risk of side effects. We tested different strategies to enhance smaller dosages, such as enhancing the CAR T-cells long-term persistence and multiple dosing. For both approaches an appropriate dosimetry strategy is necessary to produce "effective yet safe" therapeutic results. Moreover, an interesting emergent phenomenon results from the simulations, namely the formation of a shield-like structure of cells with low antigen expression. This shield turns out to protect cells with high antigen expression. Finally we tested a multi-antigen recognition therapy to overcome antigen escape and heterogeneity. Our studies suggest that larger dosages can completely eliminate the organoid, however the multi-antigen recognition increases the risk of side effects. Therefore, an appropriate small dosages dosimetry strategy is necessary to improve the outcomes. Based on our results, it is clear that a proper therapeutic strategy could enhance the therapies outcomes. In that direction, our computational approach provides a framework to model treatment combinations in different scenarios and to explore the characteristics of successful and unsuccessful treatments.

Who Will Have a Second Melanoma? A Prospective Longitudinal Study in Patients without Any Genetic Predisposition.

BACKGROUND: Melanoma patients have a higher risk of developing additional melanomas. Predisposing factors of a second primary melanoma in patients without any genetic predisposition are not well established. OBJECTIVES: The aim of this study was to identify risk factors related to the development of a second primary melanoma in order to know which patients should be followed up closely. METHODS: A longitudinal study was performed at Hospital Gregorio Marañón (Madrid, Spain), based on follow-up data of patients diagnosed with cutaneous melanoma from 1998 to 2020. RESULTS: After a median follow-up of 82 months, 58 out of 1523 (3.8%) patients developed a second melanoma. In 11 patients (19%), a second melanoma was diagnosed more than 10 years after their first melanoma. Second melanomas more commonly had a lower mean tumour thickness than the first ones, but 8 out of 58 (13.8%) had a higher tumour thickness than their first melanoma. Skin phototype I-II, having more than 50 melanocytic nevi, and recurrent sunburns were associated with the development of a second melanoma. In multivariate analysis, skin phototype I-II (odds ratio [OR] = 5.41; p < 0.001) and a higher number of nevi (OR = 3.44; p < 0.001) remained as independent risk factors for the development of a second melanoma. CONCLUSIONS: Patients with fair skin phototype and more than 50 melanocytic nevi are at increased risk of developing a second primary melanoma and should be closely monitored throughout their lives to detect earlier additional melanomas.

Do not PASS any melanoma without diagnosis: a new simplified dermoscopic algorithm.

INTRODUCTION: Dermoscopic algorithms for melanoma diagnosis could be time-expending, and their reliability in daily practice lower than expected. OBJECTIVE: To propose a simplified dermoscopic algorithm for melanoma diagnosis. MATERIAL AND METHODS: A multicenter retrospective analysis of 1,120 dermoscopic images of atypical melanocytic tumors (320 melanomas and 800 non-melanomas) was performed. An algorithm based on polychromia, asymmetry in colors or structures, and some melanoma-specific structures was designed. Univariate and multivariate logistic regression analysis was calculated to estimate the coefficients of each potential predictor for melanoma diagnosis. A score was developed based on the dermoscopic evaluations performed by four experts blinded to histological diagnosis. RESULTS: Most melanomas had ≥3 colors (280; 84.5%), asymmetry in colors or structures (289; 90.3%), and at least one melanoma-specific structure (316; 98.7%). PASS score ≥3 had a 91.9% sensibility, 87% specificity, and 88.4% diagnostic accuracy for melanoma. PASS algorithm showed an area under the curve (AUC) of 0.947 (95% CI 0.935-0.959). LIMITATIONS: This study was retrospective. A comparison between the performances of different dermoscopic algorithms is difficult because of their designs. CONCLUSION: PASS algorithm showed a very good diagnostic accuracy, independently of the observers' experience, and it seems easier to perform than previous dermoscopic algorithms.

Human monkeypox virus in a tertiary hospital in Madrid, Spain: An observational study of the clinical and epidemiological characteristics of 53 cases.

A new outbreak of monkeypox virus (MPXV) infection, a zoonotic infection endemic in Central and West Africa, is spreading throughout the world with new epidemiology and clinical features. Our aim was to characterize patients presenting to Dermatology emergency room with a MPXV infection between 15 May and 30 June 2022 in a tertiary hospital in Madrid, Spain. We collected 53 patients and describe their clinical, demographic and epidemiological characteristics and followed their evolution. Most of the patients were men who had sex with men with high-risk sexual practices and no recent travels abroad. Most of them (91%) had had a sexually transmitted infection before. All patients had typical skin lesions consisting of vesicular-pustular rash with central umbilication which was localized or disseminated. The most frequent extracutaneous symptoms were fever, painful regional lymphadenopathy and asthenia. Proctitis was present in more than one third of patients. All patients were diagnosed by real time polymerase chain reaction of samples obtained from skin lesions. Pharyngeal and/or rectal exudates demonstrated MPXV in 74% of patients. The current worldwide outbreak of MPXV infections shows epidemiological and clinical differences from previous ones. Clinicians should be aware of these characteristics to correctly diagnose this emerging disease.

Mini pulse corticosteroid therapy with oral dexamethasone for moderate to severe alopecia areata: A multicentric study.

Extensive subtypes of alopecia areata (AA) (totalis, universalis, or multifocal) still have no approved and effective treatments in Europe, although Janus kinase inhibitors, such as baricitinib, are promising treatments that have been recently approved by the FDA. Nowadays, the higher costs and the lower experience with Janus kinase inhibitors, provide more difficulties in its accessibility. On the other hand, different corticosteroids regimens have been evaluated with conflicting results from decades. In 2016, a new regimen of mini pulse corticosteroid therapy with oral dexamethasone (MPCT-OD) 0.1mg/kg/day twice per week for adult patients with alopecia areata totalis or universalis, was reported to be effective with a lower rate of adverse effects. We performed a retrospective and multicentric study to collect data from patients with extensive forms of alopecia areata who had received MPCTOD (0.1 mg/kg/day twice weekly of dexamethasone) for at least 24 weeks. We included adult patients (≥18 years) with extensive forms of AA (SALT index ≥ 10) that did not respond to previous treatments. Variables including epidemiological and clinical data were recorded. Therapeutic response was assessed through the % change in SALT score (from 0 to 100%) and the changes in eyebrow and eyelash alopecia index (EBA, ELA) from baseline to 24 weeks after the beginning of the treatment. Dexamethasone dosage, duration of the treatment, time until response, time to relapse, adverse effects, and discontinuation were also recorded.

Digital melanoma in Caucasians: a descriptive and survival study according to sublocation.

BACKGROUND AND OBJECTIVES: Digital melanoma is an uncommon form of acral melanoma that is anatomically restricted to the finger. The aim of this study is to provide specific epidemiological and clinical information about this subtype of melanoma, as well as to identify differences in recurrence and survival depending on the anatomical sublocation. PATIENTS AND METHODS: We describe a group of 45 Caucasian patients with digital melanoma divided into three groups: nail unit melanoma (group A), finger skin melanoma (group B), and those melanomas that involve both nail and adjacent skin (group C). RESULTS: The mean tumor thickness was 4.66 mm, and the most common histological subtype is acral lentiginous melanoma. Group C was more frequent in older men and was thicker and more frequently ulcerated (P < 0.05). In addition, patients in group C developed distant metastases more frequently and had a significantly lower median disease-free survival (26.60 months) compared with group A (69.47 months) and group B (89.81 months) (P < 0.05). CONCLUSIONS: According to our results, digital melanoma limited to nail apparatus or finger skin was associated with a better prognosis, while those affecting both nail apparatus and skin showed lower melanoma-specific survival.