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Yiming Cheng,1 Ying Ye,1 Allison Gaudy,1 Atalanta Ghosh,2 Yongjun Xue,3 Alice Wang,1 Simon Zhou,1 Yan Li1 1Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, Princeton, NJ, USA; 2Global Biometrics and Data Sciences, Bristol Myers Squibb, Princeton, NJ, USA; 3Nonclinical Research & Development, Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Yan Li, Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, 556 Morris Ave, Summit, Princeton, NJ, 07901, USA, Tel +1 908-481-6203, Email Yan.Li@bms.comIntroduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12.Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful.Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no clinically relevant impact on iberdomide PK and therefore, no dose adjustment is warranted.Keywords: hepatic impairment, iberdomide, pharmacokinetics

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La dinámica de la sociedad actual en que mujeres y hombres, se han integrado al ámbito laboral, genera que la población infantil sea institucionalizada a edades cada vez más tempranas, esto plantea un reto para los centros educativos que les atiende, cuya función no sólo sea asistencial, sino educativa e integral. La propuesta que se desarrolla en el este artículo surge de una investigación cualitativa etnográfica que pretende reconocer la realidad de trabajo en instituciones educativas: públicas, privadas e institucionales, en contraste con la teoría y los aportes de especialistas en el desarrollo integral. Así, se logra reconocer las fortalezas y deficiencias de la labor pedagógica en el marco de la educación costarricense con este grupo, se concreta el aporte de un perfil de desarrollo actual y contextualizado y se incentiva la creación de propuestas similares en relación con otras edades propias del nivel Preescolar. The dynamics of a current society, in which women and men have been integrated into the work force, propitiate an institutionalization of the child population at increasingly early ages, this poses a challenge for schools that receive them, whose function is not only to see their needs, but are also educational and comprehensive. The proposal developed in this article stems from an ethnographic qualitative research that seeks to recognize the reality of working in educational institutions: public, private and institutional, as opposed to the theory and contributions from specialists in comprehensive development. Thus, with this group, the strengths and weaknesses of the educational work in the context of the education in Costa Rica are recognized, specifically, through the contribution of a current development profile, which contextualizes and encourages the creation of similar proposals, in relation to other age groups part of the Preschool level.

Glioblastoma multiforme (GBM) is the most frequent malignant and aggressive type of glioma. Most cases of GBM present as a single solitary solid tumor; however, there are rare instances in which it may present as a cystic lesion. Here, we report an even rarer case of GBM presenting as bilateral multicystic lesions, mimicking infectious etiology. Our case highlights the importance of identifying clinical features of cystic GBM to ensure early diagnosis and treatment. A literature review was conducted in PubMed, looking at the common characteristics and treatment options for cystic GBM.

Background: Cancer therapies targeting actionable molecular alterations (AMA) have developed, but the clinical routine impact of high-throughput molecular profiling remains unclear. We present a monocentric experience of molecular profiling based on liquid biopsy in patients with cancer. Methods: Patients included had solid cancer and underwent cfDNA genomic profiling with FoudationOne Liquid CDx (F1LCDx) test, analyzing 324 genes. Primary endpoint was to describe patients with an AMA for whom clinical decisions were impacted by F1LCDx test results. Results: 191 patients were included, mostly with lung cancer (46%). An AMA was found in 52%. The most common molecular alterations were: TP53 (52%), KRAS (14%) and DNMT3 (11%). The most common AMA were: CHEK2 (10%), PIK3CA (9%), ATM (7%). There was no difference in progression-free survival (2.66 months vs. 3.81 months, p = 0.17), overall survival (5.3 months vs. 7.1 months, p = 0.64), or PFS2/PFS1 ratio ≥ 1.3 (20% vs. 24%, p = 0.72) between patients receiving a molecularly matched therapy (MMT) or a non-MMT, respectively. Patients with a MMT had an overall response rate of 19% and a disease control of 32%. Conclusions: Routine cfDNA molecular profiling is feasible and can lead to the access of targeted therapies. However, no notable benefit in patient’s outcomes was shown in this unselected pan-cancer study.

Background Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF , NRAS , or CKIT targeting, has rarely been reported. Materials and Methods By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF , NRAS , or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Results We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11 , MAP2K1 , FYCO1-RAF1 , HRAS , ATM , CCND1 , MDM2/CDK4 , and CDKN2A/NRAS alterations. Conclusions High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments. [ABSTRACT FROM AUTHOR]

Bispecific T‐cell Engagers (TCEs) are promising anti‐cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on‐target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies. This review assesses dose selection and the role of quantitative clinical pharmacology in the development of the first eight approved TCEs. Model informed drug development (MIDD) strategies can be used at every stage to guide TCE development. Mechanistic modeling approaches allow for (1) efficacious yet safe first‐in‐human dose selection as compared with in vitro minimum anticipated biological effect level (MABEL) approach; (2) rapid escalation and reducing number of patients with subtherapeutic doses through model‐based adaptive design; (3) virtual testing of different step‐up dosing regimens that may not be feasible to be evaluated in the clinic; and (4) selection and justification of the optimal clinical step‐up and full treatment doses. As the knowledge base around TCEs continues to grow, the relevance and utilization of MIDD strategies for supporting the development and dose optimization of these molecules are expected to advance, optimizing the benefit–risk profile for cancer patients. [ABSTRACT FROM AUTHOR]

Alnuctamab, a B‐cell maturation antigen (BCMA)‐targeting T‐cell engager, has demonstrated encouraging antitumor activity in the phase I study CC‐93269‐MM‐001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure–response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15–10 mg) or in step‐up doses to a maximum 10‐mg target dose. Subcutaneous (SC) step‐up doses of 3 and 6 mg were followed by a target dose range of 10–60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two‐compartment PopPK model with first‐order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure–response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure–CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure–safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure–response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg. [ABSTRACT FROM AUTHOR]

Background Objective Method Results Conclusion There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision‐making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas.To generate a consensual and operational classification of cSCCs.Unsupervised independent clustering of 248 cases of cSCCs considered difficult‐to‐treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K‐mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners.Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy‐to‐treat cSCC was included, resulting in a six‐group final classification: easy‐to‐treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases.Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials. [ABSTRACT FROM AUTHOR]

Este artículo presenta las experiencias de la población estudiantil de diferentes carreras de la Sede Interuniversitaria de Alajuela de la Universidad Nacional, que, como parte de su proceso de aprendizaje en el curso Actividades y Eventos Recreativos, diseña y ejecuta actividades que promueven la actividad física y la recreación con diferentes poblaciones de la provincia de Alajuela. Para la sistematización de esta experiencia se aplicó un cuestionario al estudiantado y a las personas responsables de las organizaciones donde se efectuaron las actividades, con el propósito de conocer su percepción en relación con los resultados obtenidos. Este ejercicio es una prueba de cómo por medio del aprendizaje y de la extensión es posible fortalecer habilidades en el estudiantado e impactar a las comunidades.

Ultraviolet radiation (UVR) increases melanoma incidence. Here, the authors report that UVR-damaged dermal fibroblasts upregulate MMP1 to degrade collagen which inhibits melanoma invasion and that aged primary melanomas in skin with degraded collagen have a better prognosis, while new collagen synthesis restores invasion and leads to death.