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Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical, molecular, and genomic characterization confirming the features of the original tumor. The tissue-of-origin prediction was obtained from the tumor microRNA expression profile and confirmed by single-cell transcriptomics. Genomic testing and fluorescence in situ hybridization analysis identified FGFR2 gene amplification in both models, in the form of homogeneously staining region (HSR) in CUP#55 and double minutes in CUP#96. FGFR2 was recognized as the main oncogenic driver and therapeutic target. FGFR2-targeting drug BGJ398 (infigratinib) in combination with the MEK inhibitor trametinib proved to be synergic and exceptionally active, both in vitro and in vivo. The effects of the combined treatment by single-cell gene expression analysis revealed a remarkable plasticity of tumor cells and the greater sensitivity of cells with epithelial phenotype. This study brings personalized therapy closer to CUP patients and provides the rationale for FGFR2 and MEK targeting in metastatic tumors with FGFR2 pathway activation., Competing Interests: Declaration of interests F.G. received personal fees from AstraZeneca and honoraria for advisory board participation from Eli-Lilly. G.A.C. is a member of the Editorial Board of Molecular Therapy., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Asthma is one of the most common non-communicable diseases, and its prevalence and morbidity are influenced by a wide array of factors that are only partially understood. In addition to individual predisposition linked to genetic background and early life infections, environmental factors are crucial in determining the impact of asthma both on an individual patient and on a population level.Several studies have examined the role of the environment where asthmatic subjects live in the pathogenesis of asthma. This review aims to investigate the differences in the prevalence and characteristics of asthma between the pediatric population residing at higher altitudes and children living at lower altitudes, trying to define factors that potentially determine such differences. For this purpose, we reviewed articles from the literature concerning observational studies assessing the prevalence of pediatric asthma in these populations and its characteristics, such as spirometric and laboratory parameters and associated sensitization to aeroallergens.Despite the heterogeneity of the environments examined, the hypothesis of a beneficial effect of residing at a higher altitude on the prevalence of pediatric asthma could be confirmed, as well as a good profile on airway inflammation in asthmatic children. However, the possibility of a higher hospitalization risk for asthma in children living at higher altitudes was demonstrated. Moreover, a positive association between residing at a higher altitude and sensitization to pollens and between lower altitude and sensitization to house dust mites could be confirmed in some pediatric patients, even if the results are not homogeneous, probably due to the different geographical and climatic regions considered. Nonetheless, further studies, e.g., extensive and international works, need to be conducted to better understand the complex interplay between different environmental factors, such as altitude, and the pathogenesis of asthma and how its prevalence and characteristics could vary due to climate change., (© 2023. The Author(s).)

isomiRs, the sequence-variants of microRNA, are known to be tissue and cell type specific but their physiological role is largely unknown. In our study, we explored for the first time the expression of isomiRs across different Stage I epithelial ovarian cancer (EOC) histological subtypes, in order to shed new light on their biological role in tumor growth and progression. In a multicentric retrospective cohort of tumor biopsies (n = 215) we sequenced small RNAs finding 971 expressed miRNAs, 64% of which are isomiRs. Among them, 42 isomiRs showed a clear histotype specific pattern, confirming our previously identified miRNA markers (miR192/194 and miR30a-3p/5p for mucinous and clear cell subtypes, respectively) and uncovering new biomarkers for all the five subtypes. Using integrative models, we found that the 38% of these miRNA expression alterations is the result of copy number variations while the 17% of differential transcriptional activities. Our work represents the first attempt to characterize isomiRs expression in Stage I EOC within and across subtypes and to contextualize their alterations in the framework of the large genomic heterogeneity of this tumor., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Stage I epithelial ovarian cancer (EOC) encompasses five histologically different subtypes of tumors confined to the ovaries with a generally favorable prognosis. Despite the intrinsic heterogeneity, all stage I EOCs are treated with complete resection and adjuvant therapy in most of the cases. Owing to the lack of robust prognostic markers, this often leads to overtreatment. Therefore, a better molecular characterization of stage I EOCs could improve the assessment of the risk of relapse and the refinement of optimal treatment options., Materials and Methods: 205 stage I EOCs tumor biopsies with a median follow-up of eight years were gathered from two independent Italian tumor tissue collections, and the genome distribution of somatic copy number alterations (SCNAs) was investigated by shallow whole genome sequencing (sWGS) approach., Results: Despite the variability in SCNAs distribution both across and within the histotypes, we were able to define three common genomic instability patterns, namely stable, unstable, and highly unstable. These patterns were based on the percentage of the genome affected by SCNAs and on their length. The genomic instability pattern was strongly predictive of patients' prognosis also with multivariate models including currently used clinico-pathological variables., Conclusions: The results obtained in this study support the idea that novel molecular markers, in this case genomic instability patterns, can anticipate the behavior of stage I EOC regardless of tumor subtype and provide valuable prognostic information. Thus, it might be propitious to extend the study of these genomic instability patterns to improve rational management of this disease., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Summary: We present NewWave, a scalable R/Bioconductor package for the dimensionality reduction and batch effect removal of single-cell RNA sequencing data. To achieve scalability, NewWave uses mini-batch optimization and can work with out-of-memory data, enabling users to analyze datasets with millions of cells., Availability and Implementation: NewWave is implemented as an open-source R package available through the Bioconductor project at https://bioconductor.org/packages/NewWave/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Pseudomyogenic hemangioendothelioma (PMH) can be a challenge for diagnosis and might be confused with other tumors, such as epithelioid sarcoma. Here we present a case and a systematic review of the literature to identify and discuss PMH treatment in primary bone involvement. A 25-year-old woman was referred for bone pain (10/10) in the left lower limb. Magnetic resonance imaging (MRI) showed multiple bone lesions (left femur, tibia, patella, ankle, and foot) with well-defined borders without signs of local aggressiveness. Positron Emission Tomography-Computed Tomography (PET-CT) showed multiple metabolic musculoskeletal lesions in the left lower limb. A CT scan-guided biopsy was performed. Histological and immunohistochemical findings confirmed the diagnosis of PMH. After treatment with intravenous pamidronate (90 mg/monthly), the patient had clinical improvement, mild pain 2/10 without the use of non-steroidal anti-inflammatory drugs or opiates. Follow-up was assessed by MRI and PET-CT. PET-CT showed metabolic resolution of most of the bone and muscular lesions and a significant improvement of the femoral lesion. MRI showed that the lesions in the left femur, tibia, and foot had a marked decrease in size without intravenous post-contrast enhancement and smaller lesions had disappeared. After a 3-year follow-up, PET-CT showed no metabolically active images. Literature review identified 31 records including 58 clinical cases of PMH with primary bone involvement and treatment description for qualitative analysis. Most lesions (69%) were treated by local excision or curettage. In addition, amputations were performed in a significant percentage of cases (20.7%). In the last years, mTOR inhibitors (n = 7) and anti-resorptive treatments (n = 4) were considered as alternative treatment options, especially in multifocal lesions., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)