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Objective: This study aimed to assess the influence of medical history, perceived physician-patient communication, and perceived social support on changes in the quality of life (QoL) during the first year of follow-up in patients undergoing surgery for endometrial cancer (EC), the most prevalent gynecological cancer in Western countries, especially in Central and Eastern Europe and North America. Methods: This prospective longitudinal study included 98 EC patients. All participants completed the Short Form 36 (SF-36) and the Multidimensional Scale of Perceived Social Support (MSPSS) one month and one year after surgery. Additionally, one month after surgery, they responded to a questionnaire designed by the researchers concerning the key aspects of physician-patient communication. Results: Our findings revealed that patients reporting high social support one month after surgery demonstrated significantly improved emotional well-being (EWB) at both one month and one year after the surgery, with statistically significant higher scores in the dimension of EWB (p<0.05). The support from a significant other at one year correlates with greater PF (p<0.005), fewer limitations due to physical health (p<0.05), less pain (p<0.05), less fatigue (p<0.05), and better general and EWB (p<0.05). Conclusion: This study underscores the significance of perceived social support for patients cross endometrial cancer. The multifaceted nature of social support, encompassing emotional assistance and information sharing, emerges as a pivotal factor aiding patients in confronting the challenges inherent to EC. This form of support contributes to bolstering psychological well-being and enhancing overall QoL.
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Background: Cervical cancer is the most common genital cancer worldwide and is mainly caused by a persistent human papillomavirus infection. Well-known prognostic factors are age, histology, stage, stromal invasion, tumor size, and tumor grade. The relationship between the ABO and Rh system with cervical cancer has been studied since the 1950s, though without obtaining clear results. Here we investigated the association between the ABO blood group and Rh system and consecutively treated cervical cancer patients in our department. Methods: Clinical charts of cervical cancer patients treated and followed from 2010 to 2021 were checked for inclusion and exclusion criteria. Clinical and pathological data were recorded in a separate, anonymous, password-protected electronic database. All relevant data were extrapolated and used for final analysis. Results: A population of 143 cervical cancer patients was analyzed in this study. 47.6% (68/143) were blood group O, 36.4% (52/143) were blood group A, 8.4% (12/143) were blood group AB, and 7.7% (11/143) were blood group B. 14.9% (21/141) were RhD negative, while 85.1% (120/141) were RhD positive. No significant association was found between the ABO group and survival. However, patients with blood types B and AB had a higher BMI than the other blood types. RhD-negative patients exhibited a lower age at diagnosis (P=0.035) and had a higher overall survival compared to RhD-positive patients. Conclusions: The RhD factor appears to influence cervical cancer OS, but the data are too weakly significant to draw a definitive conclusion. Further studies with larger samples are needed to confirm this finding and to investigate the true impact of blood groups in female cancers.
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Background: Gastrointestinal stromal tumors (GISTs) are a rare neoplasm, sometimes mimicking primary ovarian tumors (OTs) and/or metastasizing to the ovaries (M-OT). We performed a systematic literature review (SLR) of OTs and M-OTs, investigating differences in recurrence-free and overall survival. Methods: Our SLR was performed according to PRISMA guidelines, searching in Pubmed, Scopus, and Web of Science databases from inception until 21 April 2024. Results: Overall, 59 OTs (Group 1) and 21 M-OTs (Group 2) were retrieved. The absence of residual disease after surgery was achieved significantly in a higher percentage of patients with Group 1 GISTs (91.5%) compared with Group 2 GISTs (57.1%). Chemotherapy was more frequently administered to Group 2 patients (33% vs. 0%). Recurrence and deaths for disease were significantly more frequent in Group 2 than Group 1 cases (54.5% vs. 6.8%, and 37.5% vs. 9.8%, respectively). Conclusions: GISTs can rarely mimic primary ovarian cancers or even more rarely metastasize to the ovaries. Group 1 GISTs occurred in younger women, were not associated with elevated tumor markers, and had a better prognosis. In contrast, Group 2 GISTs occurred in older women, may exhibit elevated tumor markers, and presented a worse prognosis. However, no significant statistical difference for survival between the two studied groups was detected. Computed tomography scans can define the size of GISTs, which correlate to stage and prognostic risk classes. The gold standard treatment is complete surgical resection, which was achieved in almost all cases of Group 1 GISTs and in half of Group 2. Histopathology and immunohistochemistry are essential for the final diagnosis and guide chemotherapy treatment.
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Multiple myeloma (MM) is a dreadful disease, marked by the uncontrolled proliferation of clonal plasma cells (PCs) within the bone marrow (BM). MM is characterized by a highly heterogeneous clinical and molecular background, supported by severe genomic alterations. Important deregulation of long non-coding RNAs (lncRNAs) expression has been reported in MM patients, influencing progression and therapy resistance. NEAT1 is a lncRNA essential for nuclear paraspeckles and involved in gene expression regulation. We showed that NEAT1 supports MM proliferation making this lncRNA an attractive therapeutic candidate. Here, we used a combinatorial strategy integrating transcriptomic and computational approaches with functional high-throughput drug screening, to identify compounds that synergize with NEAT1 inhibition in restraining MM cells growth. AUKA inhibitors were identified as top-scoring drugs in these analyses. We showed that the combination of NEAT1 silencing and AURKA inhibitors in MM profoundly impairs microtubule organization and mitotic spindle assembly, finally leading to cell death. Analysis of the large publicly CoMMpass dataset showed that in MM patients AURKA expression is strongly associated with reduced progression-free (p < 0.0001) and overall survival probability (p < 0.0001) and patients displaying high expression levels of both NEAT1 and AURKA have a worse clinical outcome. Finally, using RNA-sequencing data from NEAT1 knockdown (KD) MM cells, we identified the AURKA allosteric regulator TPX2 as a new NEAT1 target in MM and as a mediator of the interplay between AURKA and NEAT1, therefore providing a possible explanation of the synergistic activity observed upon their combinatorial inhibition.
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BACKGROUND: A subset of patients affected by cutaneous squamous cell carcinoma (cSCC) can exhibit locally invasive or metastatic tumors. Different staging classification systems are currently in use for cSCC. However, precise patient risk stratification has yet to be reached in clinical practice. The study aims to identify specific histological and molecular parameters characterizing metastatic cSCC. METHODS: Patients affected by metastatic and non-metastatic cSCC (controls) were included in the present study and matched for clinical and histological characteristics. Skin samples from primary tumors were revised for several histological parameters and also underwent gene expression profiling with a commercially available panel testing 770 different genes. RESULTS: In total, 48 subjects were enrolled in the study (24 cases, 24 controls); 67 genes were found to be differentially expressed between metastatic and non-metastatic cSCC. Most such genes were involved in immune regulation, skin integrity, angiogenesis, cell migration and proliferation. CONCLUSION: The combination of histological and molecular profiles of cSCCs allows the identification of features specific to metastatic cSCC, with potential implications for more precise patient risk stratification.
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ABSTRACT: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell (PC) neoplasm that may evolve with variable frequency into multiple myeloma (MM). SMM is initiated by chromosomal translocations involving the immunoglobulin heavy-chain locus or by hyperdiploidy and evolves through acquisition of additional genetic lesions. In this scenario, we aimed at establishing a reliable analysis pipeline to infer genomic lesions from transcriptomic analysis, by combining single-cell RNA sequencing (scRNA-seq) with B-cell receptor sequencing and copy number abnormality (CNA) analysis to identify clonal PCs at the genetic level along their specific transcriptional landscape. We profiled 20 465 bone marrow PCs derived from 5 patients with SMM/MM and unbiasedly identified clonal and polyclonal PCs. Hyperdiploidy, t(11;14), and t(6;14) were identified at the scRNA level by analysis of chimeric reads. Subclone functional analysis was improved by combining transcriptome with CNA analysis. As examples, we illustrate the different functional properties of a light-chain escape subclone in SMM and of different B-cell and PC subclones in a patient affected by Wäldenstrom macroglobulinemia and SMM. Overall, our data provide a proof of principle for inference of clinically relevant genotypic data from scRNA-seq, which in turn will refine functional annotation of the clonal architecture of PC dyscrasias.
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Mieloma Múltiple , RNA-Seq , Análisis de la Célula Individual , Humanos , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Análisis de la Célula Individual/métodos , Genómica/métodos , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Perfilación de la Expresión Génica , Análisis de Expresión Génica de una Sola CélulaRESUMEN
Malignant pleural mesothelioma is a rare and lethal cancer caused by exposure to asbestos. The highly inflammatory environment caused by fibers accumulation forces cells to undergo profound adaptation to gain survival advantages. Prioritizing the synthesis of essential transcripts is an efficient mechanism coordinated by multiple molecules, including long non-coding RNAs. Enhancing the knowledge about these mechanisms is an essential weapon in combating mesothelioma. Linc00941 correlates to bad prognosis in various cancers, but it is reported to partake in distinct and apparently irreconcilable processes. In this work, we report that linc00941 supports the survival and aggressiveness of mesothelioma cells by influencing protein synthesis and ribosome biogenesis. Linc00941 binds to the translation initiation factor eIF4G, promoting the selective protein synthesis of cMYC, which, in turn, enhances the expression of key genes involved in translation. We analyzed a retrospective cohort of 97 mesothelioma patients' samples from our institution, revealing that linc00941 expression strongly correlates with reduced survival probability. This discovery clarifies linc00941's role in mesothelioma and proposes a unified mechanism of action for this lncRNA involving the selective translation of essential oncogenes, reconciling the discrepancies about its function.
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Factor 4G Eucariótico de Iniciación , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-myc , ARN Largo no Codificante , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Mesotelioma Maligno/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Neoplasias Pleurales/metabolismo , Ribosomas/metabolismo , Ribosomas/genética , Estudios Retrospectivos , Pronóstico , Proliferación CelularRESUMEN
Chromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design.
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Daño del ADN , Estructuras R-Loop , ARN Polimerasa II , Transcripción Genética , Humanos , ARN Polimerasa II/metabolismo , Línea Celular Tumoral , Inestabilidad Genómica/genética , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Linfoma Anaplásico de Células Grandes/metabolismo , Regulación Neoplásica de la Expresión Génica , ADN Helicasas/genética , ADN Helicasas/metabolismo , Regiones Promotoras Genéticas , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Linfoma de Células T/patologíaRESUMEN
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Antineoplásicos/farmacología , Células Asesinas Naturales , Proteína smad3/genética , Proteína smad3/metabolismo , Proteínas que Contienen BromodominioRESUMEN
INTRODUCTION: Selinexor, an XPO1 inhibitor, has emerged as a promising therapeutic option in the challenging landscape of relapsed/refractory multiple myeloma (RRMM). AREAS COVERED: This article provides a review of selinexor, with a focus on available clinical studies involving MM patients and its safety profile. Clinical trials, such as STORM and BOSTON, have demonstrated its efficacy, particularly in combination regimens, showcasing notable overall response rates (ORR) and prolonged median progressionfree survival (mPFS). Selinexor's versatility is evident across various combinations, including carfilzomibdexamethasone (XKd), lenalidomidedexamethasone (XRd), and pomalidomidedexamethasone (XPd), with efficacy observed even in tripleclass refractory and highrisk patient populations. However, challenges, including resistance mechanisms and adverse events, necessitate careful management. Realworld evidence also underscores selinexor's effectiveness in RRMM, though dose adjustments and supportive measures remain crucial. Ongoing trials are exploring selinexor in diverse combinations and settings, including pomalidomidenaïve patients and postautologous stem cell transplant (ASCT) maintenance. EXPERT OPINION: The evolving landscape of selinexor's role in the sequencing of treatment for RRMM, its potential in highrisk patients, including those with extramedullary disease, as revealed in the most recent international meetings, and ongoing investigations signal a dynamic era in myeloma therapeutics. Selinexor emerges as a pivotal component in multidrug strategies and innovative combinations.
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Hidrazinas , Mieloma Múltiple , Triazoles , Mieloma Múltiple/tratamiento farmacológico , Humanos , Hidrazinas/uso terapéutico , Hidrazinas/efectos adversos , Triazoles/uso terapéutico , Triazoles/efectos adversos , Carioferinas/antagonistas & inhibidores , Proteína Exportina 1 , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Supervivencia sin ProgresiónRESUMEN
Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined approaches. Here, we used spatial transcriptomics to investigate the multidimensional organization of TNBC at diagnosis and explore the contribution of each cell component to response to NAC. Starting from a consecutive retrospective series of TNBC cases, we designed a case-control study including 24 patients with TNBC of which 12 experienced a pathologic complete response (pCR) and 12 no-response or progression (pNR) after NAC. Over 200 regions of interest (ROI) were profiled. Our computational approaches described a model that recapitulates clinical response to therapy. The data were validated in an independent cohort of patients. Differences in the transcriptional program were detected in the tumor, stroma, and immune infiltrate comparing patients with a pCR with those with pNR. In pCR, spatial contamination between the tumor mass and the infiltrating lymphocytes was observed, sustained by a massive activation of IFN-signaling. Conversely, pNR lesions displayed increased pro-angiogenetic signaling and oxygen-based metabolism. Only modest differences were observed in the stroma, revealing a topology-based functional heterogeneity of the immune infiltrate. Thus, spatial transcriptomics provides fundamental information on the multidimensionality of TNBC and allows an effective prediction of tumor behavior. These results open new perspectives for the improvement and personalization of therapeutic approaches to TNBCs.
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Neoplasias de la Mama Triple Negativas , Humanos , Estudios de Casos y Controles , Terapia Neoadyuvante/métodos , Pronóstico , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , FemeninoRESUMEN
Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in cancer development and progression, with both oncogenic and tumor suppressor functions. In this work, we identified and characterized a novel lncRNA, TAZ-AS202, expressed from the TAZ genomic locus and exerting pro-oncogenic functions in non-small cell lung cancer. TAZ-AS202 expression is under the control of YAP/TAZ-containing transcriptional complexes. We demonstrated that TAZ-AS202 is overexpressed in lung cancer tissue, compared with surrounding lung epithelium. In lung cancer cell lines TAZ-AS202 promotes cell migration and cell invasion. TAZ-AS202 regulates the expression of a set of genes belonging to cancer-associated pathways, including WNT and EPH-Ephrin signaling. The molecular mechanism underlying TAZ-AS202 function does not involve change of TAZ expression or activity, but increases the protein level of the transcription factor E2F1, which in turn regulates the expression of a large set of target genes, including the EPHB2 receptor. Notably, the silencing of both E2F1 and EPHB2 recapitulates TAZ-AS202 silencing cellular phenotype, indicating that they are essential mediators of its activity. Overall, this work unveiled a new regulatory mechanism that, by increasing E2F1 protein, modifies the non-small cell lung cancer cells transcriptional program, leading to enhanced aggressiveness features. The TAZ-AS202/E2F1/EPHB2 axis may be the target for new therapeutic strategies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , ARN Largo no Codificante , Humanos , Neoplasias Pulmonares/patología , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Efrinas/genética , Efrinas/metabolismo , Línea Celular Tumoral , Pulmón/metabolismo , Regulación Neoplásica de la Expresión Génica/genéticaRESUMEN
The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma (MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1 and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively correlated with the presence of MM cells in patients' bone marrow biopsies. Finally, taking advantage of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that JAG2 gene expression level was a predictive biomarker associated with patients' overall survival and progression-free survival, independently from other main molecular or clinical features. Overall, these results strengthened the rationale for the development of a JAG1/2-tailored approach and the use of JAG2 as a predictive biomarker in MM.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores Notch/metabolismo , Biomarcadores , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Ligandos , Microambiente TumoralRESUMEN
Analyzing gene expression profiles (GEP) through artificial intelligence provides meaningful insight into cancer disease. This study introduces DeepSHAP Autoencoder Filter for Genes Selection (DSAF-GS), a novel deep learning and explainable artificial intelligence-based approach for feature selection in genomics-scale data. DSAF-GS exploits the autoencoder's reconstruction capabilities without changing the original feature space, enhancing the interpretation of the results. Explainable artificial intelligence is then used to select the informative genes for chronic lymphocytic leukemia prognosis of 217 cases from a GEP database comprising roughly 20,000 genes. The model for prognosis prediction achieved an accuracy of 86.4%, a sensitivity of 85.0%, and a specificity of 87.5%. According to the proposed approach, predictions were strongly influenced by CEACAM19 and PIGP, moderately influenced by MKL1 and GNE, and poorly influenced by other genes. The 10 most influential genes were selected for further analysis. Among them, FADD, FIBP, FIBP, GNE, IGF1R, MKL1, PIGP, and SLC39A6 were identified in the Reactome pathway database as involved in signal transduction, transcription, protein metabolism, immune system, cell cycle, and apoptosis. Moreover, according to the network model of the 3D protein-protein interaction (PPI) explored using the NetworkAnalyst tool, FADD, FIBP, IGF1R, QTRT1, GNE, SLC39A6, and MKL1 appear coupled into a complex network. Finally, all 10 selected genes showed a predictive power on time to first treatment (TTFT) in univariate analyses on a basic prognostic model including IGHV mutational status, del(11q) and del(17p), NOTCH1 mutations, ß2-microglobulin, Rai stage, and B-lymphocytosis known to predict TTFT in CLL. However, only IGF1R [hazard ratio (HR) 1.41, 95% CI 1.08-1.84, P=0.013), COL28A1 (HR 0.32, 95% CI 0.10-0.97, P=0.045), and QTRT1 (HR 7.73, 95% CI 2.48-24.04, P<0.001) genes were significantly associated with TTFT in multivariable analyses when combined with the prognostic factors of the basic model, ultimately increasing the Harrell's c-index and the explained variation to 78.6% (versus 76.5% of the basic prognostic model) and 52.6% (versus 42.2% of the basic prognostic model), respectively. Also, the goodness of model fit was enhanced (χ2 = 20.1, P=0.002), indicating its improved performance above the basic prognostic model. In conclusion, DSAF-GS identified a group of significant genes for CLL prognosis, suggesting future directions for bio-molecular research.
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Mortality from vmelanoma is associated with metastatic disease, but the mechanisms leading to spreading of the cancer cells remain obscure. Spatial profiling revealed that melanoma is characterized by a high degree of heterogeneity, which is established by the ability of melanoma cells to switch between different phenotypical stages. This plasticity, likely a heritage from embryonic pathways, accounts for a relevant part of the metastatic potential of these lesions, and requires the rapid and efficient reorganization of the transcriptional landscape of melanoma cells. A large part of the non-coding genome cooperates to control gene expression, specifically through the activity of enhancers (ENHs). In this study, we aimed to identify ex vivo the network of active ENHs and to outline their cooperative interactions in supporting transcriptional adaptation during melanoma metastatic progression. We conducted a genome-wide analysis to map active ENHs distribution in a retrospective cohort of 39 melanoma patients, comparing the profiles obtained in primary (N = 19) and metastatic (N = 20) melanoma lesions. Unsupervised clustering showed that the profile for acetylated histone H3 at lysine 27 (H3K27ac) efficiently segregates lesions into three different clusters corresponding to progressive stages of the disease. We reconstructed the map of super-ENHs (SEs) and cooperative ENHs that associate with metastatic progression in melanoma, which showed that cooperation among regulatory elements is a mandatory requirement for transcriptional plasticity. We also showed that these elements carry out specialized and non-redundant functions, and indicated the existence of a hierarchical organization, with SEs on top as masterminds of the entire transcriptional program and classical ENHs as executors. By providing an innovative vision of how the chromatin landscape of melanoma works during metastatic spreading, our data also point out the need to integrate functional profiling in the analysis of cancer lesions to increase definition and improve interpretation of tumor heterogeneity.
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Melanoma , Humanos , Melanoma/genética , Melanoma/metabolismo , Estudios Retrospectivos , Histonas/metabolismo , CromatinaRESUMEN
OBJECTIVE: To assess compliance with the 2019 regional recommendation to centralize epithelial ovarian cancer (EOC) patients and to assess whether the COVID-19 pandemic has affected the quality of care for EOC patients. METHODS: We compared data from EOC patients treated before the introduction of the 2019 regional recommendation (2018-2019) with data obtained from EOC patients treated after the regional recommendation was adopted during the first 2 years of the COVID-19 pandemic (2020-2021). Data were retrieved from the Optimal Ovarian Cancer Pathway records. R software version 4.1.2 (the R Foundation for Statistical Computing, Vienna, Austria) was used for the statistical analysis. RESULTS: 251 EOC patients were centralized. The number of EOC patients centralized increased from 2% to 49% despite the COVID-19 pandemic. During the COVID-19 pandemic, there was an increase in the use of neoadjuvant chemotherapy and interval debulking surgery. There was an improvement in the percentage of Stage III patients without gross residual disease following both primary and interval debulking surgery. The percentage of EOC cases discussed by the multidisciplinary tumor board (MTB) increased from 66% to 89% of cases. CONCLUSION: Despite the COVID-19 pandemic, centralization has increased and the quality of care has been preserved thanks to the MTB.
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COVID-19 , Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Femenino , Humanos , Carcinoma Epitelial de Ovario/terapia , Carcinoma Epitelial de Ovario/patología , Quimioterapia Adyuvante , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/terapia , Neoplasias Ováricas/tratamiento farmacológico , Pandemias , Estudios Retrospectivos , Calidad de la Atención de Salud , Accesibilidad a los Servicios de SaludRESUMEN
Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.
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Linfoma Anaplásico de Células Grandes , Linfoma de Células T Periférico , ARN Largo no Codificante , Humanos , Proteínas Tirosina Quinasas Receptoras/genética , Quinasa de Linfoma Anaplásico/genética , ARN Largo no Codificante/genética , Mitofagia/genética , Estudios Retrospectivos , Linfoma Anaplásico de Células Grandes/patologíaRESUMEN
Due to the lack of a standardized tool for risk-based stratification, the International Medullary Carcinoma Grading System (IMTCGS) has been proposed for medullary thyroid carcinomas (MTCs) based on necrosis, mitosis, and Ki67. Similarly, a risk stratification study using the Surveillance, Epidemiology, and End Results (SEER) database highlighted significant differences in MTCs in terms of clinical-pathological variables. We aimed to validate both the IMTCGS and SEER-based risk table on 66 MTC cases, with special attention to angioinvasion and the genetic profile. We found a significant association between the IMTCGS and survival because patients classified as high-grade had a lower event-free survival probability. Angioinvasion was also found to be significantly correlated with metastasis and death. Applying the SEER-based risk table, patients classified either as intermediate- or high-risk had a lower survival rate than low-risk patients. In addition, high-grade IMTCGS cases had a higher average SEER-based risk score than low-grade cases. Moreover, when we explored angioinvasion in correlation with the SEER-based risk table, patients with angioinvasion had a higher average SEER-based score than patients without angioinvasion. Deep sequencing analysis found that 10 out of 20 genes frequently mutated in MTCs belonged to a specific functional class, namely chromatin organization, and function, which may be responsible for the MTC heterogeneity. In addition, the genetic signature identified 3 main clusters; cases belonging to cluster II displayed a significantly higher number of mutations and higher tumor mutational burden, suggesting increased genetic instability, but cluster I was associated with the highest number of negative events. In conclusion, we confirmed the prognostic performance of the IMTCGS and SEER-based risk score, showing that patients classified as high-grade had a lower event-free survival probability. We also underline that angioinvasion has a significant prognostic role, which has not been incorporated in previous risk scores.
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Carcinoma Medular , Carcinoma Neuroendocrino , Neoplasias de la Tiroides , Humanos , Carcinoma Medular/genética , Perfil Genético , Carcinoma Neuroendocrino/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Pronóstico , Factores de RiesgoRESUMEN
BACKGROUND: Primary ovarian leiomyosarcoma is a very rare malignancy characterized by unclear management and poor survival. We reviewed all the cases of primary ovarian leiomyosarcoma to identify prognostic factors and the best treatment. METHODS: We collected and analyzed the articles published in the English literature regarding primary ovarian leiomyosarcoma from January 1951 to September 2022, using PubMed research. Clinical and pathological characteristics, different treatments and outcomes were analyzed. RESULTS: 113 cases of primary ovarian leiomyosarcoma were included. Most patients received surgical resection, associated with lymphadenectomy in 12.5% of cases. About 40% of patients received chemotherapy. Follow-up information was available for 100/113 (88.5%) patients. Stage and mitotic count were confirmed to affect survival, and lymphadenectomy and chemotherapy were associated with a better survival rate. A total of 43.4% of patients relapsed, and their mean disease-free survival was 12.5 months. CONCLUSIONS: Primary ovarian leiomyosarcomas are more common in women in their 50s (mean age 53 years). Most of them are at an early stage at presentation. Advanced stage and mitotic count showed a detrimental effect on survival. Surgical excision associated with lymphadenectomy and chemotherapy are associated with increased survival. An international registry could help collect clear and reliable data to standardize the diagnosis and treatment.
RESUMEN
BACKGROUND: Endometrial cancer (EC) is the most common gynecologic tumor and the world's fourth most common cancer in women. Most patients respond to first-line treatments and have a low risk of recurrence, but refractory patients, and those with metastatic cancer at diagnosis, remain with no treatment options. Drug repurposing aims to discover new clinical indications for existing drugs with known safety profiles. It provides ready-to-use new therapeutic options for highly aggressive tumors for which standard protocols are ineffective, such as high-risk EC. METHODS: Here, we aimed at defining new therapeutic opportunities for high-risk EC using an innovative and integrated computational drug repurposing approach. RESULTS: We compared gene-expression profiles, from publicly available databases, of metastatic and non-metastatic EC patients being metastatization the most severe feature of EC aggressiveness. A comprehensive analysis of transcriptomic data through a two-arm approach was applied to obtain a robust prediction of drug candidates. CONCLUSIONS: Some of the identified therapeutic agents are already successfully used in clinical practice to treat other types of tumors. This highlights the potential to repurpose them for EC and, therefore, the reliability of the proposed approach.