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American Society of Clinical Oncology... Jun 2024Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods... (Review)
Review
Cancer outcomes are largely measured in terms of disease-free survival or overall survival, which is highly dependent on timely diagnosis and access to treatment methods available within the country's existing health care system. Although cancer survival rates have markedly led in the past few decades, any improvement in the 5-year survival of gynecologic cancers has been modest, as in the case of ovarian and cervical cancers, or has declined, as in the case of endometrial cancer. The lack of effective screening options contributes to many women presenting with advanced-stage disease and the need for radical approaches to treatment. Although treatment for early-stage disease can lead to a cure, advanced-stage disease is fraught with a high potential for morbidity and mortality, and recent clinical trials have aimed to assess the noninferiority of minimally invasive options versus aggressive surgical approaches. Of particular interest is fertility-sparing treatments for endometrial and cervical cancers, which have recently been on the rise among younger women. Balancing morbidity with the risk of mortality, and loss of fertility and quality of life requires a targeted patient-centered approach to treatment. This is an ongoing area of intense research and sometimes may challenge current treatment paradigms. In this two-part review, we present an overview of current approaches to gynecologic cancer treatment and the need to de-escalate radical surgical approaches and preserve fertility. We also review the intricacies of ovarian and advanced endometrial cancer treatment, exploring the nuances in surgical debulking timing and its impact on outcomes.
Topics: Humans; Female; Genital Neoplasms, Female; Quality of Life; Gynecologic Surgical Procedures; Neoplasm Staging
PubMed: 38815208
DOI: 10.1200/EDBK_438550 -
PLoS Biology May 2024Glioblastoma, the most aggressive and prevalent form of primary brain tumor, is characterized by rapid growth, diffuse infiltration, and resistance to therapies.... (Review)
Review
Glioblastoma, the most aggressive and prevalent form of primary brain tumor, is characterized by rapid growth, diffuse infiltration, and resistance to therapies. Intrinsic heterogeneity and cellular plasticity contribute to its rapid progression under therapy; therefore, there is a need to fully understand these tumors at a single-cell level. Over the past decade, single-cell transcriptomics has enabled the molecular characterization of individual cells within glioblastomas, providing previously unattainable insights into the genetic and molecular features that drive tumorigenesis, disease progression, and therapy resistance. However, despite advances in single-cell technologies, challenges such as high costs, complex data analysis and interpretation, and difficulties in translating findings into clinical practice persist. As single-cell technologies are developed further, more insights into the cellular and molecular heterogeneity of glioblastomas are expected, which will help guide the development of personalized and effective therapies, thereby improving prognosis and quality of life for patients.
Topics: Humans; Glioblastoma; Single-Cell Analysis; Brain Neoplasms; Transcriptome; Animals
PubMed: 38814900
DOI: 10.1371/journal.pbio.3002640 -
Disease Models & Mechanisms May 2024Despite accounting for only ∼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease.... (Review)
Review
Despite accounting for only ∼0.5% of the lung epithelium, pulmonary neuroendocrine cells (PNECs) appear to play an outsized role in respiratory health and disease. Increased PNEC numbers have been reported in a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma. Moreover, PNECs are the primary cell of origin for lung neuroendocrine cancers, which account for 25% of aggressive lung cancers. Recent research has highlighted the crucial roles of PNECs in lung physiology, including in chemosensing, regeneration and immune regulation. Yet, little is known about the direct impact of PNECs on respiratory diseases. In this Review, we summarise the current associations of PNECs with lung pathologies, focusing on how new experimental disease models, such as organoids derived from human pluripotent stem cells or tissue stem cells, can help us to better understand the contribution of PNECs to respiratory diseases.
Topics: Humans; Neuroendocrine Cells; Lung; Models, Biological; Animals; Organoids; Respiratory Tract Diseases
PubMed: 38813849
DOI: 10.1242/dmm.050620 -
Haematologica May 2024T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia caused by accumulation of multiple genetic alterations in T-cell progenitors. However, for...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive type of leukemia caused by accumulation of multiple genetic alterations in T-cell progenitors. However, for many genes it remains unknown how their mutations contribute to disease development. Therefore, we performed two single-cell CRISPR screens in primary pro-T cells ex vivo to study the transcriptional impact of loss-of-function alterations in T-ALL and correlate this with effects on cell fitness. The various perturbations were clustered based on their effects on E2F/MYC or STAT/NOTCH signatures, which play a defining role in driving T-cell proliferation. Many of the perturbations resulted in positive effects on the STAT and NOTCH signatures and were predicted to behave as haploinsufficient tumor suppressors in T-ALL. Additionally, Spi1 was identified as an essential gene for pro-T cell survival, associated with deregulation of the MYC signature and epigenetic consequences. In contrast, Bcl11b was identified a strong tumor suppressor gene in immature T lymphocytes, associated with deregulation of NF-kB and JAK/STAT signaling. We found a correlation between BCL11B expression level and JAK/STAT pathway mutations in T-ALL patients and demonstrated oncogenic cooperation between Bcl11b inactivation and JAK3 hyperactivation in pro-T cells. Altogether, these single-cell CRISPR screens in pro-T cells provide fundamental insights in the mechanisms of transcriptional deregulation caused by genetic alterations in T-ALL.
PubMed: 38813729
DOI: 10.3324/haematol.2023.284901 -
Haematologica May 2024Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes...
Multiple myeloma (MM) remains an incurable hematological malignancy. Despite tremendous advances in the treatment, about 10% of patients still have very poor outcomes with median overall survival less than 24 months. Our study aimed to underscore the critical mechanisms pertaining to the rapid disease progression and provide novel therapeutic selection for these ultra-high-risk patients. We utilized single-cell transcriptomic sequencing to dissect the characteristic bone marrow niche of patients with survival of less than two years (EM24). Notably, an enrichment of LILRB4high pre-matured plasma-cell cluster was observed in the patients in EM24 compared to patients with durable remission. This cluster exhibited aggressive proliferation and drug-resistance phenotype. High-level LILRB4 promoted MM clonogenicity and progression. Clinically, high expression of LILRB4 was correlated with poor prognosis in both newly diagnosed MM patients and relapsed/refractory MM patients. The ATAC-seq analysis identified that high chromosomal accessibility caused the elevation of LILRB4 on MM cells. CRISPR-Cas9 deletion of LILRB4 alleviated the growth of MM cells, inhibited the immunosuppressive function of MDSCs, and further rescued T cell dysfunction in MM microenvironment. The more infiltration of myeloid-derived suppressive cells (MDSCs) was observed in EM24 patients as well. Therefore, we innovatively generated a TCR-based chimeric antigen receptor (CAR) T cell, LILRB4-STAR-T. Cytotoxicity experiment demonstrated that LILRB4-STAR-T cells efficaciously eliminated tumor cells and impeded MDSCs function. In conclusion, our study elucidates that LILRB4 is an ideal biomarker and promising immunotherapy target for high-risk MM. LILRB4-STAR-T cell immunotherapy is promising against tumor cells and immunosuppressive tumor microenvironment in MM.
PubMed: 38813706
DOI: 10.3324/haematol.2024.285099 -
Turkish Journal of Medical Sciences 2023Cysteine and glycine-rich protein 1 (CSRP1) is involved in the cysteine-rich protein family and is a marker of smooth muscle lineages. In colon cancer, the expression of...
BACKGROUND/AIM
Cysteine and glycine-rich protein 1 (CSRP1) is involved in the cysteine-rich protein family and is a marker of smooth muscle lineages. In colon cancer, the expression of this gene is associated with poor prognosis. In this study, the aim was to reevaluate its prognostic relationship in independent cohorts and explore potential underlying biological processes that are linked to aggressive behavior in tumors with high CSRP1 expression, such as epithelial-to-mesenchymal transition (EMT), stromal fractions in the tumor microenvironment, and consensus molecular subtypes (CMSs).
MATERIALS AND METHODS
RNA sequencing (RNAseq)-, microarray-, and single-cell RNAseq (scRNAseq)-based transcriptomic data were obtained from public databases. The EMT score was calculated based on the expression of E-cadherin and vimentin genes using a previously published method. The stromal score generated by the ESTIMATE method was utilized for the analysis of correlation with the CSRP1 expression. The scRNAseq data were analyzed via the Seurat R package. The immunohistochemistry-based protein level expression of CSRP1 was evaluated using the Human Protein Atlas database.
RESULTS
Lower CSRP1 expression was noted in colon tumors compared to normal colon tissue. Patients with a high CSRP1 expression had shorter recurrence-free, overall, and disease-specific survivals in the GSE39582 and GSE17536 datasets (p < 0.05). The methylation level of the CSRP1 gene was negatively correlated (r = -0.57, p < 0.0001) with CSRP1 expression in The Cancer Genome Atlas colon adenocarcinoma dataset. CSRP1 expression was positively correlated with the expression of mesenchymal markers, EMT score, and stromal score obtained via the ESTIMATE method. CMS4 colon tumors had a significantly higher CSRP1 expression compared to other CMSs. Analysis of the scRNAseq data revealed that CSRP1 was expressed by epithelial cells and cancer-associated fibroblasts in the colorectal tumor microenvironment, which was also confirmed by the protein expression data from the Human Protein Atlas database.
CONCLUSION
CSRP1 expression is associated with CMS4, a more mesenchymal stroma-rich molecular profile, and poor prognosis in colon cancer.
Topics: Humans; Colonic Neoplasms; Prognosis; Epithelial-Mesenchymal Transition; Male; Biomarkers, Tumor; Female; Tumor Microenvironment; Middle Aged; Repressor Proteins; Aged
PubMed: 38813484
DOI: 10.55730/1300-0144.5736 -
World Journal of Gastroenterology May 2024The GALAD score has improved early hepatocellular carcinoma (HCC) detection rate. The role of the GALAD score in staging and predicting tumor characteristics or clinical... (Comparative Study)
Comparative Study
BACKGROUND
The GALAD score has improved early hepatocellular carcinoma (HCC) detection rate. The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest.
AIM
To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis, tumor features, and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers.
METHODS
This prospective, diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital. Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer (BCLC) categorization. Demographics, HCC etiology, and HCC features were recorded. Biomarkers and the GALAD score were obtained at baseline. The performance of the GALAD score and biomarkers were prospectively assessed.
RESULTS
Exactly 115 individuals were diagnosed with HCC. The GALAD score increased with disease severity. Between BCLC-0/A and BCLC-B/C/D, the GALAD score predicted HCC staging with an area under the curve (AUC) of 0.868 (95%CI: 0.80-0.93). For identifying the curative HCC, the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein (AFP) (0.753) and Lens culinaris agglutinin-reactive fraction of AFP-L3 (0.706), and as good as that of Protein induced by vitamin K absence-II (PIVKA-II) (0.897). For detecting aggressive features, the GALAD score gave an AUC of 0.839 (95%CI: 0.75-0.92) and significantly outperformed compared to that of AFP (0.761) and AFP-L3 (0.697), with a trend of superiority to that of PIVKA-II (0.772). The performance to predict 1-year mortality of GALAD score (AUC: 0.711, 95%CI: 0.60-0.82) was better than that of AFP (0.541) and as good as that of PIVKA-II (0.736). The optimal cutoff value of GALAD score was ≥ 6.83, with a specificity of 72.63% for exhibiting substantial reduction in the 1-year mortality.
CONCLUSION
The GALAD model can diagnose HCC at the curative stage, including the characteristic of advanced disease, more than that by AFP and AFP-L3, but not PIVKA-II. The GALAD score can be used to predict the 1-year mortality of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Male; Prospective Studies; Female; Middle Aged; Neoplasm Staging; Prognosis; Biomarkers, Tumor; Aged; alpha-Fetoproteins; Prothrombin; Protein Precursors; Adult; Early Detection of Cancer; Severity of Illness Index; Predictive Value of Tests; Biomarkers
PubMed: 38813057
DOI: 10.3748/wjg.v30.i17.2343 -
SAGE Open Medical Case Reports 2024Ecrrine porocarcinoma, a rare aggressive skin tumor, develops from sweat glands located in lower limbs, followed by the head and neck, trunk, and upper limbs. The...
Ecrrine porocarcinoma, a rare aggressive skin tumor, develops from sweat glands located in lower limbs, followed by the head and neck, trunk, and upper limbs. The incidence represents only about 0.005% of all cutaneous malignant tumors. The most common site is the lower extremities in elderly patients. As it has a high chance of metastases and recurrence after surgery, mainstay of treatment modality is wide local excision or Mohs (micrographically oriented histographic surgery) micrographic surgery. Mohs micrographic surgery (MMS) is a more effective treatment modality for tumors located in cosmetically and functionally important areas of the head and neck. We present a 56-years-old male patient with a large fungating eccrine tumor on the left axilla with ipsilateral nodal involvement on histomorphological grounds supported with immunohistochemical studies.
PubMed: 38812832
DOI: 10.1177/2050313X241256868 -
Frontiers in Oncology 2024Alpha-fetoprotein (AFP) serves as a crucial diagnostic marker for primary hepatocellular carcinoma (HCC) and germ cell tumors (GCTs), with rare instances of...
Alpha-fetoprotein (AFP) serves as a crucial diagnostic marker for primary hepatocellular carcinoma (HCC) and germ cell tumors (GCTs), with rare instances of significantly elevated levels in other diseases. In this study, we present a case of an elderly patient who was diagnosed with AFP-producing gastric cancer (AFPGC) following an elevated AFP result during physical examination. In investigating liver cancer at an early stage, the diagnosis was missed because of failure in detecting the lesion, resulting in delayed treatment initiation. AFPGC is a rare aggressive tumor that demands heightened awareness among clinicians to foster early detection, diagnosis, and treatment for improved prognosis.
PubMed: 38812781
DOI: 10.3389/fonc.2024.1393074 -
Bioinformatics and Biology Insights 2024Ameloblastoma (AM) is a benign tumor locally originated from odontogenic epithelium that is commonly found in the jaw. This tumor makes aggressive invasions and has a...
BACKGROUND
Ameloblastoma (AM) is a benign tumor locally originated from odontogenic epithelium that is commonly found in the jaw. This tumor makes aggressive invasions and has a high recurrence rate. This study aimed to investigate the differentially expressed genes (DEGs), biological function alterations, disease targets, and existing drugs for AM using bioinformatics analysis.
METHODS
The data set of AM was retrieved from the GEO database (GSE132474) and identified the DEGs using bioinformatics analysis. The biological alteration analysis was applied to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein-protein interaction (PPI) network analysis and hub gene identification were screened through NetworkAnalyst. The transcription factor-protein network was constructed via OmicsNet. We also identified candidate compounds from L1000CDS2 database. The target of AM and candidate compounds were verified using docking simulation.
RESULTS
Totally, 611 DEGs were identified. The biological function enrichment analysis revealed glycosaminoglycan and GABA (γ-aminobutyric acid) signaling were most significantly up-regulated and down-regulated in AM, respectively. Subsequently, hub genes and transcription factors were screened via the network and showed FOS protein was found in both networks. Furthermore, we evaluated FOS protein to be a therapeutic target in AMs. Candidate compounds were screened and verified using docking simulation. Tanespimycin showed the greatest affinity binding value to bind FOS protein.
CONCLUSIONS
This study presented the underlying molecular mechanisms of disease pathogenesis, biological alteration, and important pathways of AMs and provided a candidate compound, Tanespimycin, targeting FOS protein for the treatment of AMs.
PubMed: 38812739
DOI: 10.1177/11779322241256459