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Scientific Reports Jun 2024Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel...
Breast Cancer is the most common cancer among women globally. Despite significant improvements in overall survival, many tumours are refractory to therapy and so novel approaches are required to improve patient outcomes. We have evaluated patient-derived explants (PDEs) as a novel preclinical platform for breast cancer (BC) and implemented cutting-edge digital pathology and multi-immunofluorescent approaches for investigating biomarker changes in both tumour and stromal areas at endpoint. Short-term culture of intact fragments of BCs as PDEs retained an intact immune microenvironment, and tumour architecture was augmented by the inclusion of autologous serum in the culture media. Cell death/proliferation responses to FET chemotherapy in BC-PDEs correlated significantly with BC patient progression-free survival (p = 0.012 and p = 0.0041, respectively) and cell death responses to the HER2 antibody therapy trastuzumab correlated significantly with HER2 status (p = 0.018). These studies show that the PDE platform combined with digital pathology is a robust preclinical approach for informing clinical responses to chemotherapy and antibody-directed therapies in breast cancer. Furthermore, since BC-PDEs retain an intact tumour architecture over the short-term, they facilitate the preclinical testing of anti-cancer agents targeting the tumour microenvironment.
Topics: Humans; Breast Neoplasms; Female; Tumor Microenvironment; Trastuzumab; Receptor, ErbB-2; Cell Proliferation; Antineoplastic Agents; Middle Aged; Biomarkers, Tumor; Antineoplastic Agents, Immunological
PubMed: 38834809
DOI: 10.1038/s41598-024-63170-0 -
Annals of Oncology : Official Journal... Jul 2024Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the...
BACKGROUND
Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice.
METHODS
The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility.
RESULTS
As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available.
CONCLUSION
Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.
Topics: Humans; High-Throughput Nucleotide Sequencing; Precision Medicine; Neoplasms; Medical Oncology; Europe
PubMed: 38834388
DOI: 10.1016/j.annonc.2024.04.005 -
ESMO Open Jun 2024Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an...
BACKGROUND
Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity.
PATIENTS AND METHODS
A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing.
RESULTS
In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002).
CONCLUSIONS
Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.
Topics: Humans; Sunitinib; Gastrointestinal Stromal Tumors; Female; Male; Middle Aged; Aged; Antineoplastic Agents; Retrospective Studies; Drug Monitoring; Adult; Treatment Outcome; Gastrointestinal Neoplasms; Dose-Response Relationship, Drug; Aged, 80 and over; Prospective Studies; Progression-Free Survival
PubMed: 38833964
DOI: 10.1016/j.esmoop.2024.103477 -
The American Journal of Case Reports Jun 2024BACKGROUND Persistent truncus arteriosus is a rare congenital cyanotic heart defect characterized by a single ventricular outflow tract. Without surgical intervention,...
BACKGROUND Persistent truncus arteriosus is a rare congenital cyanotic heart defect characterized by a single ventricular outflow tract. Without surgical intervention, it has a poor prognosis in infancy. Here, we report an adult female patient with uncorrected truncus arteriosus type I, who presented with acute-onset abdominal pain due to torsion of a small bowel gastrointestinal stromal tumor (GIST). CASE REPORT A 41-year-old woman came to our Emergency Department with acute-onset lower abdominal pain for 2 days. Congenital heart disease, truncus arteriosus, had been diagnosed at birth, and there had been no surgical intervention. Abdominal computed tomography revealed a 10×9×12-cm mixed-density mass in the pelvic capacity. Transthoracic echocardiography revealed a 33-mm ventricular septal defect. The ascending aorta originated mainly from the right ventricle, and the pulmonary artery originated from the beginning of the aorta (type I truncus arteriosus, according to Collett and Edwards classification). After a quick and detailed preoperative workup, the patient underwent tumor resection by open surgery with general anesthesia. CONCLUSIONS This is the first case to report emergency surgery for a patient with uncorrected persistent truncus arteriosus due to torsion of a small bowel GIST. A multidisciplinary team with deep understanding of the disease entity was crucial. By considering the fixed hemodynamic and respiratory physiology, overtreatment and unrealistic goals were avoided. Eventually, the patient was discharged after being hospitalized for 2 weeks.
Topics: Humans; Female; Adult; Gastrointestinal Stromal Tumors; Torsion Abnormality; Truncus Arteriosus, Persistent; Intestine, Small
PubMed: 38833428
DOI: 10.12659/AJCR.943604 -
Cancer Immunology, Immunotherapy : CII Jun 2024The genomic landscape of esophageal squamous cell cancer (ESCC), as well as its impact on the regulation of immune microenvironment, is not well understood. Thus, tumor...
The genomic landscape of esophageal squamous cell cancer (ESCC), as well as its impact on the regulation of immune microenvironment, is not well understood. Thus, tumor samples from 92 patients were collected from two centers and subjected to targeted-gene sequencing. We identified frequently mutated genes, including TP53, KMT2C, KMT2D, LRP1B, and FAT1. The most frequent mutation sites were ALOX12B (c.1565C > T), SLX4 (c.2786C > T), LRIG1 (c.746A > G), and SPEN (c.6915_6917del) (6.5%). Pathway analysis revealed dysregulation of cell cycle regulation, epigenetic regulation, PI3K/AKT signaling, and NOTCH signaling. A 17-mutated gene-related risk model was constructed using random survival forest analysis and showed significant prognostic value in both our cohort and the validation cohort. Based on the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression (ESTIMATE) algorithm, the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm, and the MCPcounter algorithm, we found that the risk score calculated by the risk model was significantly correlated with stimulatory immune checkpoints (TNFSF4, ITGB2, CXCL10, CXCL9, and BTN3A1; p < 0.05). Additionally, it was significantly associated with markers that are important in predicting response to immunotherapy (CD274, IFNG, and TAMM2; p < 0.05). Furthermore, the results of immunofluorescence double staining showed that patients with high risk scores had a significantly higher level of M2 macrophage than those with low risk scores (p < 0.05). In conclusion, our study provides insights into the genomic landscape of ESCC and highlights the prognostic value of a genomic mutation signature associated with the immune microenvironment in southern Chinese patients with ESCC.
Topics: Humans; Tumor Microenvironment; Prognosis; Male; Female; Esophageal Squamous Cell Carcinoma; Mutation; Middle Aged; Esophageal Neoplasms; Biomarkers, Tumor; Aged; China; Adult; Genomics; Asian People; East Asian People
PubMed: 38832974
DOI: 10.1007/s00262-024-03725-2 -
Journal of Translational Medicine Jun 2024Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However,...
BACKGROUND
Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression.
METHODS
In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors.
RESULTS
We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer.
CONCLUSION
These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.
Topics: Humans; Breast Neoplasms; Neoplastic Stem Cells; Female; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Transcription, Genetic; Gene Expression Profiling; Cell Line, Tumor; Spheroids, Cellular; Phenotype
PubMed: 38831317
DOI: 10.1186/s12967-024-05281-w -
STAR Protocols Jun 2024T cell acute lymphoblastic leukemia (T-ALL) is a rare but aggressive hematological cancer that occurs primarily in children and adolescents. Here, we present a protocol...
T cell acute lymphoblastic leukemia (T-ALL) is a rare but aggressive hematological cancer that occurs primarily in children and adolescents. Here, we present a protocol for in vitro co-culture assay that enables robust expansion of primary T-ALL cells. We describe steps for seeding T-ALL and stromal cells in 3D organoids and subsequent flow analysis to capture the T-ALL cell growth for long-term culture. This protocol provides a valuable platform for in vitro functional studies and drug screenings using patient-derived cells. For complete details on the use and execution of this protocol, please refer to Rivera et al..
Topics: Humans; Coculture Techniques; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Organoids; Cell Proliferation; Cell Culture Techniques; Tumor Cells, Cultured
PubMed: 38829737
DOI: 10.1016/j.xpro.2024.103103 -
PeerJ 2024Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to comprehensively depict the heterogeneity and identify prognostic targets for PDAC with single-cell RNA sequencing (scRNA-seq) analysis.
METHODS
ScRNA-seq analysis was performed on 16 primary PDAC and three adjacent lesions. A series of analytical methods were applied for analysis in cell clustering, gene profiling, lineage trajectory analysis and cell-to-cell interactions. experiments including colony formation, wound healing and sphere formation assay were performed to assess the role of makers.
RESULTS
A total of 32,480 cells were clustered into six major populations, among which the ductal cell cluster expressing high copy number variants (CNVs) was defined as malignant cells. Malignant cells were further subtyped into five subgroups which exhibited specific features in immunologic and metabolic activities. Pseudotime trajectory analysis indicated that components of various oncogenic pathways were differentially expressed along tumor progression. Furthermore, intensive substantial crosstalk between ductal cells and stromal cells was identified. Finally, genes (REG4 and SPINK1) screened out of differentially expressed genes (DEGs) were upregulated in PDAC cell lines. Silencing either of them significantly impaired proliferation, invasion, migration and stemness of PDAC cells.
CONCLUSIONS
Our findings offer a valuable resource for deciphering the heterogeneity of malignant ductal cells in PDAC. REG4 and SPINK1 are expected to be promising targets for PDAC therapy.
Topics: Humans; Carcinoma, Pancreatic Ductal; Trypsin Inhibitor, Kazal Pancreatic; Pancreatic Neoplasms; Prognosis; Single-Cell Analysis; Transcriptome; Lectins, C-Type; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Female; Male; Pancreatitis-Associated Proteins
PubMed: 38827297
DOI: 10.7717/peerj.17350 -
Cureus Apr 2024Leiomyosarcomas (LMSs) account for 10-20% of all soft-tissue sarcomas (STSs). Soft-tissue sarcomas, and more specifically LMS, typically originate from the uterus,...
Leiomyosarcomas (LMSs) account for 10-20% of all soft-tissue sarcomas (STSs). Soft-tissue sarcomas, and more specifically LMS, typically originate from the uterus, extremity, retroperitoneal, or lower intraabdominal gastrointestinal organs. Due to the rarity and variability in presentation, it is difficult to describe identifiable risk factors, determine etiology, predict disease progression, and prognosticate these types of neoplasms. We present the case of a 77-year-old woman presenting to the emergency department with shortness of breath. After being diagnosed and treated for mild exacerbation of congestive heart failure, she was incidentally found to be anemic. Further workup, including an esophagogastroduodenoscopy, revealed a bleeding gastric mass, which was biopsied. Histopathology and immunohistochemistry confirmed the mass to be primary gastric LMS. Due to its rarity, an interdisciplinary approach involving clinical, histopathologic, and immunohistochemical data is necessary to successfully identify and diagnose gastrointestinal LMS. This case report aims to contribute to the paucity of information available in the literature regarding gastric LMS so that it may be better understood.
PubMed: 38826607
DOI: 10.7759/cureus.59406