Specific Tumor Types Research Articles

Au@109Pd Core–Shell Nanoparticles Conjugated to Panitumumab for the Combined β−—Auger Electron Therapy of Triple-Negative Breast Cancer

Apart from HER2-positive, triple-negative breast cancer (TNBC) is the second most highly invasive type of breast cancer. Although TNBC does not overexpress HER2 receptors, it has been observed that EGFR protein expression is present in this specific type of tumor, making it an attractive target for immune and radiopharmaceutical treatments. In our current study, we used 109Pd (T1/2 = 13.7 h) in the form of a 109Pd/109mAg in vivo generator as a source of β− particles and Auger electrons in targeted radionuclide therapy for TNBC. 109Pd, obtained through neutron irradiation of the 108Pd target, was deposited onto 15 nm gold nanoparticles to form Au@109Pd core–shell nanoparticles, which were then conjugated to the panitumumab antibody. Au@109Pd-PEG-panitumumab nanoparticles were bound, internalized, and partially routed to the nucleus in MDA-MB-231 human breast cancer cells overexpressing EGFR receptors. The Au@109Pd-panitumumab radioconjugate significantly reduced the metabolic activity of MDA-MB-231 cells in a dose-dependent manner. In conclusion, we have found that Au@109Pd-PEG-panitumumab nanoparticles show potential as a therapeutic agent for combined β−–Auger electron targeted radionuclide therapy of TNBC. The simultaneous emission of β−, conversion, and Auger electrons from the 109Pd/109mAg generator, similar to 161Tb conjugates, significantly enhances the therapeutic effect. The partial localization of these nanoparticles into the cell nucleus, provided by the panitumumab vector, ensures effective therapy with Auger electrons. This is particularly important for the treatment of drug-resistant TNBC cells.

Signet-ring cell carcinoma of the transverse colon in a 10-year-old girl: A case report

BACKGROUND Signet-ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer. The incidence of primary colonic SRCC is relatively rare in pediatric patients, with a limited number of reported cases currently available. The prognosis for this specific tumor type is unfavorable, and the preoperative diagnosis presents challenges, potentially leading to misdiagnosis. This case report describes the diagnosis of primary SRCC in the colon of a 10-year-old girl. CASE SUMMARY The patient was admitted to the hospital due to abdominal pain and vomiting. A computed tomography scan revealed an irregular mass with soft tissue density in her transverse colon, showing uneven density and multiple calcifications. The patient underwent surgical resection of the affected bowel and lymph node dissection, which was confirmed by pathological examination to be SRCC infiltrating both nerves and the entire intestinal wall. Additionally, tumor thrombus formation was observed in blood vessels and lymphatic vessels, multiple cancerous nodules were found in the omentum, and metastasis to 18 of 26 mesenteric lymph nodes examined. Immunohistochemistry for mismatch repair gene protein demonstrated microsatellite stability. No mutations in KRAS , NRAS , BRAF , or PIK3CA genes were detected through molecular pathology analysis. After surgery, she received standard chemotherapy for 8 cycles without tumor progression or other abnormalities during a 12-month follow-up period. CONCLUSION Primary colonic SRCC is a rare malignant tumor with atypical clinical symptoms, and timely identification and intervention are crucial for improving the prognosis.

Surgical approach to pulmonary metastases and its impact on prognosis.

Pulmonary metastasectomy (PM) is an important procedure for the treatment of metastatic nodules in the lung. The choice of surgical approach, whether thoracotomy or video-assisted thoracoscopic surgery (VATS), remains controversial in terms of the impact on patient prognosis. This study aimed to evaluate the outcomes and impact on survival of patients undergoing PM with VATS compared to thoracotomy. A retrospective evaluation of 136 patients who underwent PM between September 2012 and July 2020 was performed. Data on the demographics, primary tumor histopathology, metastatic features, surgical approach, surgical outcomes, and survival status were analyzed. Statistical analyses included descriptive statistics, survival analysis and Cox regression models. Of the participants, 84 underwent thoracotomy and 52 underwent VATS. The median survival time of thoracotomized patients was 86.6 months, while it was 99.6 months for VATS patients. A gender-specific analysis revealed a significantly longer survival time for female VATS patients compared to thoracotomy. Multivariate analysis showed significant independent effects of specific tumor types and the number of nodes removed on survival. Overall, no significant difference in survival was found between the 2 surgical methods. Both VATS and thoracotomy are effective and safe options for PM. Video-assisted thoracoscopic surgery may offer advantages, particularly in certain patient groups and tumor types, potentially prolonging survival. Gender-specific analyses suggest a survival benefit of VATS, particularly in women. Further studies are needed to validate these results and optimize surgical decision-making in PM.

Autopsy findings in cancer patients infected with SARS-CoV-2 show a milder presentation of COVID-19 compared to non-cancer patients.

COVID-19, caused by SARS-CoV-2, manifests with differing severity across distinct patient subgroups, with outcomes influenced by underlying comorbidities such as cancer, which may cause functional and compositional alterations of the immune system during tumor progression. We aimed to investigate the association of SARS-CoV-2 infection and its complications with cancer in a large autopsy series and the role of COVID-19 in the fatal sequence leading to death. A total of 2641 adult autopsies were investigated, 539 of these were positive for SARS-CoV-2. Among the total number of patients analyzed, 829 had active cancer. Overall, the cohort included 100 patients who simultaneously had cancer and SARS-CoV-2 infection. The course of COVID-19 was less severe in cancer patients, including a significantly lower incidence of viral and bacterial pneumonia, occurring more frequently as a contributory disease or coexisting morbidity, or as SARS-CoV-2 positivity without viral disease. SARS-CoV-2 positivity was more frequent among non-metastatic than metastatic cancer cases, and in specific tumor types including hematologic malignancies. COVID-19 was more frequently found to be directly involved in the fatal sequence in patients undergoing active anticancer therapy, but less frequently in perioperative status, suggesting that the underlying malignancy and consequent surgery are more important factors leading to death perioperatively than viral disease. The course of COVID-19 in cancer patients was milder and balanced during the pandemic. This may be due to relative immunosuppressed status, and the fact that even early/mild viral infections can easily upset their condition, leading to death from their underlying cancer or its complications.

Enhancing brain tumor MRI classification with an ensemble of deep learning models and transformer integration.

Brain tumors are widely recognized as the primary cause of cancer-related mortality globally, necessitating precise detection to enhance patient survival rates. The early identification of brain tumor is presented with significant challenges in the healthcare domain, necessitating the implementation of precise and efficient diagnostic methodologies. The manual identification and analysis of extensive MRI data are presented as a challenging and laborious task, compounded by the importance of early tumor detection in reducing mortality rates. Prompt initiation of treatment hinges upon identifying the specific tumor type in patients, emphasizing the urgency for a dependable deep learning methodology for precise diagnosis. In this research, a hybrid model is presented which integrates the strengths of both transfer learning and the transformer encoder mechanism. After the performance evaluation of the efficacy of six pre-existing deep learning model, both individually and in combination, it was determined that an ensemble of three pretrained models achieved the highest accuracy. This ensemble, comprising DenseNet201, GoogleNet (InceptionV3), and InceptionResNetV2, is selected as the feature extraction framework for the transformer encoder network. The transformer encoder module integrates a Shifted Window-based Self-Attention mechanism, sequential Self-Attention, with a multilayer perceptron layer (MLP). These experiments were conducted on three publicly available research datasets for evaluation purposes. The Cheng dataset, BT-large-2c, and BT-large-4c dataset, each designed for various classification tasks with differences in sample number, planes, and contrast. The model gives consistent results on all three datasets and reaches an accuracy of 99.34%, 99.16%, and 98.62%, respectively, which are improved compared to other techniques.

Research status and controversy on non-small cell lung cancer stem cells.

Lung cancer is a major cause of cancer-related deaths worldwide. It can be divided into 2 main types, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Most patients with NSCLC are diagnosed at an advanced stage, and current treatments have limited success. Moreover, relapsing tumors that often appear after surgical or drug treatment are particularly difficult to treat. The existence of cancer stem cells (CSCs) has been proposed as a key factor contributing to the development of resistance to therapy, recurrence and metastasis. Targeting CSCs is a potential strategy for eradicating tumors. However, due to the tumor-type specificity and cellular plasticity, the real clinical application of lung cancer stem cells (LCSCs) has not been realized. This review details the existing phenotypic markers of LCSCs and the limitations of their identification and summarizes the roles of the tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) in the existence and maintenance of LCSCs, as well as the contribution and controversy of cellular plasticity theory on LCSCs. It is expected that future research on LCSCs can solve the present problems, and approaches targeting LCSCs may be applied in the clinic as soon as possible.

A Comprehensive Target Panel Allows to Extend the Genetic Spectrum of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

An Introduction to Tertiary Lymphoid Structures in Cancer.

Immunotherapy has revolutionized therapeutics for cancer patients, which signifies the importance of effective antitumor immunity in combatting cancer. However, the benefit of immunotherapies is limited to specific patient populations and tumor types, suggesting the overt need for new immunotherapeutic targets. Tertiary lymphoid structures (TLS) are ectopic lymph node-like structures that develop at the sites of chronic inflammation such as cancer. TLS are correlated with favorable clinical outcomes across multiple solid tumors and are associated with increased tumor-infiltrating lymphocytes (TILs), particularly effector memory CD8+ T cells. Despite strong clinical data in humans, there are still major knowledge gaps on the function of TLS in cancer. Herein, we highlight the known biology and clinical impact of TLS, which offer further evidence to harness TLS for improved immunotherapeutics.

BIOM-61. CSF CTDNA ANALYSIS OF PATIENTS WITH DIFFUSE GLIOMAS REVEALS DIAGNOSTIC MOLECULAR ALTERATIONS

Abstract There is a critical need for better strategies to diagnose and monitor patients with diffuse gliomas. Liquid biopsies are less invasive than tissue biopsies and are amenable to serial collection at multiple timepoints. However, analysis of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) in patients with diffuse gliomas remains underutilized in clinical practice due to technical challenges and a scarcity of studies demonstrating clinical utility. We evaluated ctDNA in 49 CSF samples from patients with various types of diffuse gliomas with a next generation sequencing (NGS) panel interrogating 613 cancer-related genes. Cell-free DNA concentration obtained from CSF (0.4-5mL) ranged from 0.009 to 60ng/µL. Input DNA concentration ranged from 0.12-30ng. Mutations were detected in 29/49 (59.2%) samples including 22/49 (44.9%) with single nucleotide changes, 14/49 (28.6%) with copy number changes, and 1 fusion (2.0%). The majority of samples without mutations detected (n=20) had suboptimal DNA input (<30ng): 17/20 (85%). We identified diagnostic alterations in CSF including mutations in IDH1 (3/5 IDH-mutant gliomas), TERTp and EGFR amplification (7/34 glioblastomas), H3-3A (4/6 pediatric high-grade gliomas). Some of these mutations, in combination with other clinical parameters, allowed us to identify specific CNS tumor types based on the 2021 WHO classification of CNS tumors, resulting in the reclassification of 2 patients. Matched tumor tissue sequencing results were available for 23/49 (46.9%) patients and the results showed good concordance with CSF ctDNA analysis. In summary, our results suggest that the NGS analysis of CSF-ctDNA can provide clinically relevant information in patients with diffuse gliomas.

IMMU-07. THE IMMUNE LANDSCAPE OF PEDIATRIC BRAIN TUMORS: A TRANSCRIPTOMIC ANALYSIS

Abstract Despite standard-of-care therapy, pediatric brain tumors are now the leading cause of cancer-related death in children, highlighting an urgent need for the development of new treatments. Immunotherapy is actively being evaluated as a therapeutic approach to pediatric brain tumors, however, more research is needed to reveal additional antigenic targets that exist in these malignancies. In this study, our team performed a transcriptomic analysis of pediatric brain tumor RNA sequencing data within the Children’s Brain Tumor Network (CBTN) to identify intra and extracellular antigens that are highly expressed across major tumor types. Interestingly, our team observed that most tumors had high gene expression of a group of antigens that were unique to that specific tumor type. Specifically, our analysis revealed that diffuse midline gliomas (DMGs) highly expressed the extracellular antigens CA9, CTCFL, and ST8SIA1, whereas atypical rhabdoid tumors (ATRTs) highly expressed MUC1 and TEK. Other tumors that displayed high gene expression for a variety of antigenic targets included H3-wildtype high-grade gliomas (HGGs), and ependymomas (EPNs). Strikingly, we observed minimal difference in antigen expression in primary tumors when compared to patient-matched recurrences. Beyond antigen expression, we evaluated the expression of antigen processing machinery (APM) which includes major histocompatibility complexes (MHCs). Our findings revealed that DMGs had the lowest level of APM expression, however, these tumors uniquely expressed high levels of the immune checkpoints ADORA2A, CD276, and KLRC1. Contrarily, ATRTs showed a high expression of immune checkpoints CD274 (PD-L1), PVR, and CD80. Other tumors included in our analysis had unique expression patterns of antigen, as well as APM and immune checkpoints. Our findings illustrate that pediatric brain tumors have distinct expression patterns of antigens, APM, and immune checkpoints that are specific to tumor type, emphasizing diverse, rather than general, immunotherapeutic approaches must be considered for childhood brain tumors.

Surgery With or Without Radiotherapy Versus Radiotherapy Alone for Malignant Spinal Cord Compression: An Updated Meta-analysis.

A systematic review and meta-analysis. To conduct a meta-analysis of studies that compared surgery with or without radiotherapy to radiotherapy alone for patients with malignant spinal cord compression, and a subgroup analysis of patients stratified by hematologic and solid malignancies. Two previous meta-analyses showed that surgery with or without radiotherapy was better than radiotherapy alone in patients with malignant spinal cord compression. Nevertheless, there was no stratification by tumor type, leading to uncertainty regarding best approach for patients with hematologic malignancies. We searched PubMed, Scopus, and Web of Science, for studies comparing surgery with or without radiotherapy to radiotherapy alone in patients with malignant spinal cord compression. The primary outcomes were improvement in ambulatory status and survival at 12 months. For neurological outcomes, we included studies involving both locally advanced primary malignancies of the spine and metastatic tumors. We restricted our analysis to studies on metastases for survival outcomes. We included 2536 patients from 18 studies. Surgery was performed in 890 (35%) patients. The pooled analysis of all studies revealed that improvement in ambulatory status (OR 2.65; 95% CI 1.60-4.39) and survival at 12 months (OR 1.66; 95% CI 1.10-2.52) were significantly higher in patients who underwent surgery with or without radiotherapy. Improvement in ambulatory status (OR 1.92; 95% CI 1.19-3.09) and survival at 12 months (OR 4.24; 95% CI 2.35-7.66) were significantly higher in patients with hematologic malignancies in the surgical arm. The primary outcomes were not significantly different between patients with solid malignancies. Surgical intervention demonstrates superior neurological outcomes and increased survival compared with radiotherapy alone. Subgroup analysis revealed that patients with hematologic malignancies on surgery group experienced superior primary outcomes; however, high risk of bias of the included studies preclude definitive changes in standard care based on this data. These findings underscore the need for further research regarding the efficacy of surgical versus radiotherapeutic approaches for specific tumor types. 2.

Three-Dimensional Model Analysis Revealed Differential Cytotoxic Effects of the NK-92 Cell Line and Primary NK Cells on Breast and Ovarian Carcinoma Cell Lines Mediated by Variations in Receptor-Ligand Interactions and Soluble Factor Profiles.

Background/objectives: The functional activity of a certain tumor determines the effectiveness of primary NK cells and NK-92 cell line-based cancer therapy; their therapeutic effectiveness against different tumors can vary. This work provides a direct simultaneous comparison of the cytotoxic effects of in vitro-activated peripheral NK (pNK) cells and NK-92 cells in spheroid models of BT-474, MCF7 and SKOV-3 carcinomas and uncovers the reasons for the differential effectiveness of NK cells against tumors. Methods: Tumor spheroids of similar size and shape, obtained from agarose molds, were incubated with NK-92 or pNK cells for 24 h. Tumor cell death was detected using flow cytometry or confocal microscopy. Cytokine production, granzyme B levels and NK cell degranulation analyses were performed, along with pNK and target-cell phenotypic characterization. Results: While NK-92 and pNK cells lysed BT-474 spheroids with comparably low efficiency, pNK cells were more capable of eliminating MCF7 and SKOV-3 spheroids than NK-92 cells were. The results of the functional and phenotypic analyses strongly support the participation of the NKG2D-NKG2DL pathway in pNK cell activation induced by the most sensitive cytotoxic attack on SKOV-3 spheroids, whereas the CX3CR1-CX3CL1 axis appears to be involved in the pNK reaction against MCF-7 spheroids. Conclusions: We provide a new approach for the preliminary identification of the most promising NK cell receptors that can alter the effectiveness of cancer therapy depending on the specific tumor type. Using this approach, NK-92 cells or pNK subsets can be selected for further accumulation and/or genetic modification to improve specificity and reactivity.

Formononetin suppresses the malignant progression of papillary thyroid carcinoma depending on downregulation of CBX4.

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the endocrine system globally. Formononetin (FMNT), an isoflavonoid, exerts anti-tumorigenic effects and chromobox homolog 4 (CBX4) exerts tumor-promoting effect in specific types of tumors. Nevertheless, the predictive values and biological functions of FMNT and CBX4 in the pathological progress of PTC have not been fully understood till now. In the present study, the human PTC cell line TPC-1 was exposed to 0, 10, 30 and 100 µM FMNT for 24 h to elucidate the precise effects of FMNT on the biological behaviors of PTC cells. Moreover, FMNT-treated TPC-1 cells were transfected with oe-CBX4 to evaluate whether CBX4 was implicated in the anticarcinogenic effects of FMNT against PTC. It was demonstrated that FMNT treatment suppressed the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells in a dose-dependent manner. Furthermore, it was verified that FMNT targeted CBX4 to downregulate its expression in a dose dependent manner. The suppressive effects of FMNT on the proliferation, clone formation, migration, invasion, EMT, angiogenesis and stemness of PTC cells were partially reversed by CBX4 overexpression. Upregulation of CBX4 abolished the tumor suppression effects of FMNT in the malignant progression of PTC. In conclusion, FMNT might act as a promising anti-tumorigenic agent in PTC, which depends on the downregulation of CBX4.

Surgical Treatment and Clinical Evaluation of Calvarial Metastases.

The aim of this study is to explore surgical treatment techniques and clinical attributes associated with calvarial metastases, while providing a comprehensive review of the treatment experiences relevant to this particular type of tumor. This study involves a retrospective analysis of clinical data from 12 patients diagnosed with calvarial metastatic tumors who underwent surgical intervention. Among these patients, 5 had a history of previous malignant tumor resections, while 7 presented with calvarial metastatic tumors as their initial symptom. In all cases, the surgical approach consisted of calvarial tumor resection followed by titanium mesh repair. Following the surgical intervention, all patients underwent a comprehensive course of treatment, encompassing both local radiotherapy and systemic chemotherapy. In 1 instance, a patient presented with multiple tumors located in the central area of the frontal bone and the right temporal bone. The larger tumor situated in the middle of the frontal bone was surgically excised, while the tumor in the right temporal bone was treated using radiotherapy. In 2 cases characterized by multiple metastases within the skull, a comprehensive excision of all tumors was accomplished in a single surgical procedure. In the remaining cases featuring a solitary metastatic growth, the respective tumors were surgically removed. There were 10 instances of dura mater invasion and 3 cases involving the invasion of brain tissue. Pathologic examinations revealed 1 case of metastatic lung adenocarcinoma, 1 case of metastatic paraganglioma, 1 case of metastatic hepatocellular carcinoma, 2 cases of metastatic thyroid carcinoma, and 7 cases of metastatic clear cell renal cell carcinoma. Throughout the follow-up period, spanning from 14 to 90 months, various outcomes were noted. These included three occurrences of in situ recurrence. In addition, 1 patient required 3 distinct surgical interventions, while 2 other patients underwent 2 separate surgical procedures each. Notably, 1 of these cases involved the exposure of the titanium mesh on the scalp, necessitating the removal of the titanium mesh. Regrettably, there have been 9 recorded fatalities among the patients, while 3 individuals have survived. Solitary metastasis of calvarium region is rare, and surgical resection is effective. However, it is necessary to extend the resection range and combine with local radiotherapy to avoid local recurrence. Surgical intervention can significantly enhance the quality of life for affected patients. The prognosis of the patients mainly depends on the treatment of the primary disease and the situation of important organ dissemination and treatment.

Health Disparities among Patients with Cancer Who Received Molecular Testing for Biomarker-Directed Therapy.

Health disparities present a barrier to successful oncology treatment. The potential for precision oncology to reduce health disparities has not previously been analyzed. We performed a retrospective analysis of 12,627 patients from six major cancer centers whose tumors underwent molecular testing at Caris Life Sciences between 2010 and 2020. Kaplan-Meier and Cox regression were used to describe and analyze overall survival. The molecular and demographic features of the cohort were analyzed by χ2 and ANOVA tests. Black patients composed 25% of the cohort and White patients 63%. Among this molecularly-tested cohort, there were minimal outcome differences based on race, geographic location, or poverty level. When analyzing the interaction of age, race, and sex, racial-based disparities were noted primarily for young non-White women in the study cohort but were more pronounced for men and women of all ages in the broader patient population within the Surveillance, Epidemiology, and End Results database. Mutations in five genes-APC, EGFR, STK11, TP53, and KRAS-were found to affect overall survival among our cohort, and their prevalence varied by race in specific tumor types. Real-world outcomes data in mutation-defined cohorts also provided additional context to previously reported therapeutic response trends. Our study shows that patients who undergo molecular testing display reduced racial health disparities compared with the general population, whereas persistent racial disparities are influenced by age and sex. Genomic-driven racial disparities should be examined at a tumor lineage-specific level. Increased access to molecular testing for all eligible patients may play a role in improving health equity. Significance: This study is the largest of its kind to analyze health disparities and genomic features among a diverse multiinstitutional cohort of patients who underwent molecular testing. Continuing to increase awareness of and access to molecular testing approaches may help to reduce cancer health disparities and improve outcomes for all patients.

Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.

Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology. Built on Google's Gemini Pro LLM, MEREDITH uses retrieval-augmented generation and chain of thought. We evaluated MEREDITH on 10 publicly available fictional oncology cases with iterative feedback from a molecular tumor board (MTB) at a major German cancer center. Initially limited to PubMed-indexed literature (draft system), MEREDITH was enhanced to incorporate clinical studies on drug response within the specific tumor type, trial databases, drug approval status, and oncologic guidelines. The MTB provided a benchmark with manually curated treatment recommendations and assessed the clinical relevance of LLM-generated options (qualitative assessment). We measured semantic cosine similarity between LLM suggestions and clinician responses (quantitative assessment). MEREDITH identified a broader range of treatment options (median 4) compared with MTB experts (median 2). These options included therapies on the basis of preclinical data and combination treatments, expanding the treatment possibilities for consideration by the MTB. This broader approach was achieved by incorporating a curated medical data set that contextualized molecular targetability. Mirroring the approach MTB experts use to evaluate MTB cases improved the LLM's ability to generate relevant suggestions. This is supported by high concordance between LLM suggestions and expert recommendations (94.7% for the enhanced system) and a significant increase in semantic similarity from the draft to the enhanced system (from 0.71 to 0.76, P = .01). Expert feedback and domain-specific data augment LLM performance. Future research should investigate responsible LLM integration into real-world clinical workflows.

Combination screen in multi-cell type tumor spheroids reveals interaction between aryl hydrocarbon receptor antagonists and E1 ubiquitin-activating enzyme inhibitor

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates genes of drug transporters and metabolic enzymes to detoxify small molecule xenobiotics. It has a complex role in cancer biology, influencing both the progression and suppression of tumors by modulating malignant properties of tumor cells and anti-tumor immunity, depending on the specific tumor type and developmental stage. This has led to the discovery and development of selective AhR modulators, including BAY 2416964 which is currently in clinical trials. To identify small molecule anticancer agents that might be combined with AhR antagonists for cancer therapy, a high-throughput combination screen was performed using multi-cell type tumor spheroids grown from malignant cells, endothelial cells, and mesenchymal stem cells. The AhR selective antagonists BAY 2416964, GNF351, and CH-223191 were tested individually and in combination with twenty-five small molecule anticancer agents. As single agents, BAY 2416964 and CH-223191 showed minimal activity, whereas GNF351 reduced the viability of some spheroid models at concentrations greater than 1 µM. The activity of most combinations aligned well with the single agent activity of the combined agent, without apparent contributions from the AhR antagonist. All three AhR antagonists sensitized tumor spheroids to TAK-243, an E1 ubiquitin-activating enzyme inhibitor. These combinations were active in spheroids containing bladder, breast, ovary, kidney, pancreas, colon, and lung tumor cell lines. The AhR antagonists also potentiated pevonedistat, a selective inhibitor of the NEDD8-activating enzyme E1 regulatory subunit, in several tumor spheroid models. In contrast, the AhR antagonists did not enhance the cytotoxicity of the proteasome inhibitor bortezomib.

Characterization of the Rat Osteosarcoma Cell Line UMR-106 by Long-Read Technologies Identifies a Large Block of Amplified Genes Associated with Human Disease.

The rat osteosarcoma cell line UMR-106 is widely used for the study of bone cancer biology but it has not been well characterized with modern genomic methods. To better understand the biology of UMR-106 cells we used a combination of optical genome mapping (OGM), long-read sequencing nanopore sequencing and RNA sequencing.The UMR-106 genome was compared to a strain-matched Sprague-Dawley rat for variants associated with human osteosarcoma while expression data were contrasted with a public osteoblast dataset. Using the COSMIC database to identify the most affected genes in human osteosarcomas we found somatic mutations in Tp53 and H3f3a. OGM identified a relatively small number of differences between the cell line and a strain-matched control animal but did detect a ~45 Mb block of amplification that included Myc on chromosome 7 which was confirmed by long-read sequencing. The amplified region showed several blocks of non-contiguous rearranged sequence implying complex rearrangements during their formation and included 14 genes reported as biomarkers in human osteosarcoma, many of which also showed increased transcription. A comparison of 5mC methylation from the nanopore reads of tumor and control samples identified genes with distinct differences including the OS marker Cdkn2a. This dataset illustrates the value of long DNA methods for the characterization of cell lines and how inter-species analysis can inform us about the genetic nature underlying mutations that underpin specific tumor types. The data should be a valuable resource for investigators studying osteosarcoma, in general, and specifically the UMR-106 model.

A pan-cancer analysis ofWnt family member 7Bin human cancers.

Previous studies have highlighted the crucial role of Wnt7B in the development of various cancers, including breast, pancreatic, and gastric cancers. However, research into the involvement of Wnt7B is often confined to specific tumor types, with a noticeable lack of comprehensive studies spanning multiple cancer forms. The potential of Wnt7B as a diagnostic or prognostic cancer biomarker has not been fully explored. In this study, we combined bioinformatics and immunohistochemistry analyses to examine the expression patterns and functions of Wnt7B in cancerous and adjacent noncancerous tissues across a range of tumors. Our data indicate that Wnt7B may serve as a novel prognostic biomarker and therapeutic target in certain cancers. We found significant upregulation of Wnt7B expression levels in the majority of cancer cases examined. Furthermore, Wnt7B can influence cancer prognosis by modulating the tumor microenvironment, immune cell infiltration, and tumor stemness, among other factors. Additionally, we examined the associations between anticancer drug sensitivity and Wnt7B expression, which could aid in the development of more precise clinical therapies.

Aneuploidy in neoplasia: Single-cell data on 83,862 tumors.

Chromosomal aneuploidy, that is, numerical chromosome aberrations, is one of the molecular hallmarks of cancer. However, when neoplasms are studied with sequencing- and array-based approaches, chromosome numbers and ploidy states are typically inferred from bulk DNA data. Furthermore, published molecular estimates of neoplasia-associated aneuploidy often also include genomic imbalances resulting from various types of structural rearrangement, which likely result from other mechanisms than numerical chromosome aberrations. We thus analyzed chromosome numbers using single-cell cytogenetic data from 83,862 tumors, and show that both benign and malignant tumors are highly heterogeneous with regard to deviations from the normal, diploid state. Focusing on the chromosome numbers in 112 specific tumor types, defined by both exact morphologic diagnosis and organ location and from which data from ≥50 cases were available, we found two major clusters: one predominated by near-diploid neoplasms and one by neoplasms with extensive aneuploidy and one or more whole genome doublings. The former cluster included most benign solid tumors, myeloid neoplasms, and malignant gene fusion-associated solid tumors, whereas the latter was predominated by malignant solid tumors and lymphomas. For 16 malignant tumor types, the distribution of chromosome numbers could be compared to TCGA ploidy level data. Cytogenetic and molecular data correlated well, but the former indicates a higher level of clonal heterogeneity. The results presented here suggest shared pathogenetic mechanisms in certain tumor types and provide a reference for molecular analyses.