Primary Tumor Research Articles

Primary Results of NRG-RTOG1106/ECOG-ACRIN 6697: A Randomized Phase II Trial of Individualized Adaptive (chemo)Radiotherapy Using Midtreatment 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Stage III Non-Small Cell Lung Cancer.

NRG-RTOG0617 demonstrated a detrimental effect of uniform high-dose radiation in stage III non-small cell lung cancer. NRG-RTOG1106/ECOG-ACRIN6697 (ClinicalTrials.gov identifier: NCT01507428), a randomized phase II trial, studied whether midtreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can guide individualized/adaptive dose-intensified radiotherapy (RT) to improve and predict outcomes in patients with this disease. Patients fit for concurrent chemoradiation were randomly assigned (1:2) to standard (60 Gy/30 fractions) or FDG-PET-guided adaptive treatment, stratified by substage, primary tumor size, and histology. All patients had midtreatment FDG-PET/CT; adaptive arm patients had an individualized, intensified boost RT dose to residual metabolically active areas. The primary therapeutic end point was 2-year centrally reviewed freedom from local-regional progression (FFLP), defined as no progression in or near the planning target volume and/or regional nodes. FFLP was analyzed on a modified intent-to-treat population at a one-sided Z-test significance level of 0.15. The primary imaging end point was centrally reviewed change in SUVpeak from baseline to midtreatment; its association with FFLP was assessed using the two-sided Wald test on the basis of Cox regression. Of 138 patients enrolled, 127 were eligible. Adaptive-arm patients received a mean 71 Gy in 30 fractions, with mean lung dose 17.9 Gy. There was no significant difference in centrally reviewed 2-year FFLP (59.5% and 54.6% in standard and adaptive arms; P = .66). There were no significant differences in protocol-specified grade 3 toxicities, survival, or progression-free survival (P > .4). Median SUVpeak and metabolic tumor volume (MTV) in the adaptive arm decreased 49% and 54%, from pre-RT to mid-RT PET. However, ΔSUVpeak and ΔMTV were not associated with FFLP (hazard ratios, 0.997; P = .395 and .461). Midtreatment PET-adapted RT dose escalation as given in this study was safe and feasible but did not improve efficacy outcomes.

Machine learning-based prediction model for brain metastasis in patients with extensive-stage small cell lung cancer

Brain metastases (BMs) in extensive-stage small cell lung cancer (ES-SCLC) are often associated with poor survival rates and quality of life, making the timely identification of high-risk patients for BMs in ES-SCLC crucial. Patients diagnosed with ES-SCLC between 2010 and 2018 were screened from the Surveillance, Epidemiology, and End Results (SEER) database. Four different machine learning (ML) algorithms were used to create prediction models for BMs in ES-SCLC patients. The accuracy, sensitivity, specificity, AUROC, and AUPRC were compared among these models and traditional logistic regression (LR). The random forest (RF) model demonstrated the best performance and was chosen for further analysis. The AUROC and AUPRC were calculated and compared. The findings from the RF model were utilized to identify the risk factors linked to BMs in patients diagnosed with ES-SCLC. Examining 4,716 instances of ES-SCLC, the research conducted an analysis, with brain metastases arising in 1,900 cases. Through evaluation of the ROC curve and PRC concerning the RF Model, results depicted an AUROC of 0.896 (95% CI: 0.889–0.899) and AUPRC of 0.900 (95% CI: 0.895–0.904). Test accuracy measured at 0.810 (95% CI: 0.784–0.833), sensitivity at 0.797 (95% CI: 0.756–0.841), and specificity at 0.819 (95% CI: 0.754–0.879). Based on the SHAP analysis of the RF predictive model, the top 10 most relevant features were identified and ranked in order of relative importance: bone metastasis, liver metastasis, radiation, age, tumor size, primary tumor location, N-stage, race, T-stage, and chemotherapy. The research developed and validated a predictive RF model using clinical and pathological data to predict the risk of BMs in patients with ES-SCLC. This model may assist physicians in making clinical decisions that could delay the onset of BMs and improve patient survival rates.

ACROPath Oligometastases: The American College of Radiation Oncology Clinical Pathway.

Radiation oncology is among the most data-driven specialties in medicine. Recently, a wealth of peer-reviewed data has been published supporting the treatment of oligometastatic malignancies, demonstrating improved survival with metastasis-directed therapy, such as stereotactic body radiation therapy (SBRT), when combined with appropriate patient selection and treatment. However, there are currently few, if any, established guidelines that synthesize the abundance of data specific to radiotherapy into a single, easily accessed resource for clinicians. ACROPath®is a major initiative of the American College of Radiation Oncology (ACRO) that aims to present aggregated clinical pathway data in a highly usable format that is readily accessible to clinicians at the point of care in real time. The oligometastases pathway is the first published algorithm in this collection, with additional pathways anticipated in future publications.Clinical radiation oncologists with expertise in the treatment and management of oligometastatic disease were recruited from across ACRO's diverse membership, including both academic and private practice physicians, to ensure a broad-based experience and insight. Individual participants were assigned subsections of the pathway for guideline development, and then, each subsection was presented to the full group for evaluation and consensus development based on published data. Rather than presenting an unstructured set of treatment options, as is common in other treatment guidelines, this initiative aimed to categorize appropriate treatments based on published clinical evidence in a hierarchy further ranked by efficacy, toxicity, and cost. Based on these strata, treatment recommendations were collated and grouped into three rank categories (gold, silver, or bronze) to denote the degree of applicability.The team assembled an interactive document that will eventually be available online, and it is summarized in detail here. Recommendations are grouped both by the anatomic site of metastasis and by the primary tumor type, recognizing that original histology might impact the treatment differently in different anatomic locations. After a review of available published clinical evidence, the committee reached a consensus on all recommendations presented, categorizing each option as gold, silver, or bronze to guide clinicians appropriately. This first iteration of ACROPath®Oligometastases represents one of the few comprehensive clinical decision support tools available for managing patients with limited metastatic disease. It presents available data in a highly accessible, easily used reference, which will be formally reviewed and updated by the committee as frequently as emerging data requires, likely at six- to 12-month intervals.

Role of 18FDG PET/CT in Detecting Primary Tumors in Patients with Carcinoma of Unknown Primary: Single-Center Cross-Sectional Study from 2017 to 2023 (Extension Study)

AbstractCarcinoma of unknown primary (CUP) is a diverse group of cancers in which the primary tumor site remains occult despite detailed investigations. This is an extension of a published parent study with a smaller cohort, to further validate the published facts of detection efficiency of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG PET/CT) in patients with CUP over a larger sample from 2017 to 2023. Patients with CUP referred for 18FDG PET/CT scan for detection of primary sites during the study period were recruited. 18FDG PET/CT scan was acquired using a standardized protocol, and patients with suspected primary sites underwent biopsies. Scan findings and biopsy results were analyzed to find the detection rate, sensitivity, area under the curve (AUC), and positive predictive value (PPV). As no biopsy was performed in cases with negative scan, these cases were considered false negatives (FNs). Total 230 patients with CUP were included with similar demographic trend (mean age: 58 ± 14 years; 63% male and 37% female; mean body mass index: 26.82 ± 5.4 kg/m2); 138/230 (60 vs. 74% in parent study) patients were found to have a hypermetabolic focus suggestive of primary tumor sites and subjected to biopsy which turned out positive in 127/138 (true positive [TP]: 92 vs. 76% in parent study) and negative in 11/138 (true negative [TN]: 8 vs. 24% in parent study). Sensitivity and PPV of 18FDG PET/CT were 58 and 92%, respectively (68 and 76%, respectively, in parent study). The remaining 92/230 (40%) patients with negative 18FDG PET/CT for primary focus did not have biopsy. No significant demographic difference was seen in patients with TP and FN studies (p > 0.05). Receiver operating characteristics (ROC) curve revealed fair diagnostic strength of 18FDG PET/CT for detecting unknown primary (AUC 0.710; p ≤ 0.05; standard error = 0.0167; confidence interval: 0.647–0.768; vs. nonsignificant in parent study). We conclude that this extension study with a larger cohort compared with the parent study has found a similar detection efficiency of 18FDG PET/CT for identifying primary tumor in patients with CUP (58 vs. 57%) but with better PPV and sensitivity. Upfront use of 18FDG PET/CT in CUP could preclude the use of many futile diagnostic procedures. Furthermore, the use of tumor-specific PET tracers, higher resolution scanners, and acquiring delayed images in patients with negative 18FDG study could reduce FN results in patients with CUP.

Alpha-fetoprotein-producing intramucosal gastric cancer found during examination of metastatic lymph nodes.

Endoscopic resection has been applied as an absolute indication for early gastric cancer showing intramucosal cancer ≤ 2cm in diameter, differentiated-type adenocarcinoma without ulcerative findings. We describe the case of a 76-year-old man who underwent radical gastrectomy for alpha-fetoprotein-producing gastric cancer, in which the depth of invasion was clinically diagnosed as T1a after lymph node metastases were detected. Upper gastrointestinal endoscopy revealed a type 0-IIc tumor nearly 10mm in diameter at the antrum. Computed tomography showed a 47-mm nodule along the common hepatic artery and a 22-mm nodule in the infrapyloric area. Both were pathologically confirmed as adenocarcinoma by endoscopic ultrasound-guided aspiration. No evidence of malignancy elsewhere was seen on 18F-fluorodeoxyglucose positron emission tomography. Serum alpha-fetoprotein level was elevated. Postoperatively, microscopic examination revealed moderately differentiated adenocarcinoma confined to the mucosal layer without lymphovascular involvement. Immunohistochemical examination for alpha-fetoprotein revealed that the metastatic nodes were positive despite the primary tumor being negative. The patient died of exacerbation of myelodysplastic syndrome 5years 8months postoperatively with no recurrence. Our experience suggests the need for further studies to validate whether the indications for endoscopic resection can apply to alpha-fetoprotein-producing gastric cancer in the same manner as to conventional gastric cancer.

Early clinical efficacy of 3D-printed artificial vertebral body in spinal reconstruction after total en bloc spondylectomy for spinal tumors

BackgroundTotal en bloc spondylectomy (TES) is a recognized surgical approach for managing spinal tumors. With advancements in three-dimensional (3D) printing technology, the use of 3D-printed prosthetics for vertebral reconstruction post-tumor resection has gained traction. However, research on the clinical implications of these prosthetics remains limited.MethodsThis retrospective study evaluated patients who underwent TES for primary and metastatic thoracolumbar tumors at the Department of Spinal Surgery, Tianjin Hospital, between October 2017 and September 2020. These patients received anterior reconstruction with 3D-printed artificial vertebral bodies.Results14 patients completed the surgery, with intraoperative blood loss ranging from 1,400 to 4,200 ml (mean 2,767 ± 790 ml) and operative duration between 240 and 520 min (mean 382 ± 75.9 min). The follow-up period extended from 7 to 43 months, with an average of 19.9 ± 9.5 months. Standardized prefabricated prosthetics were utilized in nine patients, while five received customized prosthetics. Throughout the follow-up, there were no reports of posterior connecting rod, 3D-printed prosthetic, or pedicle screw failures. Notably, one patient presented with significant prosthetic subsidence resulting in screw loosening, and three cases of prosthetic subsidence were observed.ConclusionThe incorporation of 3D-printed prosthetics in TES procedures yielded favorable clinical outcomes. Further research is warranted to optimize these prosthetics for enhanced postoperative stability and patient-specific applications.

Berberine inhibits colorectal liver metastasis via modulation of TGF-β in a cecum transplant mouse model.

Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model. The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon-liver metastasis in an animal model, and to elucidate the underlying mechanisms. Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100mg/kg) for 21days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R). The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling. In conclusion, berberine evidently possess an anti-colon-liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC.

Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma.

Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.

Explainable Machine Learning Models Using Robust Cancer Biomarkers Identification from Paired Differential Gene Expression.

In oncology, there is a critical need for robust biomarkers that can be easily translated into the clinic. We introduce a novel approach using paired differential gene expression analysis for biological feature selection in machine learning models, enhancing robustness and interpretability while accounting for patient variability. This method compares primary tumor tissue with the same patient's healthy tissue, improving gene selection by eliminating individual-specific artifacts. A focus on carcinoma was selected due to its prevalence and the availability of the data; we aim to identify biomarkers involved in general carcinoma progression, including less-researched types. Our findings identified 27 pivotal genes that can distinguish between healthy and carcinoma tissue, even in unseen carcinoma types. Additionally, the panel could precisely identify the tissue-of-origin in the eight carcinoma types used in the discovery phase. Notably, in a proof of concept, the model accurately identified the primary tissue origin in metastatic samples despite limited sample availability. Functional annotation reveals these genes' involvement in cancer hallmarks, detecting subtle variations across carcinoma types. We propose paired differential gene expression analysis as a reference method for the discovering of robust biomarkers.

ASO Author Reflections: The Role of Primary Tumor Resection in Liver Metastasis.

ASO Author Reflections: The Role of Primary Tumor Resection in Liver Metastasis.

Advanced Nanoplatform Mediated by CRISPR-Cas9 and Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics.

Immunotherapy combined with phototherapy is emerging as a promising strategy to treat omnipotent cancers. In this study, a clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system, aggregation-induced emission (AIE) photosensitizer (PS) and surface coating of polyethylene imine/hyaluronic acid were combined to construct a multifunctional nanoplatform, denoted as TCPH nanoparticles (NPs), for comprehensive cancer theranostics. TCPH NPs are featured by intrinsic functions including efficient reactive oxygen species (ROS) production, good photothermal conversion, programmed death-ligand 1 (PD-L1)-eliminating capability, and effective intracellular transport. The generated ROS and hyperthermia do not only achieve primary tumor elimination but also regulate the tumor immune microenvironment. Genomic disruption of PD-L1 conspicuously augments its therapeutic efficacy, especially in tumor metastasis and recurrence. Exceptional multimodal imaging navigation has also been developed. Excellent theranostics performance was substantiated in diverse tumor models, implying that this synergistic strategy of phototheranostics and immunotherapy provides a paradigm shift in emerging CRISPR-mediated nanomedicines.

PD-L1 promotes tumor metastasis by regulating the infiltration of FGFBP2(+)Tm cells in colorectal cancer.

Tumor-infiltrating lymphocytes can influence tumorigenesis and progression. We found PD-L1 can inhibit the infiltration of memory T (Tm) cells in vivo and in vitro by reducing the secretion of CXCL9, CXCL10 in colorectal cancer. Patients with high PD-L1 expression have minimal Tm cell infiltration, accompanied with a higher incidence of tumor metastasis. Single-cell sequencing revealed that PD-L1 mainly inhibited the infiltration of a specific Tm cell subset characterized by the expression of FGFBP2 gene. To clarify the distribution of FGFBP2(+)Tm cells, peripheral blood, lymph nodes, colon polyps, primary tumor, and liver metastases samples were collected. As the tumor progressed, the infiltration of FGFBP2(+) memory T cells gradually increased and accumulated in liver metastases. By establishing a mouse metastasis model, we found in high PD-L1 expression group, the luciferin intensity of metastatic tumor was significantly higher, the number of metastatic nodules and the weight of metastases were also increased. The number of FGFBP2(+) Tm cells in peripheral blood and in liver/lung metastases were increased. Therefore, the expression of PD-L1 in primary tumor can promote the occurrence of metastases, and FGFBP2(+)Tm cells may be involved in the formation of metastases. Furthermore, the result showed that the number of FGFBP2(+) Tm cells in metastases was positively correlated with the number of vessels in liver/lung metastases. In conclusion, we confirmed that the expression of PD-L1 in primary tumor can increase the number of FGFBP2(+) Tm cells in peripheral blood and promote tumor metastasis, which is likely to be caused by the angiogenesis of FGFBP2(+) Tm cells in metastases.

Integrated single-cell analysis reveals distinct epigenetic-regulated cancer cell states and a heterogeneity-guided core signature in tamoxifen-resistant breast cancer.

Inter- and intra-tumor heterogeneity is considered a significant factor contributing to the development of endocrine resistance in breast cancer. Recent advances in single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) allow us to explore inter- and intra-tumor heterogeneity at single-cell resolution. However, such integrated single-cell analysis has not yet been demonstrated to characterize the transcriptome and chromatin accessibility in breast cancer endocrine resistance. In this study, we conducted an integrated analysis combining scRNA-seq and scATAC-seq on more than 80,000 breast tissue cells from two normal tissues (NTs), three primary tumors (PTs), and three tamoxifen-treated recurrent tumors (RTs). A variety of cell types among breast tumor tissues were identified, PT- and RT-specific cancer cell states (CSs) were defined, and a heterogeneity-guided core signature (HCS) was derived through such integrated analysis. Functional experiments were performed to validate the oncogenic role of BMP7, a key gene within the core signature. We observed a striking level of cell-to-cell heterogeneity among six tumor tissues and delineated the primary to recurrent tumor progression, underscoring the significance of these single-cell level tumor cell clusters classified from scRNA-seq data. We defined nine CSs, including five PT-specific, three RT-specific, and one PT-RT-shared CSs, and identified distinct open chromatin regions of CSs, as well as a HCS of 137 genes. In addition, we predicted specific transcription factors (TFs) associated with the core signature and novel biological/metabolism pathways that mediate the communications between CSs and the tumor microenvironment (TME). We finally demonstrated that BMP7 plays an oncogenic role in tamoxifen-resistant breast cancer cells through modulating MAPK signaling pathways. Our integrated single-cell analysis provides a comprehensive understanding of the tumor heterogeneity in tamoxifen resistance. We envision this integrated single-cell epigenomic and transcriptomic measure will become a powerful approach to unravel how epigenetic factors and the tumor microenvironment govern the development of tumor heterogeneity and to uncover potential therapeutic targets that circumvent heterogeneity-related failures.

Single-cell RNA-seq analysis of cancer-endothelial cell interactions in primary tumor and peritoneal metastasis from a single patient with colorectal cancer

BackgroundPeritoneal metastasis, a major complication of colorectal cancer (CRC), often leads to poor quality of life and unfavorable outcomes. Despite numerous studies characterizing its biological features in CRC, intratumor heterogeneity and interactions between cancer cells and tumor microenvironment cells remain poorly understood.MethodsTo explore these aspects, we performed single-cell transcriptome analysis of matched primary tumor and peritoneal metastasis samples from a treatment-naïve patient.ResultsOur analysis revealed enrichment of “tip” endothelial cells in the primary tumor, driving angiogenic sprouting, whereas these cells were absent in peritoneal metastases. Moreover, cancer cells in peritoneal metastasis displayed a distinct expression signature associated with epithelial–mesenchymal transition and tumor invasiveness. Analysis of cell–cell communication between endothelial and tumor cells revealed decreased VEGF signaling and increased CXCL–ACKR1 interactions in peritoneal metastasis.ConclusionsAlthough limited by its N-of-1 design and requiring further validation, our study provides preliminary observations suggesting that alterations in cancer-endothelial cell interactions could reduce dependence on VEGF signaling and influence immune cell infiltration in CRC peritoneal metastasis.

Predicting pan-cancer immune-checkpoint therapy and prognosis with a chromatin-accessibility-related alternative splicing signature: a retrospective study

Background: This study examines alternative splicing (AS) events in genes linked to chromatin accessibility in various cancers and their relation to the tumor immune microenvironment. Methods: Data from the Cancer Genome Atlas Database (TCGA) were used to identify independent prognostic factors for pan-cancer. We explored the correlation between differentially expressed genes and tumor immunity, including immune checkpoint genes, tumor development, and immune cells. A regulatory network diagram of alternative splicing-splicing factors (AS-SFs) was constructed to find potential immunotherapy targets. Results: IRF5 and E2F8 genes showed significant differential expression in pan-cancer. Age, cancer grade, primary tumor, cancer lymph nodes, and distant metastasis were independent prognostic factors. The risk model achieved good predictive performance, with AUC values of 0.705, 0.746, 0.743, and 0.743 for 1-year, 3-year, 5-year, and 10-year survival predictions, respectively. Positive correlations were found between IRF5/E2F8 and CD274/CTLA4 in certain cancers using TIMER and CIBERSORT software. Conclusions: AS events in chromatin accessibility genes (IRF5 and E2F8) have significant predictive value in pan-cancer prognosis. Our model assesses patient survival probability and highlights the synergistic impact of immune checkpoints and the AS-SF regulatory network on tumor immunotherapy.

Mitochondrial Dysfunction: Effects and Therapeutic Implications in Cerebral Gliomas.

Gliomas are the most common primary brain tumors, representing approximately 28% of all central nervous system tumors. These tumors are characterized by rapid progression and show a median survival of approximately 18 months. The therapeutic options consist of surgical resection followed by radiotherapy and chemotherapy. Despite the multidisciplinary approach and the biomolecular role of targeted therapies, the median progression-free survival is approximately 6-8 months. The incomplete tumor compliance with treatment is due to several factors such as the presence of the blood-brain barrier, the numerous pathways involved in tumor transformation, and the presence of intra-tumoral mutations. Among these, the interaction between the mutations of genes involved in tumor bio-energetic metabolism and the functional response of the tumor has become the protagonist of numerous studies. In this scenario, the main role is played by mitochondria, cellular organelles delimited by a double membrane and containing their own DNA (mtDNA), which participates in numerous cellular processes such as the regulation of cellular metabolism, cellular proliferation, and apoptosis and is also the main source of cellular energy production. Therefore, it is understood that the mitochondrion, specifically its functional alteration, is a leading figure in tumor transformation, including brain tumors. The acquisition of mutations in the mitochondrial DNA of tumor cells and the subsequent identification of the so-called mitochondria-related genes (MRGs), both functional (mutation of Complex I) and structural (mutations of Complex III/IV), have been seen to play an important role in metabolic reprogramming with increased proliferation, resistance to apoptosis, and the progression of tumorigenesis. This demonstrates that these mitochondrial alterations could have a role not only in the intrinsic tumor biology but also in the extrinsic one associated with the therapeutic response. We aim to summarize the main mitochondrial dysfunction interactions present in gliomas and how they might impact prognosis.

Artificial intelligence-based personalized survival prediction using clinical and radiomics features in patients with advanced non-small cell lung cancer

BackgroundMultiple first-line treatment options have been developed for advanced non-small cell lung cancer (NSCLC) in each subgroup determined by predictive biomarkers, specifically driver oncogene and programmed cell death ligand-1 (PD-L1) status. However, the methodology for optimal treatment selection in individual patients is not established. This study aimed to develop artificial intelligence (AI)-based personalized survival prediction model according to treatment selection.MethodsThe prediction model was built based on random survival forest (RSF) algorithm using patient characteristics, anticancer treatment histories, and radiomics features of the primary tumor. The predictive accuracy was validated with external test data and compared with that of cox proportional hazard (CPH) model.ResultsA total of 459 patients (training, n = 299; test, n = 160) with advanced NSCLC were enrolled. The algorithm identified following features as significant factors associated with survival: age, sex, performance status, Brinkman index, comorbidity of chronic obstructive pulmonary disease, histology, stage, driver oncogene status, tumor PD-L1 expression, administered anticancer agent, six markers of blood test (sodium, lactate dehydrogenase, etc.), and three radiomics features associated with tumor texture, volume, and shape. The C-index of RSF model for test data was 0.841, which was higher than that of CPH model (0.775, P < 0.001). Furthermore, the RSF model enabled to identify poor survivor treated with pembrolizumab because of tumor PD-L1 high expression and those treated with driver oncogene targeted therapy according to driver oncogene status.ConclusionsThe proposed AI-based algorithm accurately predicted the survival of each patient with advanced NSCLC. The AI-based methodology will contribute to personalized medicine.Trial registrationThe trial design was retrospectively registered study performed in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Nagoya University Graduate School of Medicine (approval: 2020 − 0287).

Clinicopathological features and outcomes of rare lung adenocarcinoma metastasis to the thyroid gland: A single-center, 11-year experience.

Metastasis to the thyroid gland from lung adenocarcinoma is rare and challenging to diagnose due to similar histopathological features. This study aimed to analyze the clinicopathological characteristics of and treatment strategies for lung adenocarcinoma metastasis to the thyroid based on 11 years of institutional experience. A retrospective study included patients with lung adenocarcinoma metastasis to the thyroid at our center from 2010 to 2023. Clinicopathological features and clinical outcomes were analyzed. Among 9714 lung adenocarcinoma patients, nine patients (five females, 55.6%) were diagnosed with thyroid metastasis, presenting primarily with cough symptoms. Most patients (88.9%) had synchronous tumors, whereas a minority (11.1%) had metachronous tumors. The median time from primary tumor diagnosis to metastasis was 4.8 months. Most patients developed bilateral thyroid metastases (88.9%). Diagnosis of thyroid metastasis was primarily through fine-needle aspiration (FNA), with one case misdiagnosed as papillary thyroid carcinoma. Immunohistochemical staining revealed thyroid transcription factor-1 (TTF-1) and novel aspartic proteinase of pepsin family A (Napsin-A) positivity and paired box 8 (PAX8) negativity. Genetic testing found epidermal growth factor receptor mutations in 71.4% of patients. The individualized comprehensive therapy included surgery, chemotherapy, immunotherapy, and targeted and supportive therapy. The median overall survival was 56.0 months, with a progression-free survival of 12.7 months. Kaplan-Meier (K-M) analysis suggested improved survival with no advanced symptoms (p = 0.03) and targeted therapies (p = 0.05). Lung adenocarcinoma metastasis to the thyroid is a rare disease, with an incidence of 0.1% among lung adenocarcinoma patients. Early treatment after symptom onset and personalized targeted therapies may improve prognosis. Despite rapid disease progression, favorable outcomes can be achieved with comprehensive treatment.

Abstract B025: Primary and metastatic tumors from triple negative breast cancer possess distinct immunological profiles

Abstract Metastatic triple negative breast cancer (mTNBC) is almost always fatal due to progressive chemoresistance and a lack of therapeutic targets. Stromal cells, including tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs), are linked to differences in prognosis and therapy response. While evidence in primary TNBC demonstrates how TIL characteristics may influence outcomes and treatment efficacy, studies in the metastatic setting are lacking. Here, we aimed to characterize TIL phenotype and localization relative to CAFs and cancer cells between primary and metastatic tumors in mTNBC, and to correlate these features with clinical outcomes. CAF cellularity was assessed in H&amp;E stained sections of 15 primary and 40 metastatic lesions, including brain (n=4), liver (n=5), lymph node (n=3), chest wall (n=4), as well as local (n=12) and distant cutaneous (n=12) metastases. Based on the surface area covered by fibroblasts, CAF cellularity was designated as low (0-33%) or high (34-100%). Immunohistochemical staining (IHC) was performed to identify cytotoxic (CD8+) and regulatory T cells (FOXP3+). Percentages of CD8+ and FOXP3+ cells were quantified with QuPath, and infiltration patterns were assessed by pathologists. Results were correlated with overall survival (OS) and response to treatment after biopsy, which was defined according to RECIST criteria. As expected, metastases had less CD8+ (p=0.02) and FOXP3+ (p=0.007) cells than primary tumors. While CD8+ cells strongly correlated between primary and metastatic tumors (r=0.71, p=0.03), increased FOXP3+ cells in metastases were associated with high CAF regions (p=0.02). CD8+ cells alone were not prognostic; however, infiltration into the epithelium of metastases significantly improved OS (p=0.02). There was a strong correlation between CD8+ and FOXP3+ cell proportions in metastases (r=0.68, p&amp;lt;0.0001) not seen in primary tumors. CD8:FOXP3+ cell ratios in metastases correlated with longer OS (r=0.51, p=0.006) and were increased in patients with stable disease (p=0.02). These findings support the hypothesis that TIL characteristics may significantly affect mTNBC outcomes. We demonstrate that, although metastases have reduced immune presence, a higher CD8:FOXP3+ T cells may indicate a better prognosis in the metastatic setting. Furthermore, the correlation between CD8+ and FOXP3+ cells in metastases across sites, not observed in primary tumors, suggests that immunogenicity in metastases may be governed by different mechanisms than those in primary tumors, possibly contributing to the therapy resistance and worse outcomes observed in metastatic setting. The increased presence of FOXP3+ cells in metastases with high CAF levels suggests that metastatic CAFs promote an immunosuppressive environment, highlighting them as potential therapeutic targets. By identifying CAF-derived factors associated with increased FOXP3+ cell presence, novel therapies may help to overcome immunosuppression, enhance the cytotoxic immune response, and improve treatment efficacy in mTNBC. Citation Format: Alexandra D. Goudreau, Alexandre Penoit, Jade Marie Lasiste, Olga Aleynikova, Khaled Katergi, Josiane Lafleur, Adriana Aguilar-Mahecha, Mark Basik. Primary and metastatic tumors from triple negative breast cancer possess distinct immunological profiles [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B025.

Abstract C013: Single cell analysis reveals tumor size-driven immune changes in primary breast tumors and corresponding lymph nodes

Abstract Introduction A sentinel lymph node is the primary node draining the tumor and is likely affected early in the metastatic process. The sentinel node holds a key position in the immune response against tumor in breast and represents a unique connection between the tumor and the host immune response. Detection of lymph node metastasis is important for staging a patient’s disease and is closely associated with prognosis. Although the clinical significance is debated, isolated tumor cells (&amp;lt;0.2 mm) appear to have no impact on survival while macro-metastasis (&amp;gt;2 mm) are linked to a poorer prognosis. Alterations in the immune response in lymph nodes with large versus small metastases have been observed, but little is known about the relationship between the immune response in the primary tumor and the metastatic status of the corresponding lymph nodes. Methods We analyzed single-cell suspensions from primary tumors and lymph nodes of 38 patients with early, operable breast cancer enrolled in the OSLO2 clinical observational trial using mass cytometry with a 47- antibody immune panel (including PanKeratin and EpCAM). In total 3.7 million single cells were analyzed and clustered into 40 metaclusters using FlowSOM. A second set of 22 metastatic lymph nodes from the OSLO2 cohort was used to validate results form the metastatic tumor cells. Additionally, immunofluorescence with E-cadherin and PanKeratin was applied, and intensity measured in 4 metastatic lymph nodes and imaging mass-cytometry was applied on one metastatic lymph node Results We found that the immune microenvironment in primary tumor was dominated by CD4 and CD8 T cells, particularly of exhausted and memory phenotype and with a higher frequency of activated regulatory T cells (Treg). In contrast, the immune composition in lymph nodes was predominantly composed of naturally occurring naive B and T cells. Notably, in line with previous publications we observed a skewing towards memory and exhausted phenotype in T cells, along with increased abundance of activated Treg in lymph nodes with larger metastasis to those with smaller or no metastasis. Furthermore, there were no correlation between the immune profile in the primary tumor and corresponding lymph node. The immune profile in the primary tumor was influenced by tumor size, with larger tumors showing a higher frequency of activated Tregs and exhausted CD8 T cells. Furthermore, In situ analysis revealed that the microenvironment in smaller metastase had an mesenchymal phenotype, while larger tumor deposits exhibited a more epithelial-like phenotype. ConclusionThe immune profile of the primary tumor did not predict the immune profile or metastatic status of the corresponding lymph node. Tumor size in both primary tumors and metastatic lymph nodes is the main drivers of changes in immune cell composition. Tumor cells from smaller metastases exhibited an mesenchymal phenotype, while larger metastasis displayed an epithelial phenotype. Citation Format: Inga Hansine H. Rye, Marit Otterlei Fjørtoft, Inger Riise Bergheim, Karin Teien Lande, Kanutte H. Huse, June Helen H. Myklebust, Ole Christian H. Lingjærde, Øystein. Garred, Jon H. Lømo, Hege H. Russnes. Single cell analysis reveals tumor size-driven immune changes in primary breast tumors and corresponding lymph nodes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C013.