Occurrence Of Lung Metastases Research Articles

Clinical characteristics and predisposing factors of lung metastasis in sacral chordoma: a cross-sectional cohort study of 221 cases.

Limited studies are available on the topic of lung metastasis in sacral chordoma. The primary objective of this study was to investigate the prevalence, characteristics, associated factors, and prognosis of lung metastasis in sacral chordoma. A total of 221 cases with primary sacral chordoma, all of whom underwent surgical resection at our center, were included in this study. Comprehensive demographic information, imaging findings, and oncological evaluations were collected and thoroughly analyzed. The diagnosis of lung metastasis in the majority of cases was established through radiographic examinations. The prevalence of lung metastasis in the cohort was 19.5%, with the lung emerging as the predominant site of distant metastasis. Recurrent chordoma cases exhibited a significantly higher lung metastasis rate in comparison to newly diagnosed chordoma cases (33.33% and 12.76%, p=0.0005). Patients with lung metastasis had a larger tumor size, a higher proportion of previous sacral chordoma surgeries and a greater likelihood of postoperative recurrence. Associated factors of lung metastasis were tumor size, postoperative recurrence and radiotherapy. Patients with lung metastasis exhibited decreased median overall survival (91 vs. 144 months for those without lung metastasis, p<0.05) and recurrence-free survival (27 vs. 68 months, p<0.001) times. Lung is the most common site of distant metastasis in sacral chordoma with an incidence rate nearly 20%. Larger tumor size and postoperative recurrence are risk factors for lung metastasis while radiotherapy is a protective factor. Occurrence of lung metastasis in sacral chordoma is a negative prognostic factor.

Quercetin inhibits chronic stress-mediated progression of triple-negative breast cancer by blocking β2-AR/ERK1/2 pathway

Chronic stress-mediated sustained release of neurotransmitters, which ultimately leads to the activation of β2-adrenergic receptor (β2-AR) signaling, is one of the most important reasons for triple-negative breast cancer (TBNC) progression. Quercetin (Que) has been proven to have the advantage of ameliorating stress psychological disorder. Our present study aimed to investigate the effect of Que on tumor growth and metastasis in TNBC xenograft mice undergoing stress, and to explore its underlying mechanisms. We first evaluated the effect of Que on the progression of TNBC in nude mice in vivo. The results showed that, Que could inhibit chronic stress-induced TNBC growth and occurrence of lung metastasis. We subsequently employed epinephrine (E) as a representative of stress hormone to investigate its possible mechanism in vitro. The results showed that, Que could inhibit E-mediated proliferation and migration of TNBC cells by blocking β2-AR/ERK1/2 pathway. In conclusion, our data demonstrated that Que could inhibit chronic stress-induced ERK1/2 activity in TNBC cells, and thereby weakening the potential for TNBC growth and metastasis.

A148 OSTEOSARCOMA GASTROINTESTINAL METASTASIS: A RARE ENTITY IN ADULTS

Abstract Background Osteosarcoma is highly aggressive and is the most common primary bone malignancy for both children and adults with a bimodal age distribution. The first peak coincides with pubertal growth spurt and the second is in the seventh and eighth decade of life. They frequently metastasize to the lungs. Metastasis to the gastrointestinal tract is extremely rare and to our knowledge, there have only been 15 cases reported in the literature since 1987, of those only three in the second peak. Aims Describe a case of 61-year-old female with periampullary metastatic osteosarcoma. Describe the demographics of osteosarcoma patients who develop gastrointestinal metastasis. Methods Search Pubmed using the terms: ("Osteosarcoma"[MeSH Terms] OR "Osteosarcoma"[Title/Abstract]) AND ("Gastrointestinal Tract"[MeSH Terms] OR "Gastrointestinal Tract"[Title/Abstract] AND "Case Reports"[Publication Type]. 113 articles were identified and screened by title. 15 articles were further screened by abstract or full text. 7 articles were identified. the remainder 7 articles were located by screening the references of the previously identified articles. Results A 61-year-old woman with a medical history significant for metastatic Osteosarcoma was referred to Gastroenterology clinic July 2023 for anemia investigation. Her Osteosarcoma was first diagnosed in the left femur in 2009. She was known for extensive bilateral lung metastasis, subcutaneous metastatic deposits, and distant bone metastasis. She had undergone over 37 surgeries and multiple sessions of radiotherapy. Aside from neoadjuvant and adjuvant chemotherapy for the primary tumor and the first occurrence of lung metastasis, she refused to undergo further cycles of chemotherapy. She had a 60 mg/dl hemoglobin drop from a previous one in December 2023 and intermittent melena. On gastroscopy, she was found to have a 2 cm bleeding mass in the periampullary area. The pathology report of the biopsies was consistent with metastatic osteosarcoma. It showed fragments of ampullary mucosa incorporating a malignant spindle cell neoplasm with a fascicular growth pattern, including scattered osteoclast-like giant cells, morphologically consistent with the known history of metastatic osteosarcoma. Of the 15 cases published, 9 were in patients 27 years old and younger, 3 were in patients 50 and older, and 3 were only available as titles. 50% of cases presented with intussusception while the rest had anemia or melena. The site of metastasis was the jejunum in the majority of patients (58%). Other sites included the ileum, stomach, colon, and esophagus. Only one other patient had periampullary metastasis. All patients had lung metastasis. Conclusions Gastrointestinal metastasis of osteosarcoma remains a rare occurrence. Our case report describes the second case reported in the literature of periampullary metastasis and the first case reported in older patients Funding Agencies None

Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma

BackgroundRisk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment.MethodsHigh-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated.ResultsHigh-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors.ConclusionsOncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.

Medical and Personal Characteristics Can Predict the Risk of Lung Metastasis

AimsUnderstanding the correlations between underlying medical and personal characteristics of a patient with cancer and the risk of lung metastasis may improve clinical management and outcomes. We used machine learning methodologies to predict the risk of lung metastasis using readily available predictors. Materials and methodsWe retrospectively analysed a cohort of 11 164 oncological patients, with clinical records gathered between 2000 and 2020. The input data consisted of 94 parameters, including age, body mass index (BMI), sex, social history, 81 primary cancer types, underlying lung disease and diabetes mellitus. The strongest underlying predictors were discovered with the analysis of the highest performing method among four distinct machine learning methods. ResultsLung metastasis was present in 958 of 11 164 oncological patients. The median age and BMI of the study population were 63 (±19) and 25.12 (±5.66), respectively. The random forest method had the most robust performance among the machine learning methods. Feature importance analysis revealed high BMI as the strongest predictor. Advanced age, smoking, male gender, alcohol dependence, chronic obstructive pulmonary disease and diabetes were also strongly associated with lung metastasis. Among primary cancers, melanoma and renal cancer had the strongest correlation. ConclusionsUsing a machine learning-based approach, we revealed new correlations between personal and medical characteristics of patients with cancer and lung metastasis. This study highlights the previously unknown impact of predictors such as obesity, advanced age and underlying lung disease on the occurrence of lung metastasis. This prediction model can assist physicians with preventive risk factor control and treatment strategies.

A clinically feasible circulating tumor cell sorting system for monitoring the progression of advanced hepatocellular carcinoma

BackgroundHematogenous metastasis is essential for the progression of advanced hepatocellular carcinoma (HCC) and can occur even after patients receive multidisciplinary therapies, including immunotherapy and hepatectomy; circulating tumor cells (CTCs) are one of the dominant components of the metastatic cascade. However, the CTC capture efficiency for HCC is low due to the low sensitivity of the detection method. In this study, epithelial cell adhesion molecule (EpCAM)/vimentin/Glypican-3 (GPC3) antibody-modified lipid magnetic spheres (LMS) were used to capture tumor cells with epithelial phenotype, mesenchymal phenotype and GPC3 phenotype, respectively, in order to capture more CTCs with a more comprehensive phenotype for monitoring tumor metastasis.ResultsThe novel CTC detection system of Ep-LMS/Vi-LMS/GPC3-LMS was characterized by low toxicity, strong specificity (96.94%), high sensitivity (98.12%) and high capture efficiency (98.64%) in vitro. A sudden increase in CTC counts accompanied by the occurrence of lung metastasis was found in vivo, which was further validated by a clinical study. During follow-up, the rapid increase in CTCs predicted tumor progression in HCC patients. Additionally, genetic testing results showed common genetic alterations in primary tumors, CTCs and metastatic tissues. The proportion of patients predicted to benefit from immunotherapy with the CTC detection method was higher than that for the tissue detection method (76.47% vs. 41.18%, P = 0.037), guiding the application of clinical individualized therapy.ConclusionsThe Ep-LMS/Vi-LMS/GPC3-LMS sequential CTC capture system is convenient and feasible for the clinical prediction of HCC progression. CTCs captured by this system could be used as a suitable alternative to HCC tissue detection in guiding immunotherapy, supporting the clinical application of CTC liquid biopsy.

RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with the worst prognosis, and tumor recurrence and metastasis are the main factors leading to poor prognosis of HCC patients. Accumulating studies show that RNF126, ring finger protein 126, is involved in the pathological process of many tumors. However, the biological function and exact molecular mechanism of RNF126 in HCC remain unclear. In this study, we investigated the role of RNF126 in the pathogenesis of HCC. By analyzing database and verifying with our clinical specimens, it was found that RNF126 was highly expressed in HCC tissues, which is associated with shorter overall survival and higher recurrence rate. Overexpressed RNF126 can significantly promote the proliferation, migration, invasion and angiogenesis of HCC cells, whereas knockdown RNF126 can reverse this effect. Mechanically, RNF126 down-regulates liver kinase B1 (LKB1) expression by ubiquitination of LKB1 to weaken its stability, thereby significantly promoting stem-cell-like activity, migration, and angiogenesis of HCC. Notably, consistent with in vitro results, RNF126 was stably transformed in Hep3B and subcutaneously injected into nude mice. In established mouse xenograft models, tumor growth can be effectively inhibited and the occurrence of lung metastasis is reduced. In HCC, RNF126 may down-regulate LKB1 through ubiquitination, thus becoming a powerful prognostic biomarker and a recognized tumor suppressor. Therefore, our study may provide a promising new therapeutic strategy for targeting RNF126 for HCC patients.

Stereotactic Body Radiation Therapy for Lung Metastases From Sarcoma in Oligometastatic Patients: A Phase 2 Study

The lung is the most frequent site of metastasis in patients with sarcoma. Pulmonary metastasectomy is the most common treatment performed. Stereotactic body radiation therapy (SBRT) has proven to be a potential alternative to resection. This prospective phase 2 study aimed to assess the role of SBRT for patients with lung metastases. Adult patients with up to 4 lung metastases (LMs) ≤5 cm in diameter and unsuitable for surgery were included. Dose prescription was based on site and size: 30 Gy/1 fraction for peripheral lesions ≤10 mm, 60 Gy/3 fractions for peripheral lesions 11 to 20 mm, 48 Gy/4 fractions for peripheral lesions >20 mm, and 60 Gy/8 fractions for central lesions. The primary endpoint was the proportion of treated lesions free from progression at 12 months. Secondary endpoints were disease-free survival (DFS), overall survival (OS), and toxicity. Between March 2015 and December 2020, 44 patients with a total of 71 LMs were enrolled. Twelve-month local control was 98.5% ± 1.4%, reaching the primary aim; the median DFS time was 12 months (95% CI, 8-16 months), and the 1-, 2-, 3-, 4-, and 5-year PFS rates were 50% ± 7.5%, 19.5% ± 6.6%, 11.7% ± 5.8%, 11.7% ± 5.8%, and 11.7% ± 5.8%, respectively. The median OS time was 49 months (95% CI, 24-49 months), and the 1-, 2-, 3-, 4-, and 5-year OS rates were 88.6% ± 4.7%, 66.7 ± 7.6%, 56.8% ± 8.4%, 53.0% ± 8.6%, and 48.2% ± 9.1%, respectively. Prognostic factors recorded as significantly affecting survival were age, grade of primary sarcoma, interval time from diagnosis to occurrence of LMs, and number of LMs. No severe pulmonary toxicity (grade 3-4) occurred. The study found a local control of LMs in almost all patients treated, with negligible toxicity. Survival was also highly satisfactory. Well-designed randomized trials comparing surgery with SBRT for patients with metastatic lung sarcoma are needed to confirm these preliminary data.

Systematic Pan-Cancer Population-Based Analysis Reveals the Incidence and Prognosis of Lung Metastases at Diagnosis.

Background Metastasis is one of the most prevalent causes of death in cancer patients and the lungs are among the organs most commonly affected by metastasis. However, analysis of the incidence and prognosis of lung metastasis (LM) based on primary cancer sites is lacking. Methods We enrolled cancer patients with LM from the Surveillance, Epidemiology, and End Results (SEER) database. The risk factors for LM were determined using multivariate logistics regression. Forest plots were used to compare the impact of with LM versus without LM alone among different primary caner site subgroups. Results Among 1,525,441 cases, 47,537 presented with LM at initial diagnosis. Multivariate logistics regression revealed that male sex, older age, later T/N stage, unmarried status, and lack of insurance were risk factors for LM. The incidence of LM was 11.91% in bone cancer and 11.19% in pancreatic cancer. In terms of the distribution of primary cancers, 19.22% of LMs originated from the colon and rectum, with 11.63% from the kidneys. The median survival for LM cases was 6 months, with the best survival in testicular cancer (19 months) and bone cancer (12 months). Patients with LM had higher hazard ratio (HR) for mortality compared to those without LM, except for those with primary cancer in the brain (P=0.09). We stratified patients by primary cancer site, and subgroup analyses showed that LM had a significant negative impact on survival. The most significant was in thyroid cancer (HR = 44.79), followed by melanoma (HR = 24.26), prostate (HR = 16.0), breast (HR = 13.46), endometrial (HR = 12.64), testicular (HR = 12.31), and kidney (HR = 11.33) cancer (all P < 0.001). Conclusion Patients presenting with LM had higher HR for mortality compared to those without LM, except for those with brain tumor. Clinicians should pay more attention to the occurrence of LM, especially in patients with a significantly increased HR for mortality, such as those with thyroid cancer, melanoma, and prostate cancer.

Factors Affecting Prognosis and Survival in Extremity Osteosarcoma.

Osteosarcoma is a malignant bone tumor affecting mainly children and young adults and commonly involves extremities. The aim of this study was to assess the patient-related, tumor-related, and treatment-related factors affecting the overall survival in patients with non-metastatic extremity osteosarcoma. A retrospective, single institutional study of 100 patients with non-metastatic extremity osteosarcoma was done between 2014 and 2019. Age, sex, histologic type, tumor site, use of preoperative chemotherapy and its duration, response to chemotherapy, type of surgery, presence of local recurrence, occurrence of lung metastasis, and survival data were recorded. Survival analysis was done using Kaplan-Meier method. p < 0.05 by log-rank test was considered statistically significant. Statistical data were analyzed using SPSS v.25(IBM). The median age of presentation was 18 years with male sex preponderance. The most common site of presentation was distal femur, and commonest histological variant was osteoblastic osteosarcoma. Incidence of local recurrence was 9%, and lung metastasis was identified in 12% on follow-up. The 5-year overall survival (OS) was 65.5%, and 5-year local recurrence-free survival was 57.6%. The 5-year OS in neoadjuvant chemotherapy group was 80% compared to 39.5% in upfront surgery group (p = 0.015). The 5-year OS in patients with tumor necrosis > 90% and < 90% was 93.2% and 71.2%, respectively (p = 0.038). The 5-year OS in patients without lung metastasis was 76%, whereas none who developed lung metastasis has survived 5 years (p < 0.001). The use of neoadjuvant chemotherapy, good response to chemotherapy, and the absence of lung metastasis on follow-up can independently predict better overall survival.

MiR-887 Promotes the Progression of Hepatocellular Carcinoma via Targeting VHL

Background:MiR-887 has been proved to promote the tumorigenesis in diverse cancers, but its function and downstream mechanism in hepatocellular carcinoma remain obscure.Methods:Quantitative real-time polymerase chain reaction was performed to detect the expression levels of miR-887 in hepatocellular carcinoma tissues and cell lines. MiR-887 mimics and miR-887 inhibitor were transfected into Huh7 and MHCC97H to establish miR-887 overexpression or inhibition models. Cell Counting Kit-8 and colony formation experiment were conducted to monitor cell proliferation. Subcutaneous xenotransplanted tumor model and tail vein injection model in mice were also established to further verify the effect of miR-887 on hepatocellular carcinoma in vivo. The targeting relationship between miR-887 and von Hippel-Lindau tumor suppressor (VHL) was determined by quantitative real-time polymerase chain reaction, Western blot, and luciferase reporter gene assay.Results:miR-887 expression in hepatocellular carcinoma tissues was significantly upregulated. Compared with the control cells, the proliferation and metastasis of cancer cells were enhanced by miR-887 mimics and suppressed by miR-887 inhibitor. Compared with control mice, the volume and weight of subcutaneous tumors of mice in the miR-887 mimics group were significantly elevated, and the significant increase was found in the occurrence of lung metastasis. Moreover, bioinformatics tools showed that miR-887 and VHL had 2 binding sites. Luciferase activity assay demonstrated that miR-887 can inhibit the luciferase activity of VHL, and miR-887 mimics could reduce the expressions of VHL at both messenger RNA and protein levels to increase hypoxia-inducible factor α expression.Conclusion:The upregulation of miR-887 could facilitate the proliferation and metastasis of hepatocellular carcinoma cells via targeting VHL.

Denosumab does not decrease the risk of lung metastases from bone giant cell tumour.

There are conflicting reports on the effect of denosumab on lung metastases in patients with giant cell tumor (GCT) of bone. To address these reports, we performed this study to determine if denosumab prevents lung metastasis and to evaluate univariate and multivariate predictors for lung metastases in these patients. We retrospectively studied 381 GCT patients with surgery alone and 30 GCT patients with surgery and denosumab administration. The median follow-up was 85.2months (IQR, 54.2-124.4months). We evaluated lung metastases and local recurrences, univariate and multivariate predictors for lung metastases, response, and adverse events of denosumab administration. The occurrence of lung metastases was similar (surgery alone 4.7%, 18 patients; denosumab administration 3.3%, 1 patient); however, the occurrence of local recurrences was significantly higher in the patients with denosumab administration. Denosumab administration was not an important predictor for lung metastases; Campanacci stage and type of surgery were the only univariate predictors for lung metastases, and type of surgery and local recurrence were the only multivariate predictors for lung metastases. Histology showed viable tumour in all tumor specimens of the patients with denosumab administration. Denosumab does not decrease the risk of lung metastases in patients with bone GCT; the only important predictors for lung metastases in these patients are type of surgery and local recurrence. However, because the number of patients with lung metastases was small for a multivariate analysis, the possibility of denosumab's effect could not be completely eliminated.

Diesel exhaust particle promotes tumor lung metastasis via the induction of BLT1-mediated neutrophilic lung inflammation

BLT1, the primary functional receptor of Leukotriene B4 (LTB4), is involved in tissue inflammation by mediating leukocyte recruitment, and recently LTB4-dependent inflammation was reported to promote lung tumor growth. Exposure to diesel exhaust particle (DEP), the major component of particulate matter 2.5 (PM2.5), can elicit lung inflammation, which may increase the risk of lung cancer. However, it remains unknown about the critical factors mediating DEP-induced lung inflammation and the subsequent effect on tumor metastasis. In this study, we found that DEP exposure led to acute lung inflammation, characterized by abundant infiltration of neutrophils and elevated lung levels in LTB4, as well as several pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α, CXCL1/2. Furthermore, DEP exposure promoted lung metastasis of 3LL and 4T1 cells. BLT1 blockade by its specific antagonist U75302 significantly inhibited neutrophilic lung inflammation following DEP exposure. Importantly, BLT1 blockade before the onset of inflammation significantly reduced DEP-enhanced lung metastasis, which was associated with greatly decreased infiltrating neutrophils in lungs. Interestingly, BLT1 blockade after the occurrence of lung metastases had no effect on the magnitude of lung metastasis, suggesting that inhibition of BLT1-mediated lung inflammation was insufficient to suppress established metastatic tumor. Administration of BLT2 inhibitor LY255283 fails to inhibit DEP-induced lung inflammation and tumor metastasis. Collectively, our results demonstrate that DEP exposure causes BLT1-mediated lung neutrophilic inflammation, which is critical for tumor lung metastasis, and suggest that interruption of the LTB4-BLT1 axis could be useful for preventing PM2.5-induced inflammation and subsequent susceptible to lung metastasis.

Clinical Factors Predicting Better Survival Outcome for Pulmonary Metastasectomy of Hepatocellular Carcinoma

Background: In patients with lung metastasis of hepatocellular carcinoma (HCC), it remains uncertain how a better survival outcome can be predicted after metastasectomy. This study aims to identify clinical factors that may be used to guide patient selection for such a therapeutic modality. A total of 28 patients who received pulmonary metastasectomy for HCC between 1993 and 2012 were identified. All relevant clinical factors were extracted from medical records up to September 2015. Patients were classified into high- and low-risk groups according to survival outcome after metastasectomy. All pertinent clinical factors were analyzed for correlation with survival outcome. Summary: The overall survival of 28 patients after pulmonary metastasectomy was studied first. The survival curve was biphasic and reached a plateau at 40 months after metastasectomy. The results indicate the presence of 2 groups of patients with a different survival outcome. Among all clinical parameters, remission status in the liver before pulmonary metastasectomy and distant metastasis-free interval between the last treatment of HCC and the occurrence of lung metastasis were found to be significantly associated with excellent survival outcome after pulmonary metastasectomy (p = 0.019 and 0.007 by Fisher exact test, and p = 0.002 and 0.0002 by Cox regression analysis).

Monitoring therapeutic efficacy of sunitinib using [(18)F]FDG and [(18)F]FMISO PET in an immunocompetent model of luminal B (HER2-positive)-type mammary carcinoma.

BackgroundClinical studies implying the sunitinib multi-kinase inhibitor have led to disappointing results for breast cancer care but mostly focused on HER2-negative subtypes. Preclinical researches involving this drug mostly concern Triple Negative Breast Cancer (TNBC) murine models. Here, we explored the therapeutic efficacy of sunitinib on a PyMT-derived transplanted model classified as luminal B (HER2-positive) and monitored the response to treatment using both in vivo and ex vivo approaches.MethodsTumour-induced animals were treated for 9 (n = 7) or 14 (n = 8) days with sunitinib at 40 mg/kg or with vehicle only. Response to therapy was assessed in vivo by monitoring glucose tumour metabolism and hypoxia using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and [18F]fluoromisonidazole ([18F]FMISO) Positron Emission Tomography (PET). After primary tumour excision, ex vivo digital microscopy was performed on treated and control samples to estimate vascular density (CD31), apoptosis (Tunel), proliferation (Ki-67), Tumour-Associated Macrophage (TAM) infiltration (F4/80), metabolism (GLUT1) and cellular response to hypoxia (HIF1 alpha). The drug impact on the metastasis rate was evaluated by monitoring the PyMT gene expression in the lungs of the treated and control groups.ResultsConcomitant with sunitinib-induced tumour size regression, [18F]FDG PET imaging showed a stable glycolysis-related metabolism inside tumours undergoing treatment compared to an increased metabolism in untreated tumours, resulting at treatment end in 1.5 less [18F]FDG uptake in treated (n = 4) vs control (n = 3) tumours (p < 0.05). With this small sample, [18F]FMISO PET showed a non-significant decrease of hypoxia in treated vs control tumours. The drug triggered a 4.9 fold vascular volume regression (p < 0.05), as well as a 17.7 fold induction of tumour cell apoptosis (p < 0.001). The hypoxia induced factor 1 alpha (HIF1 alpha) expression was twice lower in the treated group than in the control group (p < 0.05). Moreover, the occurrence of lung metastases was not reduced by the drug.Conclusions[18F]FDG and [18F]FMISO PET were relevant approaches to study the response to sunitinib in this luminal B (HER2-positive) model. The sunitinib-induced vascular network shrinkage did not significantly increase tumour hypoxia, suggesting that tumour regression was mainly due to the pro-apoptotic properties of the drug. Sunitinib did not inhibit the metastatic process in this PyMT transplanted model.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1540-2) contains supplementary material, which is available to authorized users.

Abstract 3539: The noncoding PTEN pseudogene influences PI3K signaling and inhibits breast cancer progression

Abstract The PTEN pseudogene is a non-coding RNA, reported to function as a decoy for microRNAs (miRNAs) degrading PTEN mRNA. The purpose of this study was to examine PTENP1 expression and its influence on PTEN expression and PI3K-Akt-mTOR signaling in human breast cancer. Tumor samples from 30 patients with locally advanced breast cancer were examined for PTEN and PTENP1 expression before and after treatment, and the results were correlated to tumor response rates. Furthermore, the human PTENP1 positive MDA-MB231 and the murine PTENP1 negative C3HBA breast cancer cell lines were lentivirally transfected with PTENP1 to assess the effects of PTENP1 overexpression on cell proliferation in vitro, tumor growth in mice, as well as its influence on PTEN and PI3K-Akt-mTOR signaling. Knockdown of PTENP1 by siRNA in MDA-MB231 cells was performed to examine how down regulated gene expression of the pseudogene would affect PTEN. To evaluate PTENP1-associated miRNAs, RNA sequencing from MDA-MB231 transfected with PTENP1 was performed. PTENP1 was present genomically in all human breast cancer samples. PTEN and PTENP1 mRNA expression was concordant in the breast cancer samples before and after 16 weeks of doxorubicin treatment. When comparing the response group, tumor samples from patients with progressive disease (PD) had the lowest PTEN mRNA levels, whereas tumors with stable disease (SD) or partial response (PR) had a higher PTEN expression. PD tumors had a minor change in PTEN and PTENP1 levels after treatment, whereas PTEN and PTENP1 increased in SD and PR tumors. PTENP1 overexpression significantly reduced C3HBA tumor growth in C3H mice. MDA-MB231 primary tumor growth was not affected, but a reduced occurrence of lung metastases was observed in NOD/SCID mice. Cell proliferation was not affected in neither cell line in vitro. This disparate response in vitro vs. in vivo suggests that PTENP1 influences tumor-host interactions in vivo. Lentiviral PTENP1 transfection increased PTEN mRNA and protein expression in murine C3HBA, but with increased pAkt and S6K protein levels indicative of non-PI3K dependent activation. In MDA-MB231 tumors, PTENP1 did not affect PTEN mRNA, but PTEN protein expression increased slightly. The MDA-MB231 tumors were found negative for pAKT and with a low S6K protein expression. PTENP1 knockdown decreased PIK3CA, PTEN, S6K and mTOR gene expression in MDA-MB231, suggesting that PTENP1 facilitates PI3K pathway signaling. While PTENP1 had an effect on PTEN gene and protein expression, it had no obvious effect on PTEN targeting miRNAs in MDA-MB231. Thus, the mechanism behind PTEN regulation mediated by PTENP1 in breast cancer needs to be elaborated on further. In conclusion, PTENP1 is present in human breast cancers and reacts concordantly with PTEN when tumors are exposed to doxorubicin. Up- and down regulation of PTENP1 influences PI3K signaling, and PTENP1 transfection inhibits tumor progression in mice. Citation Format: Synnøve Yndestad, Eilin Austreid, Hans Petter Eikesdal. The noncoding PTEN pseudogene influences PI3K signaling and inhibits breast cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3539. doi:10.1158/1538-7445.AM2014-3539

Evaluation of Human Circulating Tumor Cells By Htert-Specific Replication-Selective Adenovirus in Soft Tissue Sarcoma

ABSTRACT Aim: Circulating tumor cells (CTCs) in peripheral blood are a useful prognostic factor and a tool for measuring the treatment effects in various carcinomas. We attempted to detect viable CTCs in the peripheral blood of sarcoma patients using a telomerase-specific viral agent. We then investigated whether there was a correlation between numbers of CTCs and other clinical features of sarcomas to determine whether these factors can be used as parameters of aggressiveness or prognosis. Methods: Seventeen blood samples were obtained from 12 soft tissue sarcoma patients with soft tissue sarcoma of trunk or extremity before and/or after surgery. The samples were collected from 7 males and 5 females with an average age of 73 years. Four patients presented with myxoidfibrosarcoma, 2 with pleomorphic sarcoma, 2 with liposarcoma histology and others. Histological grades were assigned according to the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system. One patient was diagnosed with grade 1, 2 with grade 2, and 9 with grade 3 sarcoma. The average duration of postoperative observation was 18.1 months (range: 3 to 40 months). Four patients developed a lung metastasis without local recurrence after surgery. We detected viable CTCs in the 7.5ml blood samples after incubating them with a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP) gene (OBP-401). GFP-positive cells were counted under a fluorescence microscope. Results: The average number of CTCs was 6.5 (range: 0-65). There was a significant difference in number of CTCs between the patients with grade 3 (average 7.2) and those with grade 1 and 2 (average 2.8) (p=0.045). A decrease in the number of postoperative CTCs compared to number of preoperative CTCs was significantly related to lung metastasis (p=0.046). The number of CTCs was not related to gender, age, tumor location, and tumor size. Conclusions: A significant relationship emerged among the number of CTCs, histological grade, and occurrence of lung metastasis in patients with sarcoma. The detection of CTCs using OBP-401 may be useful for prognostic evaluation. Disclosure: All authors have declared no conflicts of interest.

CXCL16 and CXCR6 in Ewing sarcoma family tumor

Chemokines are a family of peptide mediators that play an essential role in cellular migration and intracellular communication in tumor cells as well as immune cells. We hypothesized that the CXCL16-CXCR6 ligand-receptor system plays an important role in Ewing sarcoma (ES) family tumor (ESFT) progression. Using real-time quantitative reverse transcription-polymerase chain reaction, we investigated the mRNA expression of CXCL16, CXCR6, and ADAM 10 in various cell lines. We also investigated the expression of CXCL16, CXCR6, ADAM 10, and ADAM 17 in tissue samples from 61 ESFT patients using immunohistochemistry. The mRNA expression levels of CXCL16 and CXCR6 in the ES cell line were higher than those in the other cell lines. Immunohistochemical staining revealed that CXCL16 and CXCR6 were highly expressed in tumor cells of ESFT and showed a positive correlation between them. The expression of CXCL16 and CXCR6 was associated with the occurrence of lung metastasis. Univariate analysis revealed that CXCL16 or CXCR6 expression was associated with worse prognosis of ESFT patients. In addition, CXCL16 and CXCR6 expression was associated with shorter overall survival irrespective of other prognostic factors. Our results suggest that the CXCL16/CXCR6 axis appears to be important in the progression of ESFT, resulting in more aggressive clinical behavior. Furthermore, there may be a decrease in the overall survival in ESFT patients who have tumors that stain strongly for CXCL16 and CXCR6.

Inhibition of mTORC1 signaling reduces tumor growth but does not prevent cancer progression in a mouse model of thyroid cancer

Selective drugs targeting dysregulated oncogenic pathways are promising cancer therapies. Because the mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in human follicular thyroid cancer (FTC), we hypothesized that its inhibition could block cancer development and progression. We, therefore, analyzed the effect of a treatment with a specific mTORC1 inhibitor (RAD001) in a faithful mouse model of FTC with constitutive mTORC1 activation (TRbeta(PV/PV)Pten(+/-) mice). The treatment did not prevent capsular and vascular invasion of the thyroid and the occurrence of lung metastasis. However, it substantially decelerated thyroid tumor growth, thereby prolonging TRbeta(PV/PV)Pten(+/-) mouse life span. RAD001 efficiently inhibited mTORC1 activity, as shown by the reduced phosphorylation of its downstream targets involved in the activity of the translation machinery, such as ribosomal S6 kinase (p70(S6K)), eukaryotic translation initiation factor 4E binding protein (4E-BP1) and the eukaryotic translation initiation factors eIF-4B and eIF-4G. Whereas mTORC1 signaling inhibition did not alter cell apoptosis, it induced a significant decrease in cell proliferation that was associated with the reduced abundance and altered activity of key regulators of cell cycle progression. Altogether, our data indicate that mTORC1 signaling plays a major role in the integration of the mitogenic signal in FTC. Therefore, our preclinical study with a relevant mouse model of FTC demonstrates for the first time that RAD001 efficaciously stabilizes cancer growth although it does not prevent its fatal outcome. In conclusion, our work underscores that in the treatment of FTC patients, RAD001 can only be used in combination with drugs and therapies inducing tumor shrinkage and blocking metastasis.

Tumour Volume and Lung Metastasis in Patients with Osteosarcoma

To assess the association between tumour volume and occurrence of lung metastasis in patients with osteosarcoma and to determine the cut-off value. Records of 70 patients with histopathologically confirmed primary osteosarcoma in the extremities who had magnetic resonance imaging and computed tomography of the thorax less than one month before treatment were reviewed, with reference to the official report of tumour dimensions and lung metastasis by radiologists. The status of lung metastasis was assessed. Tumour volume was measured using the formula for an ellipsoidal mass. Of the 70 patients with osteosarcoma, 33 (47%) had evidence of lung metastasis. Tumour volume was directly associated with occurrence of lung metastasis (p=0.048). The proportion having lung metastasis when the primary tumour volume exceeded 371 cm3 was 69%, compared to 34% in those with smaller tumours. Larger tumours are more likely to correlate with lung metastasis. Both features are predictive of patient survival and prognosis.