Number Of Pulmonary Metastases Research Articles

Chronic Exposure to Low Levels of Parabens Increases Mammary Cancer Growth and Metastasis in Mice.

Methylparaben (MP) and propylparaben (PP) are commonly used as food, cosmetic, and drug preservatives. These parabens are detected in the majority of US women and children, bind and activate estrogen receptors (ER), and stimulate mammary tumor cell growth and invasion in vitro. Hemizygous B6.FVB-Tg (MMTV-PyVT)634Mul/LellJ female mice (n = 20/treatment) were exposed to MP or PP at levels within the US Food and Drug Administration's "human acceptable daily intake." These paraben-exposed mice had increased mammary tumor volume compared with control mice (P < 0.001) and a 28% and 91% increase in the number of pulmonary metastases per week compared with the control mice, respectively (P < 0.0001). MP and PP caused differential expression of 288 and 412 mammary tumor genes, respectively (false discovery rate < 0.05), a subset of which has been associated with human breast cancer metastasis. Molecular docking and luciferase reporter studies affirmed that MP and PP bound and activated human ER, and RNA-sequencing revealed increased ER expression in mammary tumors among paraben-exposed mice. However, ER signaling was not enriched in mammary tumors. Instead, both parabens strongly impaired tumor RNA metabolism (eg, ribosome, spliceosome), as evident from enriched KEGG pathway analysis of differential mammary tumor gene expression common to both paraben treatments (MP, P < 0.001; PP, P < 0.01). Indeed, mammary tumors from PP-exposed mice had an increased retention of introns (P < 0.05). Our data suggest that parabens cause substantial mammary cancer metastasis in mice as a function of their increasing alkyl chain length and highlight the emerging role of aberrant spliceosome activity in breast cancer metastasis.

Curative-intent treatment of pulmonary metastases from colorectal cancer: A comparison between imaging-guided thermal ablation and surgery.

Pulmonary metastases (PM) are the most frequent extra-abdominal metastases from colorectal cancer.Lung resection and imaging-guided thermal ablation (IGTA) are used as curative-intent treatment. We compared the outcomes of patients with PM, treated with resection or ablation. We retrospectively analyzed data from patients who underwent surgery or IGTA for colorectal PM between April 2011 and November 2020. Surgery was performed for peripheral PM and IGTA for deep-located PM not in contact with major vessels. Patients who had both procedures were excluded. Patients were compared using propensity score matching (PSM) analysis, stratified according to number, size, and unilaterality of PM. One hundred and fourty-six patients were included, 65 (44.5%) underwent surgery and 81 (55.5%) underwent IGTA. After PSM analysis, each group contained 46 patients. IGTA patients had a lower morbidity rate (13.1% vs. 15.2%, p = 0.028) and a shorter length of stay (5.13 vs. 2.63 days, p < 0.001). Oncological outcomes were similar in both groups with 5-year OS of 80% and 5-year progression-free survival(PFS) of 30% (p = 0.657 and p = 0.504, respectively) with similar recurrence patterns. Lung resection and IGTA seem to have similar oncologic outcomes for both OS and PFS. IGTA could be an alternative effective treatment for small PM, whenever technically feasible.

Surgical Strategy for Primary Colorectal Carcinoma and Synchronous Pulmonary Metastasis Resection.

BackgroundThe surgical strategy for single-stage resection of primary colorectal cancer (CRC) and synchronous pulmonary metastases remains a matter of debate.MethodsPerioperative data of patients who underwent single-stage resection of primary CRC and synchronous pulmonary metastases were compared to those of patients who underwent 2-stage resections. The demographic data, number of metastases, type of pulmonary and colorectal resections, operation time, blood loss, postoperative complications, morbidities, mortality, medical costs, and length of hospital stay were analyzed.ResultsTwenty-two patients underwent single-stage resection of primary CRC and pulmonary metastases, while 27 patients underwent 2-stage resection. Tumor size and the number of pulmonary metastases were not significantly different between the 2 groups. The extent of pulmonary metastasectomy and abdominal procedures were similar in both groups, as was the thoracic surgical approach (video-assisted thoracic surgery vs. thoracotomy). However, open laparotomy was performed more frequently in the 2-stage group than in the single-stage group (p=0.045), which also had a longer total anesthetic time (p=0.013). The operation time, medical costs, estimated blood loss, complication rates, and severity were similar in both groups, but the length of hospital stay was shorter in the single-stage group (p<0.001).ConclusionSingle-stage colorectal and pulmonary resection shortened the overall hospital stay, with no significant changes in operation time, medical costs, hospital mortality, and morbidity. Therefore, single-stage resection could be a good surgical strategy in selected patients.

Thoracoscopic pulmonary metastasectomy in metastatic colorectal cancer: Surgical outcomes and prognostic factors.

BackgroundThis study aimed to confirm the effectiveness of thoracoscopic metastasectomy for colorectal cancer (CRC) and determine its prognostic factors.MethodsOf the 181 patients who underwent video‐assisted thoracoscopic surgery (VATS) for pulmonary metastases from CRC between 2011 and 2017, 173 were retrospectively reviewed. Surgical outcomes, long‐term survival, and the factors affecting the prognosis were analyzed.ResultsThe patients in the study were predominantly male (n = 104, 60.1%), and the median age was 65 years (range, 25–83 years). The median follow‐up time was 46 months (range, 0–114 months). The surgical procedures were 156 wedge resections, five segmentectomies, and 12 lobectomies. Conversion to thoracotomy was required in nine patients. The postoperative complication rate was 2.9%, and the in‐hospital mortality rate was 1.2%. The overall 1‐, 3‐, and 5‐year survival rates were 94.8%, 70.6%, and 51.8%, respectively. Univariate analysis showed that the prognostic factors for survival were age (p = 0.027), pathological stage of CRC (p = 0.019), prior extrathoracic metastasis (p = 0.005), preoperative carcinoembryonic antigen level (p = 0.020), number of pulmonary metastases (p = 0.011), and disease‐free interval (p = 0.026). In the multivariate analysis, two factors were related to prognosis: age (hazard ratio [HR], 1.881; 95% confidence interval [CI]; 1.189–2.976; p = 0.007) and prior extrathoracic metastasis (HR, 2.170; 95% CI; 1.269–3.711; p = 0.005).ConclusionsVATS for pulmonary metastasectomy for CRC can be performed relatively safely, and our results regarding long‐term survival are comparable with those of other studies. In this study, older age (≥70 years) and prior extrathoracic metastasis were independent prognostic factors of poor prognosis.

Abstract 2828: The prognostically significant immunological indices for patients who underwent curative resection of pulmonary metastases of colorectal cancer

Abstract Background: In recent years, it has been revealed that the immunological state of the host affects with the effect of cancer treatments. The neutrophil-to-lymphocyte ratio (NLR) as a systemic inflammatory marker and the density of tumor-infiltrating lymphocytes (TILs) at cancer microenvironment have been reported to be useful prognostic indices in various cancers, including colorectal cancer (CRC). The aim of this study is to evaluate the prognostic significance of immunological indices in patients who underwent curative resection of pulmonary metastases of CRC. Patients and Methods: The medical records of 17 patients who underwent potentially curative resection for pulmonary metastases of CRC were retrospectively reviewed. The correlation between the relapse-free survival (RFS) or the overall survival (OS) after curative resection of pulmonary metastases of CRC and the clinicopathological factors, NLR or TILs were evaluated. The NLR was calculated from the blood sample which was obtained within 2 weeks before pulmonary resection by dividing the absolute neutrophil count by the absolute lymphocyte count. According to the receiver operating characteristic (ROC) curve analysis, patients with an NLR of ≥ 2.5 were classified as high-NLR group. The density of TILs was examined by immunohistochemistry of pulmonary metastatic tumor sample, by staining anti-CD3 and anti-CD8 antibody. The number of CD3+TILs and CD8+TILs at the border of tumor was counted in a randomly selected field at a magnification of ×400. The mean of the values obtained in five different areas was used. According to the ROC curve analysis, the patients with the number of CD3+TILs ≥ 31 were classified as high- CD3+TILs group and patients with the number of CD8+TILs ≥ 21 were classified as high- CD8+TILs group. Results: The RFS and OS after resection of pulmonary metastases were significantly worse in the high-NLR group than in the low-NLR group (p=0.001, p=0.003, respectively). The RFS after resection of pulmonary metastases was significantly better in the high-CD3+TILs group than in the low-CD3+TILs group (p=0.041). Multivariate analysis revealed that the number of pulmonary metastases and the NLR before resection of pulmonary metastases were independent prognostic factors of the RFS (p=0.007, p=0.002, respectively) and the NLR before resection of pulmonary metastasis was the independent prognostic factor of the OS (p=0.009). Conclusion: The immunological indices such as the NLR and the density of TILs, may have prognostic significance in patients who underwent curative resection of pulmonary metastases of CRC. Citation Format: Yuki Okazaki, Masatsune Shibutani, En Wang, Hisashi Nagahara, Tatsunari Fukuoka, Yasuhito Iseki, Shinichiro Kashiwagi, Hiroaki Tanaka, Kiyoshi Maeda, Kosei Hirakawa, Masaichi Ohira. The prognostically significant immunological indices for patients who underwent curative resection of pulmonary metastases of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2828.

Synchronous Lung Adenocarcinoma and Papillary Thyroid Carcinoma The Metastases at the Centre of the Discussion.

Although rare, synchronous primary tumours are a possibility and physicians should be aware of this possibility.Papillary thyroid carcinoma may metastasize to the lungs and its differential diagnosis should be made in the presence of lung carcinoma.When in doubt, anatomo-pathological examination of the metastases should be performed for proper staging of both tumours and to decide on the best therapeutic option.

Lack of Plasminogen Activator Inhibitor-1 Effect in a Transgenic Mouse Model of Metastatic Melanoma

Tumor cell invasion and metastasis is a complex, multistep process that is postulated to require degradation of extracellular matrix at several steps. Urokinase-type plasminogen activator (uPA) is expressed on the cell surface of B16 murine melanoma cells and is thought to contribute to the pericellular proteolysis necessary for tumor cell migration. In vitro modification of B16 melanoma cell surface uPA activity has been shown to alter the invasive and metastatic potential of these murine melanoma cells in vivo. Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of both uPA and tissue-type plasminogen activator (tPA) is the major physiologic regulator of plasminogen activator activity. To test the role of host PAI-1 in the invasive and metastatic capacity of B16 melanoma cells we analyzed local tumor growth and pulmonary metastasis in transgenic mice engineered to overexpress murine PAI-1 in multiple tissues including lung, and in mice completely deficient in PAI-1. No significant difference in the number of pulmonary metastases was observed after intravenous inoculation of tumor cells into PAI-1-overexpressing and PAI-1-deficient mice when compared with wild-type controls. Similarly, in a spontaneous metastasis model, PAI-1-overexpressing and PAI-1-deficient mice demonstrated no difference in primary tumor size or overall survival. These data demonstrate that wide variations of host PAI-1 expression, from complete absence to marked overexpression, does not significantly influence the metastatic potential of B16 melanoma cells in a murine model.

Phase II trial of adjuvant mFOLFOX6 after metastasectomy for pulmonary metastasis of colorectal cancer: WJOG5810G.

4097 Background: Resection of pulmonary metastasis (PM) is widely accepted to improve the prognosis in selected patients (pts) with metastatic colorectal cancer (CRC). However, the clinical implication of adjuvant chemotherapy after metastasectomy of PM is unknown. We conducted a multi-center phase 2 trial of adjuvant chemotherapy with mFOLFOX6 after metastasectomy of PM-CRC. Methods: Main eligibility criteria were first curative metastasectomy of 4 or less PMs and no prior chemotherapy except for adjuvant chemotherapy with fluoropyrimidine monotherapy after curative resection of primary or extrathoracic CRC metastasis. The study treatment was 12 courses of mFOLFOX6 (oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, 5-fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion, every 2 w). The primary endpoint was overall survival (OS). The secondary endpoints included disease-free survival (DFS), adverse events (AEs), and recurrence sites. The sample size was determined to be 93 expecting 5-year OS rate of 50% with threshold 35% (90% power, alpha error 5%). Results: Fifty-two pts from 34 institutions were enrolled between July 2011 and July 2014. Patient enrollment was closed prematurely because of slow accrual. Four patients were ineligible after enrollment and the safety and efficacy cohort comprised 52 and 48 patients, respectively. Patient backgrounds were as follows: gender (male/female) 31/21, median age (range) 63 (42-75) years, ECOG PS (0/1) 48/4, primary site (colon/rectum) 18/34, number of PM (1/2/3/4) 36/9/5/2, synchronous/metachronous PM 11/41, and unilateral/bilateral PM 40/12. With the median follow-up time of 6.0 (1.8-7.7) years, 5-year OS rate was 86% (95% CI: 72-93) and 5-year DFS rate was 59% (95% CI: 43-71). Tumors recurred in 19 patients (13 lung, 3 liver and 7 others). Total 41 pts (79%) completed 12 courses of mFOLFOX6 (reasons for discontinuation: AEs in 3, refusal due to AEs in 8). AEs ( &gt; Grade 3) were neutropenia 50%, fatigue 8%, peripheral sensory neuropathy 8%, appetite loss 4%, diarrhea 4%, febrile neutropenia 2% and allergic reaction 2%. There was no treatment related death. Conclusions: Adjuvant mFOLFOX6 is feasible and may be effective after metastasectomy for PM-CRC, considering much better OS than we had expected. Clinical trial information: UMIN000005693 .

Stereotactic body radiotherapy (SBRT) in patients with lung metastases - prognostic factors and long-term survival using patient self-reported outcome (PRO)

ObjectivesThe present study aims to evaluate long-term side-effects and outcomes and confirm prognostic factors after stereotactic body radiotherapy (SBRT) of pulmonary lesions. This is the first work that combines the investigated data from patient charts and patient-reported outcome (PRO) up to 14 years after therapy.Materials and methodsWe analyzed 219 patients and 316 lung metastases treated between 2004 and 2019. The pulmonary lesions received a median dose and dose per fraction of 35 Gy (range: 14–60.5 Gy) and 8 Gy (range: 3–20 Gy) to the surrounding isodose. During the last 1.5 years of monitoring, we added PRO assessment to our follow-up routine. We sent an invitation to a web-based survey questionnaire to all living patients whose last visit was more than 6 months ago.ResultsMedian OS was 27.6 months. Univariate analysis showed a significant influence on OS for KPS ≥90%, small gross tumor volume (GTV) and planning target volume (PTV), the absence of external metastases, ≤3 pulmonary metastases, and controlled primary tumor. The number of pulmonary metastases and age influenced local control (LC) significantly.During follow-up, physicians reported severe side-effects ≥ grade 3 in only 2.9% within the first 6 months and in 2.5% after 1 year. Acute symptomatic pneumonitis grade 2 was observed in 9.7%, as grade 3 in 0.5%.During PRO assessment, 39 patients were contacted, 38 patients participated, 14 participated twice during follow-up. Patients reported 15 cases of severe side effects (grade ≥ 3) according to PROCTCAE classification. Severe dyspnea (n = 6) was reported mostly.ConclusionWe could confirm excellent local control and low toxicity rates. PROs improve and complement follow-up care. They are an essential measure in addition to the physician-reported outcomes. Future research must be conducted regarding the correct interpretation of PRO data.

Clinical outcomes of percutaneous thermal ablation for pulmonary metastases from hepatocellular carcinoma: a retrospective study

Purpose To determine the effectiveness of ablation for pulmonary metastases (PM) from hepatocellular carcinoma (HCC). Methods Between 2010 and 2017, the study analyzed 39 patients who had a median age of 59 years. Primary HCC was under control and the number of PM was less than 5 (median: 2), with a maximum diameter of ≤60 mm (median: 15 mm). The primary endpoints were overall survival (OS) and local tumor progression-free survival (LTPFS). Secondary endpoints included technique success (TS), complication and tumor response. TS referred to PM treated using the treatment protocol. Multivariate analysis using the Cox proportional hazard model was conducted on the potential risk factors (univariate: p < 0.5) to determine the independent factors (multivariate: p < 0.05). Results The TS rate was 100%. Major complications included pneumothorax (n = 3) requiring chest tube placement and pleural effusion requiring drainage (n = 2). Complete ablation was achieved in 32/38 patients (valid percent: 84.2%) at 1 month after ablation. The 1-, 3- and 5-year OS rates were 79.8, 58 and 30.9%, respectively. The 1-, 3- and 5-year LTPFS rates were 60.7, 34.2 and 22.8%, respectively. The extent (unilateral vs. bilateral) of PM (hazard ratio (HR): 0.197, 95% confidence interval (CI): 0.043–0.890, p = 0.035) and the number (≤2 vs. >2) of PM (HR: 0.555, 95% CI: 0.311–0.991, p = 0.047) were found to be the independent risk factors for predicting OS. Conclusion Percutaneous thermal ablation is a safe and effective treatment for PM from HCC.

High Expression of MicroRNA-196a is Associated with Progression of Hepatocellular Carcinoma in Younger Patients.

MicroRNAs are small RNAs involved in various biological processes and cancer metastasis. miR-196a was associated with aggressive behaviors in several cancers. The role of miR-196a in hepatocellular carcinoma (HCC) metastasis remains unknown. This study aimed to examine the role of miR-196a in HCC progression. Expression of miR-196a was measured in 83 human HCC samples. The HCC patients with high miR-196a expression had younger ages, lower albumin levels, higher frequency with alpha-fetoprotein (AFP) levels ≥20 ng/mL, more macrovascular invasion, and non-early stages. Kaplan–Meier analysis showed that high miR-196a expression was associated with lower recurrence-free survival. Knockdown of miR-196a decreased transwell invasiveness, sphere formation, transendothelial invasion, and Slug, Twist, Oct4, and Sox2 expression, suppressed angiogenesis, and reduced sizes of xenotransplants and number of pulmonary metastasis. Down-regulation of miR-196a decreased Runx2 and osteopontin (OPN) levels. Knockdown of Runx2 in vitro resulted in comparable phenotypes with miR-196a down-regulation. Restoration of Runx2 in miR-196a-knockdown HCC reverted tumor phenotypes. This study showed that high expression of miR-196a is associated with HCC progression in a subset of younger patients. miR-196a mediates HCC progression via upregulation of Runx2, OPN, epithelial–mesenchymal transition (EMT) regulators, and stemness genes. We proposed that miR-196a can be used as a prognostic marker and a potential therapeutic target.

Three risk factors for pulmonary metastasectomy in patients with hepatocellular carcinoma

ObjectiveThe outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors.MethodsThis retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital.ResultsThe 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226–10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594–10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0–1 risk factors and those with 2–3 risk factors, respectively (P < 0.001).ConclusionsFor patients who underwent pulmonary metastasectomy for hepatocellular carcinoma, median survival time was 25.0 months and decreased with three risk factors which included viral hepatitis, multiple number of pulmonary metastases, and the presence of other site recurrence before metastasectomy.

Surgery for pulmonary metastases from colorectal cancer: survival and prognostic factors

This study aimed to describe overall survival following pulmonary metastasectomy for colorectal cancer (CRC) in Sweden, and to assess the discrimination of a recently proposed risk prediction model. Individual-level data of 756 patients who underwent resection of pulmonary metastases from CRC between 2009 and 2015 were obtained from ThoR, a Swedish national quality register for thoracic surgery. We classified patients into three risk categories according to the number of preoperative risk factors [age, disease-free interval (DFI), presence of extrathoracic lesions, number of pulmonary metastases] established in a prior study. We estimated the hazard ratios (HRs) and 95% confidence interval (CI) by Cox regression and the restricted mean survival time difference as group contrast measures. During a median follow-up time of 2.9 years, 35% (268/756) patients died. At 5 years, overall survival was 56% (95% CI: 51-60%). In a Cox regression model with risk category as the only independent variable, the HR for all-cause mortality was 1.94 (95% CI: 1.38-2.72, P<0.001) and 4.35 (95% CI: 2.49-7.62, P<0.001) in the moderate- (n=558) and high-risk categories (n=32), respectively, versus the low-risk category (n=166). At 5 years, the differences in restricted mean survival time were 6 months (P<0.001) and 1.5 years (P<0.001) in the moderate- and high-risk categories, respectively, versus the low-risk category. Five-year survival after surgery for pulmonary metastases from CRC in Sweden was similar or higher compared with contemporary reports. A prognostic model, initially developed in Japanese patients, had excellent discrimination in an external validation cohort of Swedish patients.

Predictive Factors of Thoracic Lymph Node Metastasis Accompanying Pulmonary Metastasis from Colorectal Cancer.

The aim of this study was to identify the factors predicting thoracic lymph node (LN) metastases for pulmonary resection from colorectal cancer (CRC). The records of 160 patients who underwent pulmonary metastasectomy for CRC were retrospectively reviewed. Clinicopathologic factors were analyzed with chi-square test or t-test and logistic regression to identify predictable factors for LN metastases. Sixty patients (37.5%) underwent LN dissection during pulmonary metastasectomy, and LN metastases were found in five patients. Twenty-three patients had LN recurrence among the 100 patients (62.5%) without LN dissection during the follow-up period. Twenty-eight patients out of 160 (17.5%) had LN metastases. By multivariate analysis, the number of pulmonary metastasis and metastasis from colon cancers were independent factors predicting LN metastases. The number of pulmonary metastasis and metastasis from colon cancers were independent factors predicting LN metastases. LN sampling should be performed especially in cases with strong predictive factors to improve staging and help guide further treatment.

MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence

BackgroundThe high incidence of recurrence and metastasis of hepatocellular carcinoma (HCC) necessitate the discovery of new predictive biomarkers of invasion and prognosis. Minichromosome maintenance complex component 6 (MCM6), which has been reported to up-regulate in multiple malignancies, was considered to be a novel diagnoses biomarker in HCC. However, its functional contributions and prognostic value remain unclear.MethodsThe expression of MCM6 was analyzed in 70 HCC tissues and 5 HCC cell lines by immunohistochemistry and real-time RT-PCR. The roles of MCM6 in HCC cell proliferation, migration and invasion were explored by CCK8, Wound healing and Transwell assays, respectively. Western blotting and Immunofluorescence staining were conducted to detect the protein expressions of ERK signaling pathway and EMT-related markers. To verify the above findings in vivo, we established subcutaneous xenograft tumor and orthotopic xenograft tumor models in nude mice. Finally, Enzyme-linked immunosorbent assay was used to evaluate the serum MCM6 level.ResultsMCM6 was significantly up-regulated in HCC tissues. Increased MCM6 expression was associated with aggressive clinicopathological features and worse prognosis in HCC patients. These results were consistent with our analyses of The Cancer Genome Atlas database (TCGA). Furthermore, knockdown of MCM6 significantly decreased proliferative and migratory/invasive capability of HCC cells in vitro, as well as decreased tumor volume, weight and the number of pulmonary metastases in vivo. Mechanistic analyses indicated that MCM6 promoted EMT and activated MEK/ERK signaling. More importantly, serum MCM6 levels in HCC patients were significantly higher than those in cirrhosis and healthy controls (P < 0.0001), and allowed distinguishing early recurrence with high accuracy (AUC = 0.773).ConclusionsOur findings indicate that MCM6 predicts poor prognosis and promotes metastasis in HCC. Postoperative serum MCM6 level could be valuable to detect preclinical early recurrence, indicative of a need for more careful surveillance and aggressive therapeutic intervention.

Abstract 5939: Dissemination of breast cancer

Abstract Breast cancer is the second leading cause of death in US women. Despite advances in early detection, diagnosis and treatment of breast cancer, metastasis and tumor recurrence persist leading to continued morbidity and mortality. Several breast cancer studies have highlighted the role of cyclooxygenase-2 (COX-2) and its interaction with the tumor microenvironment (TME) in breast cancer progression. The TME consists of stromal cells that include fibroblasts, macrophages, the extracellular matrix (ECM), and several secreted factors that contribute to aggressiveness of the cancer and resistance to therapy. Increased density of collagen 1 (Col1) fibers, a major structural component of the ECM in solid tumors, and their alignment in tumors frequently result in increased invasion and metastasis of cancer cells. To understand the role of COX-2 at the lung metastatic site, and its relationship with Col1 fibers, COX-2 overexpressing triple negative SUM-149 human breast cancer cells (SUM-149-COX-2) or empty vector SUM-149 cells (EV) were injected through tail vein in SCID mice to compare Col1 fiber patterns in metastatic lesions. We isolated the lungs, processed the tissue, and imaged for Col1 fiber by second harmonic generation microscopy on H&amp;E stained sections. The number of cancer associated fibroblasts (CAFs) were detected in adjacent sections by immunostaining for α-SMA. COX-2 overexpression did not increase the size of the cancer cell emboli in blood vessels or the size of pulmonary metastasis formed in the lungs. However, COX-2 overexpression did significantly increase the number of pulmonary metastases. Significantly higher Col1 fiber volume was observed in emboli compared to pulmonary metastases independent of COX-2 overexpression. Interestingly, the Col1 fibers were significantly more aligned in the COX-2 overexpressing pulmonary metastases compared to COX-2 overexpressing and EV emboli. The COX-2 overexpressing emboli had significantly higher amounts of CAFs detected by α-SMA expression compared to the EV emboli and the EV and COX-2 overexpressing pulmonary metastases. Pulmonary metastases from COX-2 overexpressing cells were detected further away from the nearest blood vessel compared to the metastases from EV cells suggesting that COX-2 may facilitate the formation of distant metastases. These data provide new insights into the role of COX-2, Col1 fibers, and CAFs in enabling emboli to extravasate to form pulmonary metastatic foci. These insights are important as COX-2 upregulation during treatment may potentiate metastasis. This work was supported by NIH R01 CA82337. Citation Format: Samata Kakkad, Mikayla Hanna, Desmond Jacob, Balaji Krishnamachary, Zaver M. Bhujwalla. Dissemination of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5939. doi:10.1158/1538-7445.AM2017-5939

Abstract 5572: AX09: an immunotherapy candidate targeting the breast cancer stem cell protein xCT

Abstract Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks the estrogen, progesterone and HER2 receptors, and accounts for 15-20% of all breast cancers in the US. The particularly aggressive features of TNBC may be due to the enrichment of breast cancer stem cells (BCSC). Due to their resistance to traditional radio- and chemo-therapies, BCSC represent a reservoir for the relapse, metastatic evolution and progression of the disease after treatment. Therefore, successful eradication of BCSC represents a major barrier towards effective cancer treatments. The ability of BCSC to resist common cytotoxic therapies relies on different mechanisms, including improved detoxification ability. The cystine-glutamate antiporter protein xCT (SLC7A11) regulates cystine intake, conversion to cysteine and subsequent glutathione synthesis, protecting cells against oxidative and chemical insults via the p38MAPK pathway. xCT expression is highly restricted to a few normal cell types but is upregulated in a variety of breast cancer subtypes where its expression correlates with poor prognosis. xCT is highly expressed in a variety of solid tumor CSC including BCSC where it interacts with CD44 and plays a functional role in BCSC biology. Agilvax has developed a novel immunotherapy candidate (AX09) based on our virus-like-particle technology for the treatment and prevention of metastatic breast cancer that targets the BCSC protein xCT. Immunization with AX09 elicited a strong antibody response against xCT including high levels of IgG2a antibody. Immune sera from AX09 mice bound to tumorsphere derived BCSC and impacted BCSC function and biology in vitro. To assess if AX09 immunization would decrease metastases, we employed a syngeneic transplantation model, in which purified BCSC derived from TUBO cells were injected into the tail vein of vaccinated female BALB/c mice. Multiple independent experiments showed that immunization with AX09 conferred a significant reduction in the number of pulmonary metastases compared to vaccination with control VLP alone. In a pilot study, BCSC were transplanted into the mammary fat pad and mice were treated with AX09 after primary tumors were 1.5 mm in diameter. Results indicate that AX09 immunization conferred a reduction in lung metastases compared to controls. These data show that an active immunization approach targeting xCT can significantly reduce metastatic progression in preclinical models. Ongoing experiments are further characterizing therapeutic mechanisms and evaluating efficacy of AX09 in combination with front line chemotherapy and checkpoint inhibitors. Citation Format: John O'Rourke, Elisabett Bolli, Valeria Rolih, Laura Conti, Stefania Lanzardo, Jayne Christen, Federica Pericle, Federica Cavallo. AX09: an immunotherapy candidate targeting the breast cancer stem cell protein xCT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5572. doi:10.1158/1538-7445.AM2017-5572

Pulmonary metastasectomy with therapeutic intent for soft-tissue sarcoma

ObjectiveSoft-tissue sarcoma is a heterogeneous disease that frequently includes the development of pulmonary metastases. The purpose of this study is to determine factors associated with improved survival among patients with soft-tissue sarcoma to help guide selection for pulmonary metastasectomy. MethodsWe reviewed a prospectively maintained database and identified 803 patients who underwent pulmonary metastasectomy for metastatic soft-tissue sarcoma between September 1991 and June 2014; of these, 539 patients undergoing 760 therapeutic-intent pulmonary metastasectomies were included. Clinicopathologic variables and characteristics of treatment were examined. The outcomes of interest were overall survival and disease-free survival. Survival was estimated with the Kaplan-Meier method and compared between variables with the log-rank test. Factors associated with hazard of death and recurrence were identified via the use of univariable and multivariable Cox proportional hazards models. ResultsMedian overall survival was 33.2 months (95% confidence interval, 29.9-37.1), and median disease-free survival was 6.8 months (95% confidence interval, 6.0-8.0). In multivariable analyses, leiomyosarcoma histologic subtype (P = .007), primary tumor size ≤10 cm (P = .006), increasing time from primary tumor resection to development of metastases (P < .001), solitary lung metastasis (P = .001), and minimally invasive resection (P = .023) were associated with lower hazard of death. Disease-free interval ≥1 year (P = .002), and 1 pulmonary metastasis (P < .001) were associated with lower hazard of disease recurrence. ConclusionsIn a large single-institution study, primary tumor histologic subtype and size, numbers of pulmonary metastases, disease-free interval, and selection for minimally invasive resection are associated with increased survival in patients undergoing pulmonary metastasectomy for soft-tissue sarcoma.

Heterogeneity of Tumor Sizes in Multiple Pulmonary Metastases of Colorectal Cancer as a Prognostic Factor

The number of metastatic lesions is closely correlated with prognosis in most cancers. The aim of this study was to clarify the relationship between individual heterogeneity of metastatic tumor sizes and prognosis in patients with multiple pulmonary metastasis of colorectal cancer who received surgical treatment. Clinical data for patients who had pulmonary metastasis from colorectal cancer and underwent curative resection at 46 Japanese institutions between January 2004 and December 2008 were collected. Among 898 patients eligible considering these inclusion criteria, 247 patients had multiple metastases and were analyzed. A difference between the maximum and minimum tumor diameters (Dmax-min) on pathologic findings was used to evaluate size heterogeneity. The overall survival rate was 75% at 3 years and 58% at 5 years, with a median follow-up period of 65 months (range, 0 to 112). When Dmax-min of 5 mm was set as a cutoff value, overall survival was significantly different between small (≤5 mm, n= 95) and large (>5 mm, n= 152) tumor groups (5-year survival rates, 66.5% and 53.3%, respectively; log rank test, p= 0.025). Multivariate analysis using a Cox proportional hazards model revealed that disease-free interval from resection of primary lesion, serum carcinoembryonic antigen level, number of pulmonary metastases, and Dmax-min were independent prognostic factors. The heterogeneity of metastatic tumor sizes may be an indicator for prognosis in patients with multiple pulmonary metastases of colorectal cancer who underwent resection.

Pulmonary metastasectomy in elderly colorectal cancer patients: a retrospective single center study.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and the lung is one of the most frequent sites for CRC metastasis. The geriatric population is increasing, but clinical decision making is often influenced by the effect of aging. For this reason, the elderly population does not often receive potentially curative cancer treatments as offered to younger ones. From January 2000 to March 2016, 21 elderly patients (older than 75years) underwent pulmonary resections for colorectal cancer pulmonary metastases. A postoperative morbidity rate of 23.8% and a 30-day mortality rate of 4.8% were reported. A cumulative overall survival of 34.19±23.51months (95% CI 23.71-50.28) and a disease-free interval of 24.62±23.79months (95% CI 6.44-39.56) were observed. By considering only R0 surgically resected patients, the 1-, 3- and 5-year OS were 94.1, 59.5 and 21.2% with a mean overall survival and disease-free interval of 51.10±7.82 and 42.75±9.35, respectively. Concerning risk factors, an important correlation between the number of pulmonary metastases, surgical radicality and overall survival was reported (p=0.030 and p=0.005, respectively). In summary, according to our series, pulmonary metastasectomy in selected elderly CRC oligometastatic patients seems to be safe and effective.