Presence Of Lung Metastases Research Articles

Colorectal cancer liver metastases \u2013 a population-based study on incidence, management and survival

BackgroundColorectal cancer (CRC) is a leading cause of cancer-associated deaths with liver metastases developing in 25–30% of those affected. Previous data suggest a survival difference between right- and left-sided liver metastatic CRC, even though left-sided cancer has a higher incidence of liver metastases. The aim of the study was to describe the liver metastatic patterns and survival as a function of the characteristics of the primary tumour and different combinations of metastatic disease.MethodsA retrospective population-based study was performed on a cohort of patients diagnosed with CRC in the region of Stockholm, Sweden during 2008. Patients were identified through the Swedish National Quality Registry for Colorectal Cancer Treatment (SCRCR) and additional information on intra- and extra-hepatic metastatic pattern and treatment were retrieved from electronic patient records. Patients were followed for 5 years or until death. Factors influencing overall survival (OS) were investigated by means of Cox regression. OS was compared using Kaplan-Meier estimations and the log-rank test.ResultsLiver metastases were diagnosed in 272/1026 (26.5%) patients within five years of diagnosis of the primary. Liver and lung metastases were more often diagnosed in left-sided colon cancer compared to right-sided cancer (28.4% versus 22.1%, p = 0.029 and 19.7% versus 13.2%, p = 0.010, respectively) but the extent of liver metastases were more extensive for right-sided cancer as compared to left-sided (p = 0.001). Liver metastatic left-sided cancer, including rectal cancer, was associated with a 44% decreased mortality risk compared to right-sided cancer (HR = 0.56, 95% CI: 0.39–0.79) with a 5-year OS of 16.6% versus 4.3% (p < 0.001). In liver metastatic CRC, the presence of lung metastases did not significantly influence OS as assessed by multivariate analysis (HR = 1.11, 95% CI: 0.80–1.53).ConclusionThe worse survival in liver metastatic right-sided colon cancer could possibly be explained by the higher number of metastases, as well as more extensive segmental involvement compared with left-sided colon and rectal cancer, even though the latter had a higher incidence of liver metastases. Detailed population-based data on the metastatic pattern of CRC and survival could assist in more structured and individualized guidelines for follow-up of patients with CRC.

Combined peripheral natural killer cell and circulating tumor cell enumeration enhance prognostic efficiency in patients with metastatic triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis. Circulating tumor cells (CTCs) are a promising predictor for breast cancer prognoses but their reliability regarding progression-free survival (PFS) is controversial. We aim to verify their predictive value in TNBC. In present prospective cohort study, we used the Pep@MNPs method to enumerate CTCs in baseline blood samples from 75 patients with TNBC (taken at inclusion in this study) and analyzed correlations between CTC numbers and outcomes and other clinical parameters. Median PFS was 6.0 (range: 1.0-25.0) months for the entire cohort, in whom we found no correlations between baseline CTC status and initial tumor stage (P=0.167), tumor grade (P=0.783) or histological type (P=0.084). However, among those getting first-line treatment, baseline CTC status was positively correlated with ratio of peripheral natural killer (NK) cells (P=0.032), presence of lung metastasis (P=0.034) and number of visceral metastatic site (P=0.037). Baseline CTC status was predictive for PFS in first-line TNBC (P=0.033), but not for the cohort as a whole (P=0.118). This prognostic limitation of CTC could be ameliorated by combining CTC and NK cell enumeration (P=0.049). Baseline CTC status was predictive of lung metastasis, peripheral NK cell ratio and PFS in TNBC patients undergoing first-line treatment. We have developed a combined CTC-NK enumeration strategy that allows us to predict PFS in TNBC without any preconditions.

Легочные метастазы при нейробластоме у детей

Lung metastases in patients with neuroblastoma (NB) are an extremely rare situation. Such patients have a worse prognosis and more aggressive clinical behavior of the underlying disease. This article presents an analysis of the epidemiological, clinical, radiologic features and prognosis of the disease in a group of patients with stage 4 NB and lung metastases. The cohort of NB patients with stage 4 according to the International Neuroblastoma Staging System (INSS) treated in NRC PHOI named after Dmitry Rogachev for the period 01.2012–12.2016 (60 months) was included in the analysis. Patients were stratified and treated according to the modified protocol NB-2004. Comparative analysis of patients with high-risk NB with and without lung metastases was done. Estimated event-free and overall survival were determined using Kaplan–Meier methods. Among 132 patients with stage 4 NB lung metastases were detected in 10 cases, which represented 7.5% of the whole group. The median age of the patients with lung metastases was 26.4 months (range 4.3–92.5). 9 (90%) patients were stratified to highrisk group, 1 (10%) to intermediate risk group. Comparative analysis of patients with stage 4 high-risk NB with and without lung metastases showed no statistical difference in comparison by sex, age, localization of the primary tumor, MYCN status, and the number of metastatic compartments. Progression during induction therapy was more frequent in patients with lung metastases (p = 0.02). 2-year overall survival (OS) in the group of patients with lung metastases was lower than in group without metastases to the lung (50.0 ± 15.8% vs 75.9 ± 3.9%, p = 0.045). In our study, the presence of lung metastases was more common than was described elsewhere and is clinically important because it portends a poor prognosis.

Retrospective study of predictors of bone metastasis in colorectal cancer patients

BackgroundWe explored risk factors for bone metastasis (BMs) in colorectal cancer (CRC) to improve in early diagnosis and follow-up and to reduce bone metastasis. MethodsWith a retrospective analysis of 2066 patients with CRC treated in our institution from January 2006 to January 2015, we assessed high-risk variables associated with bone metastasis using univariate and multivariate analyses. ResultsOf those subjects studied, 102 patients developed BMs, including 62 of 1014 the rectal cancer patients and 40 of the 1052 colon cancer patients. Lung metastases were accounting for 59.8% of the BMs (χ2 = 17.7, p<0.01) and hepatic metastases were accounting for 34.3% of BMs (χ2 = 3.06,p >0.05). BMs were diagnosed more rapidly in the presence of lung metastases(6.9 months versus 11.6 months for liver metastases). Univariate analysis revealed that BMs were associated with primary tumor location (p < 0.001), lung metastases (p < 0.001), initial stage (p = 0.001), radiotherapy (p < 0.001) and serum carcinoembryonic antigen (CEA) (p=0.001). Multivariate analysis revealed that primary tumor location (rectum), lung metastases, and serum CEA (>5μg/L) were statistically significant (p <0.05). ConclusionsBMs in rectal cancer occur more frequently than in colon cancer. Lung metastases predicted potential progression to bone in CRCs more than liver metastases. Primary rectal locations, lung metastases and serum CEA were independent risk factors for BMs in CRC. Thus, patients should receive early bones scanning when presenting with CRC.

Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer.

Mucin-4 (Muc4) is a large cell surface glycoprotein implicated in the protection and lubrication of epithelial structures. Previous studies suggest that aberrantly expressed Muc4 can influence the adhesiveness, proliferation, viability and invasiveness of cultured tumor cells, as well as the growth rate and metastatic efficiency of xenografted tumors. While it has been suggested that one of the major mechanisms by which Muc4 potentiates tumor progression is via its engagement of the ErbB2/HER2 receptor tyrosine kinase, other mechanisms exist and remain to be delineated. Moreover, the requirement for endogenous Muc4 for tumor growth progression has not been previously explored in the context of gene ablation. To assess the contribution of endogenous Muc4 to mammary tumor growth properties, we first created a genetically-engineered mouse line lacking functional Muc4 (Muc4ko), and then crossed these animals with the NDL model of ErbB2-induced mammary tumorigenesis. We observed that Muc4ko animals are fertile and develop normally, and adult mice exhibit no overt tissue abnormalities. In tumor studies, we observed that although some markers of tumor growth such as vascularity and cyclin D1 expression are suppressed, primary mammary tumors from Muc4ko/NDL female mice exhibit similar latencies and growth rates as Muc4wt/NDL animals. However, the presence of lung metastases is markedly suppressed in Muc4ko/NDL mice. Interestingly, histological analysis of lung lesions from Muc4ko/NDL mice revealed a reduced association of disseminated cells with red and white blood cells. Moreover, isolated cells derived from Muc4ko/NDL tumors interact with fewer blood cells when injected directly into the vasculature or diluted into blood from wild type mice. We further observed that blood cells more efficiently promote the viability of non-adherent Muc4wt/NDL cells than Muc4ko/NDL cells. Together, our observations suggest that Muc4 may facilitate metastasis by promoting the association of circulating tumor cells with blood cells to augment tumor cell survival in circulation.

Risk factors associated with metastatic site failure in patients with high-risk neuroblastoma.

10557 Background: This retrospective study sought to identify predictors of metastatic site failure (MSF) in patients with high-risk (HR) neuroblastoma (NB). Methods: Seventy-six patients with HR NB treated on prospective trials at from 1997 to 2014 were eligible for inclusion. All patients were treated with induction chemotherapy (chemo) with surgery followed by myeloablative chemo &amp; stem cell rescue. Primary &amp; metastatic site (MS) RT were applied according to institutional protocol. CT &amp; I-123 MIBG scans were used to assess Curie scores at diagnosis, post-induction, post-transplant &amp; failure. Overall (OS), &amp; progression-free survival (PFS) were described using the Kaplan-Meier estimator. Cox proportional hazards frailty (cphfR) &amp; CPH regression (CPHr) were used to identify covariates predictive of MSF &amp; new site MSF. Results: Forty-two (55%) patients had documented MSFs. Consolidative MS RT was applied to 30 MSs in 10 patients. Original site MSF occurred in 146 of 383 (38%) &amp; 18 of 30 (60%) non-irradiated &amp; radiated MSs respectively. Original site MSF occurred in post-induction MIBG avid lesions in 68 of 81 (84%) &amp; 12 of 14 (85%) non-irradiated &amp; radiated MSs respectively. The median OS &amp; PFS were 61 mo (95% CI 42.6-NR) &amp; 24.1 mo (95% CI 16.5-38.7). Univariate cphfR identified an increased hazard for original MSF when MIBG avid following induction chemo (HR 4.9, 95%CI 1.1-20.9, p = 0.03) &amp; transplant (HR 7.3 95%CI 1.8-30.2, p = 0.006) relative to lesions that cleared after induction. Notably, MS RT nor site location did not modify the hazard for MSF. Multivariate CPHr identified inability to undergo transplant (HR 32.4 95%CI 9.3-96.8, p &lt; 0.001) &amp;/or maintenance chemo (HR 5.2, 95%CI 1.7-16.2, p = 0.005) &amp; the presence of lung metastases (HR 4.4 95%CI 1.7-11.1, p = 0.002) at diagnosis as predictors of new site MSF. The new MSF free survival at 3 years was 25% vs. 87% in patients with high-risk factors relative to those without the risk factors suggesting limited benefit of consolidative MS RT in this population. Conclusions: Metastatic lesions that remained MIBG avid following induction chemo &amp; post-transplant had an increased hazard for MSF. Consolidative site RT likely has limited benefit in patients with HR features.

Alopecia neoplastica: An uncommon presentation of metastatic breast carcinoma

&lt;p&gt;Cutaneous metastasis may correspond to the initial clinical presentation of hidden internal malignancies. In patients presenting said neoplasia, clinical manifestations of breast cancer reaches 23.9%. Considering that neoplastic alopecia appears as an unusual pattern of the said metastasis, this report describes a case of such uncommon neoplastic alopecia which presents itself as a cutaneous metastasis of rapid progression in a patient with prior breast cancer history. We present a 47-year-old female patient reporting lesions at the scalp, and who was asymptomatic with a 1-year evolution. The patient reported prior breast cancer history and presence of lung metastasis, and was undergoing chemotherapy at the time of consultation. A dermatological evaluation showed only a nodular lesion with erythematous surface and a diameter measuring about 4 cm, firm in consistency, and immovable. She was routed to the Department of Dermatological Surgery, and the results from histopathology were consistent with a diagnosis of metastatic breast adenocarcinoma. Neoplastic alopecia appears as an unusual form of cutaneous metastasis which is predominantly described in association with breast cancer. The lesion’s clinical features play a crucial role at the differential diagnosis, as the presence of erythema could distinguish neoplastic alopecia from alopecia areata. The existence of cutaneous metastasis leads to unfavorable outcomes. As a conclusion, cutaneous evaluation of patients is essential for treating visceral metastases, since the forms of cutaneous metastasis are diverse and can also affect the scalp.&lt;/p&gt;

580P - Risk factors for brain metastases in patients with metastatic colorectal cancer

Brain metastases (BM) from colorectal cancer (CRC) are rare and usually develop late in the disease. However, it has been suggested that more patients will be diagnosed with BM from CRC due to improved diagnostics and increased survival. The aim of this study was to identify biological and clinical characteristics that could predict later BM development in long surviving patient with metastatic (m) CRC. We retrospectively reviewed a multicenter database and biobank encompassing consecutive patients with mCRC who all received cetuximab in combination with irinotecan as third-line treatment independently of RAS status between 2005 and 2008. We performed RAS (KRAS & NRAS), BRAF, and PIK3CA sequencing of DNA from primary tumor tissue. Totally, 480 patients were included in the study. BM were diagnosed in 42 patients (8.8 %) at median 29 months after mCRC diagnosis. Patient characteristics are shown in table 1. Patients with BM had a significantly longer survival from mCRC diagnosis than non-BM patients (32 months vs 28 months, p = 0.001). On univariate cox regression analysis the risk of developing BM was increased in patients with rectal cancer (Hazard ratio (HR) = 2.478, p = 0.005), metachronous metastatic disease (HR = 2.296, p = 0.013), and lung metastases at mCRC diagnosis (HR = 4.196, p < 0.0005). RAS, BRAF or PIK3CA were not associated with BM. On multivariate cox regression, only presence of lung metastases (HR = 3.534, p < 0.0005) was significantly associated with increased hazard of BM. The incidence of BM was 8.8 % in our cohort of long surviving patients with mCRC. Having lung metastases at mCRC diagnosis seems to be an independent risk factor for later BM development. Rectal cancer and metachronous metastatic disease were also linked to an increased risk of BM.Tabled 1Patient characteristics-BM 438 patients+BM 42 patientsMedian age at CRC diagnosis60 years58 yearsRectal cancer153 (35 %)26 (62 %)Metachronous metastatic disease188 (43 %)28 (67 %)Lung metastases130 (30 %)26 (62 %)RAS Mut184 (42 %)20 (48 %)BRAF Mut30 (7 %)0PIK3CA Mut58 (13 %)7 (16 %) Open table in a new tab

Effect of Bleomycin Administration on the Development of Pulmonary Toxicity in Patients With Metastatic Germ Cell Tumors Receiving First-Line Chemotherapy: A Meta-Analysis of Randomized Studies.

Limited information is available about the effect of bleomycin administration on the development of pulmonary toxicity in metastatic germ cell tumors (GCT). A literature search was conducted to identify randomized trials of first-line chemotherapy for GCT. We conducted univariate and multivariate analyses using random effects models to evaluate the predictive role of bleomycin administration in the development of all Grade and Grade 3 to 4 (G3-4) pulmonary toxicity. The results were adjusted for length of follow-up, prognostic risk group, year of treatment, presence of lung metastases, and primary mediastinal GCT. Fifty-three study arms of 25 phase II and III trials encompassing 6498 patients were selected: 40 that used bleomycin (n= 5093) and 13 that did not (n=1405). The pooled probability of all-Grade pulmonary toxicity in the bleomycin and nonbleomycin arms was 11.7% (95% confidence interval [CI], 8.4%-16.0%) and 1.7% (95% CI, 0.7%-4.2%), respectively. Univariate analysis indicated that bleomycin administration was associated with the incidence of all-Grade (odds ratio [OR], 7.57; 95% CI, 2.84-20.18; Wald test P< .001) and G3-4 pulmonary toxicity (OR, 5.19; 95% CI, 1.57-17.16; P= .007). Multivariate analysis showed a significant association of bleomycin administration with the incidence of all-Grade pulmonary toxicity (OR, 4.14; 95% CI, 1.36-12.59; P= .012) and a trend toward significance for G3-4 toxicity (OR, 2.24; 95% CI, 0.91-5.51; P= .080). We quantified the bleomycin-associated effect on the development of pulmonary toxicity in patients with GCT who received first-line chemotherapy. This information might be useful for planning clinical trials aimed at reducing chemotherapy as well as to inform patients in the clinic.

Predictors of responses to corticosteroids for anorexia in advanced cancer patients: a multicenter prospective observational study.

Although corticosteroids are widely used to relieve anorexia, information regarding the factors predicting responses to corticosteroids remains limited. The purpose of the study is to identify potential factors predicting responses to corticosteroids for anorexia in advanced cancer patients. Inclusion criteria for this multicenter prospective observational study were patients who had metastatic or locally advanced cancer and had an anorexia intensity score of 4 or more on a 0-10 Numerical Rating Scale (NRS). Univariate and multivariate analyses were conducted to identify the factors predicting ≥2-point reduction in NRS on day 3. Among 180 patients who received corticosteroids, 99 (55%; 95% confidence interval [CI], 47-62%) had a response with ≥2-point reduction. Factors that significantly predicted responses were Palliative Performance Scale (PPS)>40 and absence of drowsiness. In addition, factors that tended to be associated with ≥2-point reduction in NRS included PS 0-3, absence of diabetes mellitus, absence of peripheral edema, presence of lung metastasis, absence of peritoneal metastasis, baseline anorexia NRS of >6, presence of pain, and presence of constipation. A multivariate analysis showed that the independent factors predicting responses were PPS of >40 (odds ratio=2.7 [95% CI=1.4-5.2]), absence of drowsiness (2.6 [1.3-5.0]), and baseline NRS of >6 (2.4 [1.1-4.8]). Treatment responses to corticosteroids for anorexia may be predicted by PPS, drowsiness, and baseline symptom intensity. Larger prospective studies are needed to confirm these results.

The influence of lung metastases on the clinical course of gestational trophoblastic neoplasia: a historical cohort study.

To evaluate whether gestational trophoblastic neoplasia (GTN) patients with lung metastases have more adverse outcomes such as resistance to chemotherapy, recurrence or death of disease compared with patients without lung metastases. Historical observational cohort study. The Netherlands. We identified 434 GTN patients (72 patients with lung metastases, 362 patients without metastases) between 1990 and 2012 registered in the Dutch national databases. Baseline characteristics, recurrence rates, Methotrexate (MTX) remission rates and deaths from disease were compared between patients with lung metastases (group I) and without lung metastases (group II) using the Fisher exact test or Mann-Whitney U-test where applicable. Methotrexate resistance, recurrences and survival. Methotrexate resistance did not differ between group I and group II (62.9 versus 72.7% P=0.19). However, the observed recurrence rate was significantly increased in patients with lung metastases compared with patients without metastases (16.7 versus 2.2% P<0.0001), also after correction for antecedent pregnancy and interval (from the end of the antecedent pregnancy until the start of treatment). Disease-specific survival was 91.7% in the group with lung metastases and 100% in the patients without metastases (P<0.0001). Although lung metastases are considered to be associated with a low risk of adverse outcomes, their presence appears to increase the risk for recurrence and death of disease. Further research is needed to evaluate whether the presence of lung metastases is an independent risk factor that needs adjustment in the FIGO scoring system and clinical classification system. In gestational trophoblastic neoplasia (GTN) recurrence is more often observed in the case of lung metastases.

Tumour biology, metastatic sites and taxanes sensitivity as determinants of eribulin mesylate efficacy in breast cancer: results from the ERIBEX retrospective, international, multicenter study.

BackgroundOur retrospective, international study aimed at evaluating the activity and safety of eribulin mesylate (EM) in pretreated metastatic breast cancer (MBC) in a routine clinical setting.MethodsPatients treated with EM for a locally advanced or MBC between March 2011 and January 2014 were included in the study. Clinical and biological assessment of toxicity was performed at each visit. Tumour response was assessed every 3 cycles of treatment. A database was created to collect clinical, pathological and treatment data.ResultsTwo hundred and fifty-eight patients were included in the study. Median age was 59 years old. Tumours were Hormone Receptor (HR)-positive (73.3 %) HER2-positive (10.2 %), and triple negative (TN, 22.5 %). 86.4 % of the patients presented with visceral metastases, mainly in the liver (67.4 %). Median previous metastatic chemotherapies number was 4 [1–9]. Previous treatments included anthracyclines and/or taxanes (100 %) and capecitabine (90.7 %). Median number of EM cycles was 5 [1–19]. The relative dose intensity was 0.917. At the time of analysis (median follow-up of 13.9 months), 42.3 % of the patients were still alive. The objective response rate was 25.2 % (95 %CI: 20–31) with a 36.1 % clinical benefit rate (CBR). Median time to progression (TTP) and overall survival were 3.97 (95 %CI: 3.25–4.3) and 11.2 (95 %CI: 9.3–12.1) months, respectively. One- and 2-year survival rates were 45.5 and 8.5 %, respectively. In multivariate analysis, HER2 positivity (HR = 0.29), the presence of lung metastases (HR = 2.49) and primary taxanes resistance (HR = 2.36) were the only three independent CBR predictive factors, while HR positivity (HR = 0.67), the presence of lung metastases (HR = 1.52) and primary taxanes resistance (HR = 1.50) were the only three TTP independent prognostic factors. Treatment was globally well tolerated. Most common grade 3–4 toxicities were neutropenia (20.9 %), peripheral neuropathy (3.9 %), anaemia (1.6 %), liver dysfunction (0.8 %) and thrombocytopenia (0.4 %). Thirteen patients (5 %) developed febrile neutropenia.ConclusionEM is an effective new option in heavily pretreated MBC, with a favourable efficacy/safety ratio in a clinical practice setting. Our results comfort the use of this new molecule and pledge for the evaluation of EM-trastuzumab combination in this setting. Tumour biology, primary taxanes sensitivity and metastatic sites could represent useful predictive and prognostic factors.

Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival.

BackgroundThe development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists.MethodsClinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined.ResultsBevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS.ConclusionOur findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1648-4) contains supplementary material, which is available to authorized users.

Prognostic score in high-grade gastrointestinal neuroendocrine tumours (GI-NETs).

Background: Outcomes of patients with high-grade GI-NETs are poor; prognostic markers for risk-stratification are needed.Methods: Consecutive patients, diagnosed with high-grade GI-NETs between 1997-2014, were included. Prognostic factors were identified by the Log-rank test, Cox regression and logistic regression and ROC curve comparisons performed for prediction accuracy. Internal validation of the score by Bootstrap-corrected Harrell Concordance Index (C-index) and Resampling Model Calibration were performed.Results: One-hundred and nine patients were eligible for analysis. Median follow-up time was 9.7 months (1.3-102.9). Median age: 67.7 years (16.3-84.1); 62% male, 84% metastatic; 19% foregut, 5% midgut, 19% pancreas, 28% hindgut and 29% unknown primary. Median ki67: 70% (20-100); ECOG PS 0: 26%, 1: 52%; 70% received chemotherapy. Baseline median alkaline phosphatase (ALK) and LDH were 109 IU/l (45-2035) and 70 IU/l (258-11069), respectively. The maximum model included stage, PS, LDH, Na, ALK, ki67, number of metastatic sites, presence of liver and presence of lung metastases. The score, selected by the lowest Akaike Index Criterion, included liver metastases, PS, ki67, LDH and ALK with 0-6 points assigned to each, resulting in 4 risk groups (A-D) with predicted risk of death, detailed in Table. There was no difference in the survival prediction accuracy between the maximum model and the score. On multivariable analysis, the score was prognostic for overall survival (HR 1.95, 95%CI 1.55-2.47; p < 0.001) and had good discrimination (C-index, 0.76) and calibration (mean error, 0.021; percentile 90, 0.037).Conclusions: This simple score identified high-grade GI-NET patients with meaningful differences in survival and may inform clinical decision-making and trial design.

Abstract P4-01-06: Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis

Abstract Introduction: Real-time monitoring of biological changes in tumors that metastasize may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in patients with localized disease pose major hurdles. The goal of this study was to determine if breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes. Methods: CTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counter staining of RBC-lysed blood and bone marrow fractions, respectively. The lung metastasis (LM) rate was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher’s Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed using the gene expression arrays of primary tumors from different PDX lines and were subsequently overlapped to identify common genes. Results: A total of 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present either as single cells or as clusters, were detected in 83% (15/18) and 62.5% (10/16) of the lines, respectively. There was a positive association between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 out of 18 (50%) lines, of which all 9 had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the 2 genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified 4 genes (HLA-DP1A, GJA1, PEG3, and XIST). This 4-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients. Conclusion: This study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases. Citation Format: Mario Giuliano, Sabrina Herrera, Pavel Christiny, Chad Shaw, Chad J Creighton, Tamika Mitchell, Raksha Bhat, Xiaomei Zhang, Sufeng Mao, Lacey Dobrolecki, Ahmed Al-rawi, Fengju Chen, Bianca M Veneziani, Xiang H Zhang, Susan G Hilsenbeck, Alejandro Contreras, Carolina Gutierrez, Rinath Jeselsohn, Mothaffar F Rimawi, C Kent Osborne, Michael T Lewis, Rachel Schiff, Meghana V Trivedi. Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-01-06.

Prognostic factors and survival rate of osteosarcoma: A single-institution study.

Osteosarcoma is a highly malignant primary bone tumor. The study aim to evaluate the prognostic factors influencing the survival rate in our center. This was a retrospective cohort study of all patients treated between January 2005 and December 2010. We included 163 patients with an age range of 6-59 years (median = 19). The median follow-up was 47 months (range 36-84). The overall survival in patients who completed chemotherapy and surgery (n = 117) was 72% at 2 years and 44% at 5 years. Histologically, 99 (85%) had osteoblastic, 6 (5%) had chondroblastic and 3 (2.5%) had telangiectatic osteosarcoma. Limb salvage surgery was performed in 80 (49%) and 41 (25%) underwent amputation. However, 46 patients (28%) underwent no surgical intervention and incomplete chemotherapy. In total, 38/79 patients had a good chemotherapy response. There was a significantly better survival rate for limb salvage versus amputation. Independent prognostic factors for survival are compliance to treatment and presence of lung metastasis. The overall survival of osteosarcoma patients was influenced by the presence of pulmonary metastases and compliance to treatment. Histological subtype, different chemotherapy regimens and histological necrosis after chemotherapy did not significantly influence survival. The patients who did not complete treatment had significantly poorer survival.

Circulating and disseminated tumor cells from breast cancer patient-derived xenograft-bearing mice as a novel model to study metastasis.

IntroductionReal-time monitoring of biologic changes in tumors may be possible by investigating the transitional cells such as circulating tumor cells (CTCs) and disseminated tumor cells in bone marrow (BM-DTCs). However, the small numbers of CTCs and the limited access to bone marrow aspirates in cancer patients pose major hurdles. The goal of this study was to determine whether breast cancer (BC) patient-derived xenograft (PDX) mice could provide a constant and renewable source of CTCs and BM-DTCs, thereby representing a unique system for the study of metastatic processes.MethodsCTCs and BM-DTCs, isolated from BC PDX-bearing mice, were identified by immunostaining for human pan-cytokeratin and nuclear counterstaining of red blood cell-lysed blood and bone marrow fractions, respectively. The rate of lung metastases (LM) was previously reported in these lines. Associations between the presence of CTCs, BM-DTCs, and LM were assessed by the Fisher’s Exact and Cochran-Mantel-Haenszel tests. Two separate genetic signatures associated with the presence of CTC clusters and with lung metastatic potential were computed by using the expression arrays of primary tumors from different PDX lines and subsequently overlapped to identify common genes.ResultsIn total, 18 BC PDX lines were evaluated. CTCs and BM-DTCs, present as either single cells or clusters, were detected in 83% (15 of 18) and 62.5% (10 to16) of the lines, respectively. A positive association was noted between the presence of CTCs and BM-DTCs within the same mice. LM was previously found in 9 of 18 (50%) lines, of which all nine had detectable CTCs. The presence of LM was strongly associated with the detection of CTC clusters but not with individual cells or detection of BM-DTCs. Overlapping of the two genetic signatures of the primary PDX tumors associated with the presence of CTC clusters and with lung metastatic potential identified four genes (HLA-DP1A, GJA1, PEG3, and XIST). This four-gene profile predicted distant metastases-free survival in publicly available datasets of early BC patients.ConclusionThis study suggests that CTCs and BM-DTCs detected in BC PDX-bearing mice may represent a valuable and unique preclinical model for investigating the role of these rare cells in tumor metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0508-5) contains supplementary material, which is available to authorized users.

BM-31 * STUDY OF INCIDENCE AND ESTIMATION OF RISK FACTORS ASSOCIATED WITH HIPPOCAMPAL METASTASIS

BACKGROUND: Modern radiation techniques are being used to attempt hippocampal-sparing whole brain RT in brain metastasis in order to minimize neurocognitive decline. However this technique is accompanied by potential risk of recurrence. AIMS: To evaluate the incidence of metastasis in the region and identify factors which can predict the occurrence of metastasis in this region. METHOD: Pre-treatment MRIs of 40 cases(median age 55)with single or multiple brain metastases between Jan 2010-Dec 2013 were analysed. The hippocampus was contoured on 1mm thick planning-MRI on T1 image as per RTOG guidelines. All gross lesions were contoured, volume and minimum distance from hippocampus measured. Hippocampus was expanded by 5mm to represent peri-hippocampus. All lesions within this volume were considered as hippocampal region metastases. Various clinical parameters were analysed by Pearson's test for correlation with presence of disease. RESULTS: A total of 120 lesions were found in 40 patients.Incidence of metastasis in the region was 20%(7.5% intra-hippocampal, 12.5% peri-hippocampal) of which 50% had breast primary, 27.5% lung,12.5% endometrium. Primary was controlled in 62.5%, 62.5% had received chemotherapy before diagnosis of brain metastasis. 87.5% of patients with disease also had lung metastasis. Median aggregate volume and number of brain metastasis was 5.5cc and 2,while in those with disease it was 23.81cc and 6. Among the parameters tested for correlation with presence of metastasis, median aggregate volume(p = 0.001) and number of metastasis (p = 0.0001) had significant correlation, while presence of lung metastasis had a trend towards significance (p = 0.09). CONCLUSION: Metastasis in the region are more likely to be present in patients who have larger number, larger aggregate volume of brain metastases and advanced systemic disease(lung-metastasis).

Abstract 1088: Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases

Abstract Purpose Compared with most other cancer types, breast cancer has a long natural history. In cases with delayed relapse, the unlinearity of disease progression indicates the presence of periods of tumor dormancy. Clinical and experimental studies indicate that growth might be induced by a physiological event like tissue injury following surgery. In this study we aimed to quantify size and number of metastatic lesions in relation to time between primary surgery and first relapse. Our goal was to find clinical support for the presence of a systemic synchronizing growth signal. Patients and methods All patients (n=209) recorded with metastatic breast cancer at our department during 2004-9 were identified. 180 cases with measurable metastases according to RECIST 1.1 and no metastases at the time of primary surgery (&amp;lt; 2 months), were evaluable. Number of metastatic lesions as well as size of each lesion was recorded at the time of first recurrence. Standard Deviation (SD) of the lesions sizes in each patient was calculated and served as a marker for variability in the metastatic pattern. Patients with a high SD were assumed to have unsynchronized (individual) growth of lesions, whereas patients with low SD were regarded to have synchronized growth. Results Median number of metastatic lesions at first recurrence was 7 (1- &amp;gt;10). Cases with only 1 metastasis (n=38) were excluded from the analyses on SD. Median SD was 5.4 (0.0 - 58). Low SD was significantly associated with low histological grade in primary tumors (Pearson Chi Square p= 0.002), absence of liver metastases (p= 0.001) and presence of lung metastases (p= 0.02). No significant association was found between SD and ER status, Her2 status, nodal status or stage. There was also no significant association between nodal status and time to recurrence (TTR). Patients were grouped according to TTR into two groups; early (&amp;lt; 3years-) or late (&amp;gt; 3 years- after primary diagnosis). In the subgroup of patients that were lymph node negative at primary diagnosis (N0), the median SD was significantly lower in the early group (3.0) when compared with the late group (5.7)(Mann-Whitney U test p= 0.02). This effect was not present in the lymph node positive (N1) patients. Conclusions Our data indicate the presence of a metastatic phenotype characterized by multiple, similar sized metastases. The results support synchronized growth of dormant micrometastases in some cases of breast cancer. The fact that this effect was only present in lymph node negative patients, suggests that micrometastatic tumor dormancy is especially important in this group, with otherwise favorable prognosis. Systemic effects of growth factors released during wound healing following surgery might induce a switch from the dormant state into simultaneous growth of occult micrometastases. Further studies to explore these mechanisms are ongoing. Citation Format: Hanna Dillekås, Monica Transeth, Martin Pilskog, Jörg Assmus, Oddbjorn Straume. Differences in metastatic patterns in relation to time between primary surgery and first relapse from breast cancer suggest synchronized growth of dormant micrometastases. [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 1088. doi:10.1158/1538-7445.AM2014-1088

795P - A Prognostic Model for Predicting Radiographic Progression- Free Survival (Rpfs) in Metastatic Castrate-Resistant Prostate Cancer Men Treated with Second-Line Chemotherapy

ABSTRACT Aim: This work sought to develop and validate a prognostic model to predict rPFS in men who had progressed following first-line chemotherapy, and were selected to receive second-line chemotherapy. Methods: Data from a phase III trial in mCRPC men who had developed progressive disease following first-line chemotherapy (TROPIC trial) were used. The TROPIC was randomly split into training (n = 507) and testing (n = 248) sets. RPFS was defined as the time from randomization to first bone progression, objective progression (RECIST1.1), or death, whichever occurred first. Adaptive LASSO selected eight prognostic factors of rPFS. A prognostic score was computed from the regression coefficients and the model was assessed on the testing set for its predictive accuracy using the time-dependent area under the curve (tAUC). Results: The eight prognostic variables in the final model included: ECOG performance status, race, time since last docetaxel use, presence of lung metastases, presence of liver metastases, duration of hormonal use, hemoglobin, and treatment with cabazitaxel. In the training and testing sets, the tAUC for this model were 0.72 (95% CI = 0.66-0.79) and 0.67 (95% CI = 0.60-0.76) respectively. Conclusions: A prognostic model of rPFS in the post-docetaxel second-line chemotherapy mCRPC setting was developed and validated. This model incorporates established prognostic factors and can be used to select patients to participate in clinical trials on the basis of their prognosis. External validation is needed. Disclosure: S. Halabi: Reserach support from sanofi; A.J. Armstrong: Research support and consultant for sanofi; L. Shen: Sanofi employee; S. Oudard: Consultant and investigator for sanofi; O. Sartor: Consultant for sanofi, Bayer, Astellas, Janssen; J.S. de Bono: Consultant and Investigator for Sanofi. All other authors have declared no conflicts of interest.