Pattern Of Metastatic Spread Research Articles

Abstract 3992: Modes of metastasis evolution in human and murine cancer revealed by whole exome sequencing

Abstract Despite that fact that 90% of cancer deaths are due to metastasis, relatively little is known about how metastases evolve from primary cancers. We subjected 101 trios consisting of primary tumor, brain metastasis, and normal reference tissue to whole exome sequencing (WES). To analyze the data, we developed novel computational tools to derive high quality allelic copy-number profiles directly from the WES data. These were used to perform an integrative analysis of somatic copy-number alterations (SCNAs) and somatic single nucleotide variants (SSNVs). This analysis allowed us to estimate the clonal architecture of the primary and metastatic samples from each patient, and to reconstruct a single phylogenetic tree relating all of the subclones detected in both samples. We determined that all of the matched metastases analyzed likely formed from a single clone. In all cases, we observed a sibling relationship between the metastasis and primary tumor samples, indicating that they share a common ancestor, but ongoing evolution in the primary tumor resulted in fully clonal mutations in the primary biopsy that were not present in the metastasis sample. An important corollary of this is that in no case was a metastasis-founding subclone detected in a primary tumor sample. Using mutational spectra associated with tobacco exposure in lung cancers, we determined that most of the evolution leading up to the brain metastasis like occurred within the lung. In contrast with these findings, analysis of related primary tumor and metastasis families in a mouse model of small cell lung cancer using identical methodology revealed evidence of more variable patterns of metastatic spread. Analysis of draining lymph nodes revealed that multiple subclones of the primary contributed to these metastases. In addition, we uncovered evidence for the sequential spread of metastases, consistent with multiregion sequencing of primary and metastatic human pancreatic cancer. The extension of this finding to a mouse cancer model suggests this may be a more frequent feature of cancer metastasis, and raises the possibility of genetically dissecting these processes in this experimental system. Citation Format: Scott L. Carter, Priscilla K. Brastianos, David G. McFadden, Thales Papagiannakopoulos, Amaro Taylor-Weiner, Kristian Cibulskis, Tyler Jacks, William Hahn, Gad Getz. Modes of metastasis evolution in human and murine cancer revealed by whole exome sequencing. [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 3992. doi:10.1158/1538-7445.AM2014-3992

Histopathological mapping of metastatic tumor cells in sentinel lymph nodes of oral and oropharyngeal squamous cell carcinomas.

Sentinel lymph node biopsy is a reliable technique for accurate determination of the cervical lymph node status in patients with early oral and oropharyngeal cancer but analyses on the distribution pattern of metastatic spread within sentinel lymph nodes are lacking. The localizations of carcinoma deposits were analyzed with a virtual microscope by creating digital images from the microscopic glass slides. Metastatic deposits were not randomly distributed within sentinel lymph nodes but were predominant in the central planes closer to the lymphatic inlet. Initial evaluation of the 4 most central slices achieved a high rate of 90% for the detection of micrometastases and of 80% for the detection of isolated tumor cells (ITCs). Based on the distribution we recommend an initial cut through the hilus and to proceed with the 4 most central 150-µm slices. Complete step sectioning is only required in case of a so far negative result.

Sunitinib, Pazopanib or Sorafenib for the Treatment of Patients with Late Relapsing Metastatic Renal Cell Carcinoma

Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Pattern of metastatic spread and prognosis of breast cancer biologic subtypes.

e12532 Background: Few studies have described patterns of metastatic spread according to the major breast cancer biologic subtypes (BS). The aim of this study was to determine the association of BS...

Patterns of metachronous metastases after curative treatment of colorectal cancer

BackgroundThis study aimed to provide information on timing, anatomical location, and predictors for metachronous metastases of colorectal cancer based on a large consecutive series of non-selected patients. MethodsAll patients operated on with curative intent for colorectal cancer (TanyNanyM0) between 2003 and 2008 in the Dutch Eindhoven Cancer Registry were included (N=5671). By means of active follow-up by the Cancer Registry staff within ten hospitals, data on development of metastatic disease were collected. Median follow-up was 5.0 years. ResultsOf the 5671 colorectal cancer patients, 1042 (18%) were diagnosed with metachronous metastases. Most common affected sites were the liver (60%), lungs (39%), extra-regional lymph nodes (22%), and peritoneum (19%). 86% of all metastases was diagnosed within three years and the median time to diagnosis was 17 months (interquartile range 10–29 months). Male gender (HR=1.2, 95%CI 1.03–1.32), an advanced primary T-stage (T4 vs. T3 HR=1.6, 95%CI 1.32–1.90) and N-stage (N1 vs. N0 HR=2.8, 95%CI 2.42–3.30 and N2 vs. N0 HR=4.5, 95%CI 3.72–5.42), high-grade tumour differentiation (HR=1.4, 95%CI 1.17–1.62), and a positive (HR=2.1, 95%CI 1.68–2.71) and unknown (HR=1.7, 95%CI 1.34–2.22) resection margin were predictors for metachronous metastases. ConclusionsDifferent patterns of metastatic spread were observed for colon and rectal cancer patients and differences in time to diagnosis were found. Knowledge on these patterns and predictors for metachronous metastases may enhance tailor-made follow-up schemes leading to earlier detection of metastasized disease and increased curative treatment options.

In-vivo testing of PSMA-targeted T-cell immunotherapy for prostate cancer (TUM7P.920)

Abstract Introduction: Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Examining impact of bone metastasis in vivo remains a significant challenge, as animal models that closely mimic the natural history and malignant progression of clinical prostate cancer are not available. Objectives: To develop an animal model of human metastatic prostate cancer. Once a model has been developed and optimized, it was this to test efficacy of immunotherapy using T-cells that have been genetically targeted against prostate-specific membrane antigen (PSMA). Material and methods: PCR, western blot, flow cytometry and ELISA, we performed functional anaylsis of fucosyltransferase 3(FT3) in PC3LN3(PL)and PC3LN3-PSMA (PLP) tumour cell lines. In vivo bioluminescent imaging (BLI) was used to detect metastases. Results: In preliminary studies, we have observed that delivery of a FT3-encoding retroviral vector to PL and PLP enables them to express sialyl Lewis X and to acquire E-selectin binding activity. We also showed that FT3 promotes increased PLP motility and invasiveness in vitro. Bioluminescent animal model of metastasised prostate cancer is established to determine the effect of this upon their pattern of metastatic spread in SCID Beige mice. Conclusion: We have established an in-vivo model of PSMA-expressing prostate cancer. This will serve as a platform to test immunotherapy using P28z+ T-cells.

Metastatic Neuroblastoma Confined to Distant Lymph Nodes (stage 4N) Predicts Outcome in Patients With Stage 4 Disease: A Study From the International Neuroblastoma Risk Group Database

The presence of distant metastases is one of the most powerful predictors of outcome in patients with neuroblastoma. However, the pattern of metastatic spread is not incorporated into current risk stratification systems. Small case series have suggested that patients with neuroblastoma who have metastatic disease limited to distant lymph nodes (4N disease) may have improved outcomes. We analyzed retrospective data from the International Neuroblastoma Risk Group database for patients diagnosed from 1990 to 2002. 4N patients were compared with the remaining stage 4 patients (non-4N), excluding those with missing metastatic site data. In all, 2,250 International Neuroblastoma Staging System stage 4 patients with complete data were identified, of whom 146 (6.5%) had 4N disease. For 4N patients, event-free survival (EFS; 5-year, 77% ± 4%) and overall survival (OS; 5-year, 85% ± 3%) were significantly better than EFS (5-year, 35% ± 1%) and OS (5-year, 42% ± 1%) for non-4N stage 4 patients (P < .001). 4N patients were more likely to be younger (P < .001) and have tumors with favorable characteristics, including absence of MYCN amplification (89% v 69%; P < .001). In a multivariable analysis, 4N disease remained a significant predictor of outcome (hazard ratio for non-4N v 4N: 3.40 for EFS and 3.69 for OS). Within subgroups defined by age at diagnosis and tumor MYCN status, 4N disease was significantly associated with improved outcomes. 4N represents a subgroup with better outcome than that of other patients with metastatic disease. These findings suggest that the biology and treatment response of 4N tumors differ from other stage 4 tumors, and less intensive therapy should be considered for this cohort. Future exploration of biologic factors determining the pattern of metastatic spread is warranted.

Advanced Digestive Neuroendocrine Tumors

The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

Positive sentinel lymph node metastasis from a metastasis in Melanoma

The rationale for certain patterns of metastatic spread seen in melanoma is not well understood. Currently, there is no clear experimental evidence to support the potential for metastases to form metastases in this disease. We report a case of a 31-year-old woman, with metastatic melanoma, who developed axillary lymph node metastases hypothesized to originate from a breast metastasis rather than the primary disease. Improved understanding of the underlying molecular processes involved in systemic spread would facilitate development of improved adjuvant therapies and prognostic markers.

Prognostic factors influencing prostate cancer‐specific survival in non‐castrate patients with metastatic prostate cancer

In non-castrate prostate cancer (PCa), the prognostic value of the number of metastases on prostate cancer-specific survival (PCSS) is not well studied. We retrospectively analyzed the medical records of 1,206 patients, referred for radiotherapy of the prostate (bed) following diagnosis of PCa. Distant metastases (nodal, skeletal, and/or visceral) developed in 121 patients following curative treatment, of which 80 with complete records were not castrated at time of metastasis. The treatment at time of metastases was androgen deprivation therapy (ADT; n = 22), active surveillance (n = 10) or metastasis-directed therapy (MDT; n = 48). Cox-regression analyses were used to examine the influence of different variables on PCSS. The median follow-up from primary PCa treatment was 6.9 years with a median interval from diagnosis to first metastatic event of 4.1 year (range: 0.2-15 years). The primary site of metastases was limited to lymph nodes (48%), bone (39%), and viscera (1%) or a combination (12%). Median PCSS from diagnosis of noncastrate metastases was 6.6 years (95% confidence interval [CI], 5.6-7.7 years). A longer premetastatic PSA doubling time (DT) (hazard ratio [HR] 0.73; 95% CI: 0.57-0.92), a lower number of metastases at first presentation (HR 1.07; 95% CI: 1.02-1.12) and pattern of metastatic spread (HR 3.6; 95% CI: 1.13-11.8 for extensive vs. minimal) were associated with improved PCSS. A longer PSA DT, involvement of nodes or axial skeleton and a lower number of metastases are associated with an improved PCSS in non-castrated patients developing metastases.

Metastatic Behavior of Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy: Association with Primary Tumor Location

To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

Heterogeneity of Mesenchymal Markers Expression—Molecular Profiles of Cancer Cells Disseminated by Lymphatic and Hematogenous Routes in Breast Cancer

Breast cancers can metastasize via hematogenous and lymphatic routes, however in some patients only one type of metastases are detected, suggesting a certain proclivity in metastatic patterns. Since epithelial-mesenchymal transition (EMT) plays an important role in cancer dissemination it would be worthwhile to find if a specific profile of EMT gene expression exists that is related to either lymphatic or hematogenous dissemination. Our study aimed at evaluating gene expression profile of EMT-related markers in primary tumors (PT) and correlated them with the pattern of metastatic spread. From 99 early breast cancer patients peripheral blood samples (N = 99), matched PT (N = 47) and lymph node metastases (LNM; N = 22) were collected. Expression of TWIST1, SNAI1, SNAI2 and VIM was analyzed in those samples. Additionally expression of CK19, MGB1 and HER2 was measured in CTCs-enriched blood fractions (CTCs-EBF). Results were correlated with each other and with clinico-pathological data of the patients. Results show that the mesenchymal phenotype of CTCs-EBF correlated with poor clinico-pathological characteristics of the patients. Additionally, PT shared more similarities with LNM than with CTCs-EBF. Nevertheless, LNM showed increased expression of EMT-related markers than PT; and EMT itself in PT did not seem to be necessary for lymphatic dissemination.

Rare Pattern of Metastatic Spread of Hormone Insensitive Cancer of the Prostate: GI Tract Involvement without Bony Spread

Rare Pattern of Metastatic Spread of Hormone Insensitive Cancer of the Prostate: GI Tract Involvement without Bony Spread

Lararoscopic Retroperitoneal Lymph Node Dissection for Paratesticular Rhabdomyosarcoma in Older Children/Adolescents

Testicular tumors are far more common in adults than in children. For this reason, management of pediatric testis tumors has been based on experience in adults. However, there are important differences between testis tumors occurring in children and those occurring in adults. These differences involve tumor histopathology, malignant potential, and pattern of metastatic spread [1]. The majority of primary testis tumors in the Prepubertal Testis Tumor Registry of the Urologic Section of the American Academy of Pediatrics were yolk sac tumors, followed by teratomas and stromal tumors. Because teratomas and most stromal tumors are benign in children, it would follow that fewer than two thirds of prepubertal testis tumors have malignant potential, compared with 90 % of tumors in adults. It is even possible that the majority of prepubertal tumors are benign. Several single-center studies suggest that teratomas are more common than yolk sac tumors in pediatric patients; however, these studies were not limited to prepubertal patients [2–5] . Paratesticular rhabdomyosarcomas usually present with an enlarging painless scrotal mass. By the time they present it is usually not possible to distinguish from a primary testis tumor on physical examination, though the extra-testicular nature of the tumor is usually apparent on ultrasound. Trans-scrotal biopsies of solid scrotal masses should be avoided due to the risk of seeding of the incision if the mass is indeed a rhabdomyosarcoma. The excision of the tumor should be performed just as for a testicular malignancy. The metastatic evaluation for paratesticular rhabdomyosarcoma includes a CT (Computed tomography) of the chest, abdomen, and pelvis. A majority of patients will have clinical stage 1 disease. The most common sites of metastases are the retroperitoneum and lungs. Patients with retroperitoneal metastases should undergo a modified unilateral nerve-sparing RPLND (Retroperitoneal lymph node dissection). All patients should receive chemotherapy and those with positive retroperitoneal nodes should receive radiation therapy as well [1]. We report on two older children/adolescents who underwent Laparoscopic-RPLND.

Comparison of the clinicopathological features of invasive ductal, invasive lobular, and mixed (invasive ductal + invasive lobular) carcinoma of the breast

In this retrospective analysis, the clinicopathological features and pattern of metastatic spread of invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and mixed ductal/lobular carcinoma (MDLC), together with the type and outcome of surgical intervention, were comparatively evaluated. A total of 633 breast cancer patients with histopathological subtype IDC, ILC or MDLC were included in the study. The mean age was 52.6 ± 12.7 years. Follow-up period ranged between 0 and 33 (median 6.0) years. The groups were compared with respect to age, tumor size, nodal involvement, stage, hormonal therapy, multicentricity, multifocality, bilaterality, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2)/neu, p53, and Ki67 expression, disease-free survival (DFS) and overall survival (OS) rates, and surgical approach. The distribution of patients was as follows: IDC 508 (80.3 %), ILC 78 (12.3 %), MDLC 47 (7.4 %). Among the parameters evaluated, statistically significant differences were observed in mean tumor size (IDC 2.5 ± 1.98 cm, ILC 3.0 ± 1.8 cm, MDLC 3.2 ± 2.4 cm), advanced T stage (T3 + T4) at diagnosis (IDC 14.7 %, ILC 21.4 %, MDLC 25.6 %), N stage (N0 was dominant in IDC and ILC; N3 was dominant in MDLC), tumor-node-metastasis (TNM) stage (stage II was dominant in IDC and ILC; stage III was dominant in MDLC), HER2/neu expression (IDC 23.8 %, ILC 11.8 %, MDLC 21.4 %), and frequency of bone metastasis (IDC 14.3 %, ILC 17.9 %, MDLC 25.5 %). MDLC-type tumors have different histopathological characteristics and are often diagnosed at advanced stage. However, their survival outcomes do not vary significantly from ILC and IDC.

Patterns of metastatic spread in early breast cancer

AimsThe aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. Patients and methodsIn all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. ResultsOf the 177 patients, 114 (64%) were BM−/LN−, 38 (22%) BM−/LN+, 19 (11%) BM+/LN− and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non-significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF–C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. ConclusionThese findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers.

Clinical colorectal cancer (CRC) subsets in advanced disease: Patterns of metastatic spread to predict survival.

e14703 Background: Advanced CRC is a heterogeneous disease. Some patients exhibit diffuse metastatic spread while others show selective organ involvement. We aimed to investigate the frequency and survival implications of initial pattern of metastatic spread in a Mexican cohort. Methods: We retrospectively reviewed charts and radiologic images of patients with advanced CRC at our institution from 2004 to 2011. The initial pattern of spread was recorded. Categories depending on the predominant site of involvement were: 1) Locally advanced, 2) Hepatic, 3) Pulmonary, 4) Peritoneal or 5) Diffuse. Survival was estimated by the Kaplan Meier method and Log rank test used to determine survival differences among categories. Results: 179 patients with advanced CRC were identified. Median age was 60yo, 56% were male. Primary tumor location was 50.3% colon, 27.9% rectum, 17.9% recto-sigmoid and 3.4% had synchronous disease. 66% of patients had advanced disease at diagnosis and 34% were recurrent cases. Metastasis at diagnosis involved the liver in 105 (58.7%), peritoneum in 49 (27.4%), lung in 56 (31.3%) and non regional lymph nodes in 36 (20.1%) patients. Notably, 101 (56%) patients had a predominant site of metastatic involvement: locally advanced in 3 (1.7%), hepatic in 51 (28.5%), peritoneal in 21 (11.7%), pulmonary 21 (11.7%) while 78 patients (44%) had disseminated disease. Median overall survival was 15 months (n= 179) and differed according to predefined CRC subsets: 9, 13, 22, 23, and 52 months for peritoneal, disseminated, hepatic, locally advanced and pulmonary spread respectively p=.018 (significant after multivariate analysis). Other factors associated with better survival were female gender p=.040, absence of morbidity from primary tumor p=.27, resection of primary tumor p=.004, recurrent presentation p=.039, and access to 1stline chemotherapy p=.00. Conclusions: Over 50% of patients exhibited selective metastatic spread. Clinically defined subsets correlate with better (pulmonary) or worse (peritoneal/disseminated) survival. This finding might have implications in patient selection for regional therapies and encourage research to find the molecular determinants of this biologic behavior.

Metastatic neuroblastoma confined to distant lymph nodes (stage 4N) to predict outcome in patients with stage 4 disease: A study from the International Neuroblastoma (NB) Risk Group (INRG) Database.

10015 Background: Patients with metastatic NB typically have a poor prognosis; however case series have suggested that those with 4N disease may have improved outcomes. Methods: Retrospective analysis of data from INRG database for patients diagnosed 1990–2002. 4N patients (INSS stage 4 disease confined to distant lymph nodes) were compared to the balance of stage 4 patients (‘non-4N’), excluding those with missing metastatic site data. 5-yr estimates of overall (OS) and event-free survival (EFS) were calculated ± standard error (Kaplan-Meier method). Patient characteristics were compared by Mann-Whitney or Fisher’s exact/Chi-square tests. Results: 2,250 INSS stage 4 patients with complete data were identified, of whom 146 (6%) had 4N disease. For 4N patients, EFS and OS (5-yr: 77% ± 4%, 85% ± 3%), were significantly better than EFS and OS (5-yr: 35% ± 1%, 42% ± 1%) for non-4N stage 4 patients (p&lt;0.0001). 4N patients were more likely to be younger (median age at diagnosis 1.2 yr vs 2.5 yr for non-4N; p&lt;0.0001) and have tumors with favourable International Neuroblastoma Pathologic Classification (INPC) (63% vs 26%, p&lt;0.0001), differentiating grade (21% vs 8%, p=0.006), lower MKI (p=0.0011) and non-MYCN amplified tumors (89% vs 69%, p&lt;0.0001). Within subgroups defined by age at diagnosis and MYCN status, 4N pattern of disease remained significantly associated with improved outcomes. For patients aged ≥547 days at diagnosis and MYCN non-amplified, 5-yr EFS for 4N patients (n=42) was 63% ± 8% vs 27% ± 2% for non-4N (n=785); OS 74% ± 7% vs 38% ± 2% (both p&lt;0.0001). Within this subgroup, favourable INPC and differentiating grade remained more frequent in the 4N vs non-4N patients (45% vs 10%, p&lt;0.0001; 45% vs 8%, p=0.0017, respectively). Conclusions: 4N represents a subgroup of metastatic patients with better outcome than other INSS stage 4 patients. These findings indicate that the biology and response to treatment of 4N tumors differs from other stage 4 tumors, and different therapies should be considered for this cohort. Future exploration of biological factors determining pattern of metastatic spread and response to therapy is warranted.

681 THE DISTINCT ASSOCIATION BETWEEN PRIMARY TUMOR LOCATION AND THE PATTERNS OF METASTATIC SPREAD FOLLOWING RADICAL NEPHROURETERECTOMY IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA

681 THE DISTINCT ASSOCIATION BETWEEN PRIMARY TUMOR LOCATION AND THE PATTERNS OF METASTATIC SPREAD FOLLOWING RADICAL NEPHROURETERECTOMY IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA

Patterns of extension of gastrointestinal stromal tumors (GIST) treated with imatinib (Gleevec®) by 18F-FDG PET/CT

currently it is recognized the usefulness of 18F-FDG PET in assessing response to therapy with imatinib (Gleevec®) in the gastrointestinal tract sarcomas (GIST). To facilitate the follow-up of these studies is important to know the patterns of metastatic spread. The aim of this paper is to describe patterns observed in the 18F-FDG PET/CT. retrospective study included 29 patients who underwent 18F-FDG PET/CT after being diagnosed with unresectable or metastatic GIST. In total, 87 PET/CT studies were performed (1-6 controls per patient) with a mean time of follow-up 6-36 months. We analyzed the location of the lesions evidenced in PET, CT and fusion. Images were evaluated visually and semiquantitatively (SUV). In cases in which has been considered necessary, additional images have been undertaken: PET delayed imaging, intravenous contrast CT and inspiratory chest CT. the most common primary site was the stomach (41%), small bowel (35%), and rectum (24%). Significant changes in the location of metastatic disease between pre-treatment and the monitoring were observed, with the appearance of more extra-abdominal disease. individualization of protocol studies and interpretation of PET, CT and fused images were required for evaluation of treatment response to imatinib. Hybrid 18F-FDG PET/CT provides an accurate determination of the extent of GIST. While the most common metastatic site is the liver and peritoneum, in the following cases are common extra-abdominal disease.