Primary Metastatic Lesions Research Articles

The differentiated approach to the choice of surgical treatment options in patients with metastatic lesions of long bones

Metastatic lesions of long bones (MLLB) are one of the most frequent pathologies among all bone tumor diseases. Objective: to substantiate and develop a differentiated approach to the choice of indications to authorities retain the surgical treatment of pa­tients with metastatic lesions of long bones. Methods: the results of the examination and treatment of 104 patients with metastatic lesions of long bones. The main factors affecting the patients survive are the initial diagnosis, the amount of metastatic le­sions of long bones, pathological fracture, relapse-free period of a period, visceral dissemination, histological type of tumor, the type of metastatic lesions of long bones, according to ASA class, age of the patient. With the help of the method of mathematical modeling of the mechanical properties comparison us «implant – bone» o f t he system i n different types o f replace­ment post-resection defects in proximal and distal femur me­taphysis. Results: for to facilitate the prediction of survival of patients developed a computer program that make work-up data of the patient. The program determines the probability for a patient belonging to a survival group: I — up to 6 months, II — from 6 to 24 months, III — more than 2 years. Depend­ing on the survival prognosis developed indications for surgi­cal interventions and their types (palliative or radical). Justi­fy the most effective methods of substitution of post-resection defects braid children due to the localization of metastatic le­sions of long bones. Developed and implemented into practice the method of substitution of metaphysial defects of the distal femur using the metal construction. A tactics of surgical treat­ment of patients with primary metastatic lesions of long bones has been proposed. Conclusions: the use of the proposed tactic of treatment of patients with metastatic lesions of long bones allows substantiate indications for surgical interventions and their specific type, to prevent unreasonable and, accordingly, re­peated operations.

Abstract 4586: FGFR2 amplification in serous ovarian cancer

Abstract Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in biology of cancer. Approximately 7% of ovarian cancer (OC) exhibits FGFR1 amplification. Recently the overexpression of FGFR2 was found in 95% of clear cell OC. Up to date there is no data about FGFR2 status in OC. 54 paraffin-embedded blocks from 18 patients with serous OC were analyzed by FISH to identify FGFR2 amplification. Scoring for amplification and polysomy level was adopted from previous studies for gastric cancer (Su X, et al. BJC 2014). Material from each patient had 3 samples: from primary tumor, from primary metastatic lesions, and from relapse. Intratumoral FGFR2 amplification heterogeneity was assessed in sections from all cases with FGFR2 amplification, and was defined as the presence of areas with different FISH scores within the same tumor in full sections. Amplification was observed in 3 patients (15.7%). Interestingly, in one case amplification was observed in primary ovarian tumor but not in the metastatic nor in relapse samples. In two other cases the FGFR2 amplification was detected in relapse samples and in primary metastatic samples but not in ovary. High-level polysomy (HLP) was observed in 10 patients (55.5%). In all of those patients HLP was revealed in the samples of relapse. In 3 patients HLP was found in all 3 samples, in 3 cases HLP was observed only after relapse, in 4 cases HLP in metastasis sample was the same as in relapse sample, but it wasn't observed in ovary samples. Eight of 13 FGFR2 amplified ovarian cancers or tumors with HLP (61.5%) displayed intratumoral heterogeneity within full sections. In 5 (27.8%) cases neither amplification nor high level polysomy was observed. In conclusion, this is the first study of FGFR2 FISH in serous ovarian adenocarcinoma, demonstrating a FGFR2 amplification and HLP in primary tumor, primary metastases and relapse. Furthermore, we found evidence for intratumoral heterogeneity of FGFR2 amplification and HLP in about 61.5% of ovarian cancers. This study was supported by grant from the “Oncoprogress Foundation”. FGFR2 amplification and high-level polysomy in patients with serous cancer (13 patients)N (%), patientsPrimary tumor (N samples)Primary metastasis (N samples)Relapse (N samples)Amplification3 (15.7%)122High level polysomy10 (55.5%)3410 Citation Format: Alexandra Tyulyandina, Ilya Tsimafeyeu, Irina Demidova, Marina Gikalo, Sergei Tjulandin. FGFR2 amplification in serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4586.

Failure patterns and oligometastasis after concurrent chemoradiotherapy for stage III-IV non-small cell lung cancer

Objective To investigate the failure patterns and oligometastasis after concurrent chemoradiotherapy for stage III-IV non-small cell lung cancer (NSCLC), and to discuss the significance of local radiotherapy. Methods The patterns of failure including oligometastasis were analyzed in 299 previously untreated patients with stage III-IV NSCLC who underwent concurrent chemoradiotherapy from 2007 to 2014. Results Of all the patients with NSCLC, 88 patients with stage III NSCLC failed, among whom 22(22.7%) experienced primary tumor recurrence with or without distant metastasis and 27(30.7%) experienced oligometastasis, and brain metastasis was the most common failure pattern. A total of 211 patients with stage IV NSCLC failed, among whom 11.4% experienced primary tumor recurrence with or without distant metastasis, 10.0% experienced recurrence of the primary metastatic lesions, and 9.0% experienced new lesions in the organs with metastasis; 9 out of 94 patients with oligometastasis and 12 out of 117 patients without oligometastasis, respectively, experienced recurrence of the primary metastatic lesions. Brain metastasis had the highest incidence rate (38.2%). Conclusions After concurrent chemoradiotherapy, nearly 1/3 patients with stage III NSCLC and 10% patients with stage Ⅳ NSCLC experience the failure of oligometastasis, and brain metastasis is the most common pattern of failure. Radical radiotherapy for primary tumors in stage IV NSCLC can reduce local recurrence. Key words: Cancer, non-small-cell/concurrent chemoradiotherapy; Oligometastases; Failure analysis

Pump-probe imaging of pigmented cutaneous melanoma primary lesions gives insight into metastatic potential.

Metastatic melanoma is associated with a poor prognosis, but no method reliably predicts which melanomas of a given stage will ultimately metastasize and which will not. While sentinel lymph node biopsy (SLNB) has emerged as the most powerful predictor of metastatic disease, the majority of people dying from metastatic melanoma still have a negative SLNB. Here we analyze pump-probe microscopy images of thin biopsy slides of primary melanomas to assess their metastatic potential. Pump-probe microscopy reveals detailed chemical information of melanin with subcellular spatial resolution. Quantification of the molecular signatures without reference standards is achieved using a geometrical representation of principal component analysis. Melanin structure is analyzed in unison with the chemical information by applying principles of mathematical morphology. Results show that melanin in metastatic primary lesions has lower chemical diversity than non-metastatic primary lesions, and contains two distinct phenotypes that are indicative of aggressive disease. Further, the mathematical morphology analysis reveals melanin in metastatic primary lesions has a distinct "dusty" quality. Finally, a statistical analysis shows that the combination of the chemical information with spatial structures predicts metastatic potential with much better sensitivity than SLNB and high specificity, suggesting pump-probe microscopy can be an important tool to help predict the metastatic potential of melanomas.

Abstract A41: Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis

Abstract Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF1α or PLOD2 expression disrupts collagen modification, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Biochemical analyses revealed that overexpression of HIF1α and PLOD2 in sarcoma cells alters collagen structure and organization. The increase in lysyl hydroxylation and concomitant loss of prolyl hydroxylation, promotes adherence of tumor cells, collagen-associated migration and tumor cell dissemination. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient tumors, and analysis of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Pharmacological inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Citation Format: T.S. Karin Eisinger-Mathason, Minsi Zhang, Qiu Qiong, Nicolas Skuli, Michael S. Nakazawa, Tatiana Karakasheva, Vera Mucaj, Jessica E.S. Shay, Lars Stangenberg, Ellen Pure, Sam S. Yoon, David G. Kirsch, M. Celeste Simon. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A41. doi:10.1158/1538-7445.CHTME14-A41

Hypoxia-Dependent Modification of Collagen Networks Promotes Sarcoma Metastasis

Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-Kras(G12D/+); Trp53(fl/fl) murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α-deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifi cally the collagen-modifying enzyme PLOD2.

Prognostic analysis of Chinese patients with metastasic renal cell cancer (mRCC) receiving sorafenib: A multicenter retrospective study.

e15582 Background: This study was to investigate long-term efficacy of sorafenib and survival-related factors in Chinese patients with mRCC. Methods: 406 consecutive patients enrolled in this study between Oct. 2006 and Oct. 2009 from 6 comprehensive cancer centres in China. All cases were diagnosed as mRCC histopathologically without exception. 400mg sorafenib was orally taken twice daily until PD, death or intolerable toxic reaction. The primary endpoint was OS. The secondary endpoints were PFS and survival-related factors such as gender, age, ECOG PS, previous therapy and primary metastatic lesions. Data was analyzed using the SPSS statistical software. OS and PFS curves were output using the Kaplan-Meier method. Clinical parameters were included on univariate and multivariate analysis to evaluate associations with OS and PFS by the log-rank test and Cox proportional hazard models, P<0.05 (two-sided) was considered statistically significant. Results: 131 patients were available for survival analysis, including 96 males and 35 females. The median age was 60 years old. The median follow-up periods were 16.9 months. The median OS was 16.1 months. 1-year, 2-year and 3-year survival rates were 64.9%, 35.9% and 5.3%, respectively. The median PFS was 10.5 months. Univariate analysis demonstrated that OS was significantly associated with ECOG PS, metastatic lesions and previous therapy, whereas PFS was merely associated with ECOG PS and previous therapy. Multivariate analysis suggested that ECOG PS and previous therapy were independent prognostic factors for OS(P=0.004, P=0.019) and PFS (P=0.000, P=0.003), metastatic lesions was merely independent prognostic factor for OS (P=0.003). In the subgroup of patients with visceral metastasis, patients with lung metastasis alone had better prognosis than those with liver metastasis or dimerous metastasis. Conclusions: This long-term study demonstrated that sorafenib had good effects on Chinese patients with mRCC, especially for patients with lung metastasis alone. ECOG PS, metastatic lesions and previous therapy could be important parameters for survival and need attention in future.

Abstract IA15: HIFs, hypoxia, and tumor progression

Abstract Intratumoral hypoxia and expression of Hypoxia Inducible Factor 1α (HIF1α) correlate with metastasis and poor survival in sarcoma patients. We demonstrate here that hypoxia controls sarcoma cell metastasis through a novel mechanism in which HIF1α induces the expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). PLOD2 hydroxylates procollagen, consequently altering the structure of extracellular collagen fibers along which transformed cells migrate in primary tumors. We show that loss of HIF1α or PLOD2 expression disrupts collagen deposition, cell migration and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF1α-deficient cells and tumors, and microarray analyses of human sarcomas reveal elevated HIF1α and PLOD2 expression in metastatic primary lesions. Collectively, these data indicate that whereas HIF1α activity modifies pre-metastatic niches in carcinomas, it controls sarcoma metastasis through PLOD2-dependent collagen deposition in primary tumors. Therefore, we conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Citation Format: M. Celeste Simon. HIFs, hypoxia, and tumor progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA15.

Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype

Protease-activated receptor-1 (PAR-1) is a unique G-protein-coupled receptor belonging to the protease-activated receptor family. Its activation leads to downstream signaling events that launch a variety of cellular responses related to tumor progression. PAR-1 expression has been associated to a variety of human cancers, and our previous studies reveal a high PAR-1 expression in melanoma specimens as compared to common nevi. In the present study, we investigated the contribution of PAR-1 to the malignant phenotype of human melanoma cell lines obtained from cutaneous primary lesions, capable of different metastatic behaviors in the patients from which they have been derived. We found that melanoma cells isolated from lesions giving rise to metastases in patients (WM115, WM278A, WM1361A, WM983A), had higher PAR-1 mRNA and protein expression, as compared to those obtained from lesions that did not develop metastatic disease (WM793, WM35). The cells isolated from metastatic primary lesions were able to colonize the lungs of immunodeficient SCID mice while those isolated from non-metastatic lesions were not. Additionally, cells expressing elevated PAR-1 had higher migratory and invasive abilities than those holding minimal PAR-1 expression. The migration and invasion capabilities of the melanoma cells expressing high PAR-1 were hampered by genetic and pharmacological interventions. The reduction of PAR-1 expression by siRNA and the inhibition of PAR-1 function by the SCH79797 specific antagonist significantly decreased the melanoma cell motility and invasiveness, down to an extent similar to that of the non-metastatic and low PAR-1 expressing cells. Our results provide strong evidence supporting the implication of PAR-1 in the malignant progression of human melanoma.

MAGE1 Is Expressed by a Subset of Pancreatic Endocrine Neoplasms and Associated Lymph Node and Liver Metastases

MAGE1 was originally isolated from human melanoma cells as a target antigen for autologous cytotoxic T lymphocytes. Expression of MAGE1 has subsequently been identified in a number of neoplastic cell types, including testicular germ cell and breast cancer cells, which has led to the development of antitumor MAGE1 vaccines. To determine if Mage-1 is expressed in pancreatic endocrine neoplasms (PENs) and PEN metastases. We utilized immunolabeling analysis for Mage-1 on 49 primary PENs, 11 liver metastases, and 6 lymph node metastases. A semiquantitative labeling index (LI) of 0 (no expression), 1, 2 (moderate expression), and 3 (intense expression, correlating with internal control markers) was used to determine relative amounts of MAGE1 expression in these lesions. We have identified MAGE1 expression in a subset (42 of 49; 86%) of PENs. Normal pancreatic ducts, present in tissue adjacent to PENs, were utilized as a positive control for Mage-1 immunolabeling (index score 3); no other detectable labeling for Mage-1 was evident in normal pancreatic tissue. Primary PENs, with or without metastases (mean LI score 1.2 vs 1.0, respectively), did not demonstrate a significant difference in Mage-1 LI, although intratumoral heterogeneity was apparent in some, but not all, of these lesions. Lymph node metastases (mean score 2.0) demonstrated a significant increase in Mage-1 LI as compared to primary, non-metastatic lesions (p = 0.04984) and primary metastatic lesions (p = 0.02351). In contrast, six patients with a survival of less than one year demonstrated a low Mage-1 LI (mean score, 0.58). MAGE1 expression is present in a subset of primary PENs and in lymph node metastases, and may therefore serve as a useful marker and potential therapeutic target in PENs. Furthermore, the absence of Mage-1 expression in a subset of primary PENs may indicate a worsened prognosis.