Distant Hematogenous Metastasis Research Articles

Association of integrin expression in tumor tissue with hematogenic metastasis of breast cancer

Background. Distant hematogenous metastasis is the leading cause of tumor-related death from breast cancer. To prevent metastasis, prognostic markers for predicting the risk and location of hematogenous metastases are required. In this regard, it is of great importance to study the expression of integrins involved in the most important processes that determine the progression of cancer.The objective of the study was to investigate the association of integrin expression in tumor tissue with hematogenous metastasis of patients with breast cancer.Material and Methods. The study included 72 patients (average age – 51 ± 12 years) with stage T1–4N0–3M0–1 unspecifed invasive ductal breast carcinoma, with all molecular biological subtypes (luminal A, luminal B, HER2-positive and triple negative). The biopsy material was examined before the start of antitumor treatment. Expression of integrins in tumor cells was assessed by immunohistochemical methods. Antibodies CD61 (integrin β3, Invitrogen, USA), CD104 (integrin β4, Invitrogen, USA), CD51 (integrin αV, Invitrogen, USA) were used.Results. In patients with hematogenous metastases, cytoplasmic rather than cytoplasmic/membrane colocalization, CD61 expression was more often detected (p=0.036). Cytoplasmic and membrane colocalization of CD104 was more frequently detected in brain metastases compared to lung (p=0.026) and bone (p=0.036) metastases. Expression of CD51 integrin was more often associated with lung metastases than with bone metastases (p=0.045).Conclusion. The frequency and localization of hematogenous metastases in breast cancer patients are associated with the presence and localization of CD61, CD104 and CD51 expression in the tumor cell.

Carcinosarcomas and epithelial to mesenchymal transition (EMT)

Carcinosarcomas are rare, extremely aggressive malignant neoplasms, combining two cellular epithelial and sarcomatous components. Epithelial to mesenchymal transition (EMT) is a biological process that occurs in malignant tumors. Sarcomatous component in carcinosarcomas is derived from the carcinomatous component as a result of metaplasia/transdifferentiation (ЕМТ). We present the pathohistological characteristics and immunohistochemical analysis of four clinicalcarcinosarcoma cases with a different primary localization. Our main goal is to present the classic pathohistological picture of EMT and the role of intermediate filament (IF) proteins in cell and tissue structural integrity, as well as their importance for local invasion and distant hematogenous metastases in carcinosarcomas.

Whole Transcriptome Analysis of Breast Cancer Tumors during Neoadjuvant Chemotherapy: Association with Hematogenous Metastasis.

The assessment of molecular genetic landscape changes during NAC and the relationship between molecular signatures in residual tumors are promising approaches for identifying effective markers of outcome in breast cancer. The majority of the data in the literature present the relationship between the molecular genetic landscape and the response to NAC or are simply descriptive. The present study aimed to determine changes in expression profiles during NAC and assess the relationship between gene expression and the outcome of patients with luminal B HER2 breast cancer depending on distant hematogenous metastasis. The study included 39 patients with luminal B HER2-BC. The patients received 6-8 courses of NAC, and paired samples consisting of biopsy and surgical materials were analyzed. A full transcriptome microarray analysis was performed using the human Clariom™ S Assay platform (Affymetrix, 3450 Central Expy, Santa Clara, CA, 95051, USA). A comparison of the expression profiles of patients with breast cancer before and after NAC, depending on the status of hematogenous metastasis, was conducted. It was shown that the amount of DEGs in the tumor was reduced by more than six times after NAC. The top 10 signaling pathways were also found, the activity of which varied depending on the status of hematogenous metastasis before and after NAC. In addition, the association of DEGs with hematogenous metastasis in patients with breast cancer was evaluated: MFS was assessed depending on the expression level of 21 genes. It was shown that MFS was significantly associated with the expression level and pattern of nine genes. The expression levels of nine DEGs in the tumors of patients with breast cancer after NAC were significantly correlated with MFS when the status of hematogenous metastasis was taken into account.

Extremely rare primary undifferentiated pleomorphic thyroid sarcoma-Clinical case with a literary review

Anaplastic thyroid carcinoma (ATC) known as undifferentiated and dedifferentiated carcinoma, is a rare, highly aggressive neoplasm. We present an extremely fast growing undifferentiated pleomorphic sarcoma originating in the thyroid gland in an 80-year-old woman. Through this clinical case, we show the importance of the pathohistological characteristic and immunohistochemical analysis for diagnosis of these extremely malignant neoplasms. Due to the radiation- and chemoresistance of this malignant undifferentiated soft tissue neoplasm, early diagnosis for a small tumor volume without distant hematogenous metastases is required to perform maximum radical surgery. Locally advanced sarcomas with lung metastases are subject to symptomatic and palliative treatment and the prognosis is very unfavorable.

Evaluation of peripheral nodal recurrence in patients with endometrial cancer

Objective:To evaluate the clinico-pathological patient features, prognostic factors, treatment options and outcomes of peripheral nodal recurrence (PNR) of endometrial cancer (EC).Material and Methods:The data of nine patients with PNR of EC from two institutions were reviewed. The electronic literature was reviewed from 1972 to May 2018 to identify articles about PNR in EC. Finally, 42 cases were evaluated.Results:Nineteen (45.2%) patients were initially diagnosed with either stage I or II disease, whereas 20 (47.7%) patients had stage III or IV disease while the stages were not reported in three (7.1%). PNR developed as the first recurrence in 40 (95.2%) patients and as the second recurrence in 2 (4.8%) patients. Isolated PNR appeared in 35 (83.3%). Seven (16.7%) had PNR coexisting with multiple other sites of tumoral involvement. In the entire cohort, the 5-year and 10-year post-recurrence survival (PRS) were both 78%. Only the presence of distant hematogenous metastasis concurrent with PNR was significantly related to poor PRS (p=0.005). Among patients with isolated PNR, those who had surgery had 30% greater 5-year PRS than those treated without surgery, but this difference was not significant (80% vs 50%; p>0.05).Conclusion:A concurrent distant hematogenous metastasis was the only factor related to poor survival. A wide range of therapies exists for PNR but none of the therapies appear to be more advantageous than another. However, surgery as a component of treatment can render a survival advantage for patients who have isolated PNR.

Gastrointestinal: Autoimmune enteropathy associated with thymoma.

A 50-year-old gentleman presented with 4 months of chronic watery, non-bloody diarrhea up to 10 times a day, and weight loss. He had a history of a thymoma first diagnosed 7 years earlier, which was resected with positive histological margins. There was no macroscopic residual disease or vascular invasion. He did not receive any adjuvant treatment and developed recurrent Masaoka-Koga stage IVa thymoma with pleural, pericardial, and lung invasion requiring further treatment with resection, chemotherapy (3 cycles of cisplatin, doxorubicin, and cyclophosphamide), and radiotherapy (54 Gy in 30 fractions). There was no mediastinal lymph node involvement or evidence of distant hematogenous metastasis. Histopathology demonstrated multiple nodules of mixed WHO type B1 and B2, but predominantly type B1 thymoma. His diarrhea commenced after his thymoma recurrence. He did not have any features suggesting other autoimmune diseases associated with thymoma including myasthenia gravis. Physical examination and initial laboratory investigations were unremarkable. Stool cultures were negative for bacterial, viral, and parasitic infections. A computed tomography (CT) scan of the abdomen revealed wall thickening and fat stranding affecting the small intestine and colon (Fig. 1a). Correspondingly, mild patchy erythematous colitis in the rectum and sigmoid colon was seen on colonoscopy (Fig. 1b). Histologically, colonic biopsies showed active colitis with prominent regenerative changes. Goblet cells were noticeably absent, and there was prominent apoptosis, features typical of autoimmune enteropathy (Fig. 1c). Patient serum was incubated with frozen sections of normal small intestinal mucosa, showing strong staining by immunofluorescence for human IgA and IgG with a goblet cell distribution (Fig. 2). A diagnosis of thymoma-associated autoimmune enteropathy was made, and the patient was commenced on a weaning dose of prednisone starting at 25 mg daily leading to resolution of his symptoms. Thymomas are associated with concomitant autoimmune diseases in up to 30% of patients, possibly due to defective immune regulation. Differentials for thymoma-associated autoimmune conditions causing diarrhea include autoimmune enteropathy and Good's syndrome (thymoma-associated hypogammaglobulinemia). Thymoma-associated autoimmune enteropathy is rare with only five reported cases in the literature. Proposed diagnostic criteria include chronic diarrhea lasting over 6 weeks, malabsorption, and abnormal histology of the small bowel (villous blunting, deep crypt lymphocytosis, minimal intraepithelial lymphocytosis, and increased crypt apoptotic bodies). A spectrum of changes can be seen in the colon including increased mononuclear inflammatory infiltrate, active inflammation including neutrophilic cryptitis and microabscesses, intraepithelial lymphocytosis, and increased crypt epithelial apoptosis. Changes of chronicity including crypt architectural distortion and Paneth cell metaplasia have also been described. The presence of anti-enterocyte or anti-goblet antibodies is supportive, but the sensitivity and specificity of these markers are unknown. Steroids are the first-line management for autoimmune enteropathy; however, further immunosuppression (azathioprine, cyclosporin, tacrolimus, or infliximab) may be required in up to 90% of cases. For patients with thymoma-associated autoimmune enteropathy, resection of the thymoma may also improve symptoms.

Low Expression of Claudin-7 as Potential Predictor of Distant Metastases in High-Grade Serous Ovarian Carcinoma Patients.

High-grade serous ovarian carcinoma (HGSOC) usually spreads directly into the peritoneal cavity following a transcoelomic dissemination route, although distant hematogenous metastasis exist and have been reported. However, no tumor markers can currently predict the risk of distant metastases in HGSOC. Claudins, belonging to tight-junction proteins, are dysregulated in HGSOC and functionally related to cancer progression. Here we analyzed claudin-3, -4, and -7 expression as potential markers of distant metastases. Using quantitative RT-PCR and immunohistochemistry we assessed the expression of claudins in primary HGSOC tissues, normal ovarian, and normal fallopian tube epithelia and correlated it with clinicopathological features, including the site of metastasis and the route of dissemination. Gene set enrichment analysis was performed on microarray-generated gene expression data to investigate key pathways in patients with distant metastases. We found the overall expression level of claudin-3, -4, and -7 mRNA decreased in HGSOC compared to normal tubal epithelium, currently considered the potential site of origin of many HGSOC. The reduced expression of claudin-7 is significantly associated with the development of distant metastases (p = 0.016), mainly by hematogenous route (p = 0.025). In patients with diminished expression of claudin-7, immunohistochemical staining revealed a heterogeneous pattern of membranous staining with discontinuous expression of claudin-7 along the cell border, indicative of a dischoesive architecture. The estimated reduction in the probability of distant disease is of 39% per unit increase in the level of claudin-7 (p = 0.03). Genes involved in epithelial to mesenchymal transition, hypoxia, and angiogenesis processes resulted strongly associated to hematogenous recurrence. Our data suggest a potential role of claudin-7 in discriminating distant metastatic events in HGSOC patients. The quantification of its expression levels could be a useful tool to identify patient deserving a personalized follow-up in terms of clinical and radiological assessment.

Prediction of Survival and Recurrence Patterns by Machine Learning in Gastric Cancer Cases Undergoing Radiation Therapy and Chemotherapy

PurposeRadical surgery is the most important treatment modality in gastric cancer. Preoperative or postoperative radiation therapy (RT) and perioperative chemotherapy are the treatment options that should be added to surgery. This study aimed to evaluate the overall survival (OS) and recurrence patterns by machine learning in gastric cancer cases undergoing RT. Methods and MaterialsBetween 2012 and 2019, the OS and recurrence patterns of 75 gastric cancer cases receiving RT ± chemotherapy at the Department of Radiation Oncology were evaluated by machine learning. Logistic regression, multilayer perceptron, XGBoost, support vector classification, random forest, and Gaussian Naive Bayes (GNB) algorithms were used to predict OS, hematogenous distant metastases, and peritoneal metastases. After the correlation analysis, the backward feature selection was performed as the variable selection method, and the variables with P values less than .005 were selected. ResultsOver the median 23-month follow-up, recurrence was seen in 33 cases, and 36 patients died. The median OS was 23 (min: 7; max: 82) months, and the disease-free survival was 18 (min: 5, max: 80) months. The most common recurrence pattern was hematogenous distant metastasis, followed by peritoneal metastasis. In this study, the most successful algorithms in the prediction of OS, distant metastases, and peritoneal metastases were found to be GNB with an accuracy of 81% (95% confidence interval [CI], 0.65-0.97, area under the curve [AUC]: 0.89), XGBoost with 86% accuracy (95% CI, 0.74-0.97, AUC: 0.86), and random forest with 97% accuracy (95% CI, 0.92-1.00, AUC: 0.97), respectively. ConclusionsIn gastric cancer, GNB, XGBoost, and random forest algorithms were determined to be the most successful algorithms for predicting OS, distant metastases, and peritoneal metastases, respectively. To determine the most accurate algorithm and perhaps make personalized treatments applicable, more precise machine learning studies are needed with an increased number of cases in the coming years.

Platelet adherence to cancer cells promotes escape from innate immune surveillance in cancer metastasis.

The impacts of post‑operative abdominal infectious complications increase hematogenous distant metastasis and result in poor long‑term survival after curative resection. Even if curative resection can be performed, the presence of circulating tumor cells is affected. The liver, the most common site of metastases, is an important organ in innate immune surveillance. However, the molecular mechanisms of distant hematogenous metastasis are not yet fully known. Platelets are crucial components in the tumor microenvironment that function to promote tumor progression and metastasis. The purpose of this study was to identify the effect of platelets on escape from innate immune surveillance in post‑operative abdominal infectious complications. Platelet adherence was assessed by co‑culturing human pancreatic cancer cells including transforming growth factor (TGF‑β)‑treated BxPC‑3. CD44 isoform, transcription factors and epithelial‑mesenchymal transition markers were examined using western blotting. We also assessed whether cancer cells surrounded by activated platelets could escape from innate immune surveillance, using infectious and non‑infectious mouse models injected intraperitoneally with LPS. Platelets were found to preferentially adhere to mesenchymal cells rather than epithelial cells. BxPC‑3 epithelial cells showed upregulation of CD44‑variant and epithelial splicing regulatory protein 1 (ESRP‑1) expression. However, Panc‑1 mesenchymal cells and TGF‑β‑treated BxPC‑3 cells showed upregulation of CD44‑standard and zinc finger E‑box‑binding homeobox 1 (ZEB‑1) expression and a reduction in ESRP‑1. In the non‑infectious model, cancer cells were not found in the liver. In the infectious model, although epithelial cells without platelet adhesion were in an apoptotic state, mesenchymal cells showed many viable cancer cells surrounded by activated platelets. Cancer cells were suggested to have phenotypic plasticity through the switching of CD44 isoforms. Mesenchymal cells, which express CD44‑standard, could escape from immune surveillance by becoming surrounded by adhered activated platelets. Therefore, it may be necessary to administer antiplatelet agents to prevent distant hematogenous metastasis when post‑operative abdominal infectious complications occur.

Clinical case of complications of inguinal node metastatic lesion in gastric cancer after surgical treatment

Objective:To study the phenomena of complications of atypical distant lymphangitic metastasis by the example of gastric cancer.Methods:Within the framework of the study “Hereditary diffuse gastric cancer and measures for its prevention”, a clinical group and a control group of patients with the most likely risk of developing this genetic disease were recruited. DNA samples were taken from 119 patients of the main clinical group and the control group. In the course of filling out statistical charts, questioning and examination of patients, cases of distant lymphangitic and hematogenous metastasis were revealed in 7 patients. As diagnostic methods for distant lymphangitic and hematogenous metastasis, we used the results of studies of computed tomography, positron emission tomography combined with computed tomography of the whole body, nuclear magnetic resonance imaging, ultrasound methods, open biopsy and trephine-biopsy of lymph nodes.Results:Krukenberg’s tumors were detected in 2 patients, Virchow’s metastases - in 2 patients, metastases in the paraumbilical region - in 2 patients, Schnitzler metastases - in 1 patient, Irish node was detected in 1 of the examined patients. There was also a metastatic lesion of the lymph nodes of inguinal region on the left in 2 patients and one case of metastasis to the right testicle in a patient with true inguinal cryptorchidism. This article reflects one case of metastatic lesion of the inguinal nodes on the left and subsequent complications in the form of lymphostasis and pain syndrome.Conclusion:According to the classification of distant metastases in case of malignant neoplasms of the stomach, classical cases of metastases of Krukenberg, Virchow, Schnitzler, Sister Mary Joseph, and Irish were revealed. There is atypical metastasis to the inguinal nodes and to the undescended (true inguinal cryptorchidism) right testicle, which does not fall under the generally accepted classification of distant metastases of gastric cancer. Further tactics of treatment in the case of metastatic lesion to the inguinal regions in gastric cancer are not entirely clear, which requires an increase in the study of the amount of these clinical cases.

Correlation of focal neuroendocrine differentiation in prostate cancer with the parameters of predictive value

Background/Aim. Neuroendocrine (NE) cells are one of the epithelial populations in the prostate. It is well-known that the focal neuroendocrine differentiation (FNED) in prostate cancer (PC) is an aggressive subtype that most commonly evolves from preexisting PC which does not respond to hormone therapy (androgen independed PC). The incidence and clinical importance of FNED in PC is not clearly understood because of conflicting results in the studies, and evaluation of FNED is not routinely performed in clinical practice. The aim of the present study is to determine the importance of FNED presence in the examined prostate changes with special reference to the relationship of FNED degree in PC with some parameters of predictive value [Gleason score, preoperative serum total prostata specific antigen (PSA) value, tumor volume and tumor stage]. Methods. The study included the biopsy material from 100 untreated consecutive prostate pathological changes: 70 PC, 20 prostatic intraepithelial neoplasia (PIN) and 10 benign prostatic hyperplasia (BPH). The patients with PIN and BPH were the control groups. A block containing part of the main bulk of pathological change was chosen as representative based on hematoxylin-eosin appearance, and a section of this block was immunohistochemically stained for the tissue PSA (to mark prostatic secretory cells) and chromogranin A, serotonin and synaptophysin (to mark NE cells). Results. We found a very pronounced degree of FNED differentiation in 16 (22.9%) PC. Ten (62.5%) of them had Gleason score ? 7, the average serum PSA level was 32.62 ? 30.80 ng/mL, average tumor volume was 43.18 ? 31.45 mL and 6 (37.5%) of this PC were detected in D clinical stage with distant hematogenous metastases. The FNED is negatively correlated with the serum PSA level, Gleason score and clinical stage positively correlated with the tumor volume, but without statistically significant differences. Conclusion. The FNED has no significant role in the prognosis of PC.

Abstract OT2-06-04: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer

Abstract Background: Metastasis is the primary cause of death in breast cancer, yet no specific therapies are available that inhibit the metastatic process. TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. High TMEM score in the primary tumor is associated with higher risk of recurrence in ER+, HER2- early breast cancer. Paclitaxel induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy, and in the primary tumor and distant metastases in the PyMT/PDX models. Tumor cell intravasation is mediated by release of VEGF that promotes focal vascular leakiness specifically at TMEM sites, and is derived from TMEM-associated Tie2HI/VEGFHI macrophages that release VEGF upon binding of the Tie2 receptor to angiopoietin2 (ANG2), which is elaborated by TMEM-associated endothelial cells. Moreover, ANG2-stimulated release of IL-10 by tumor-associated macrophages suppresses T cell proliferation, increases the ratio of CD4+T cells to CD8+ T cells, and promotes the expansion of CD4+CD25highFOXP3+ cells. The Tie2 inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either paclitaxel or eribulin. We therefore hypothesize that the addition of a potent Tie2 inhibitor (rebastinib) to antitubulin therapy in patients with HER2 negative metastatic breast cancer (MBC) will prevent hematogenous dissemination and distant metastasis by inhibition of TMEM function, reduction in CTC burden, and inhibition of immune-system suppression resulting in improvement in breast clinical outcomes Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of rebastinib in two dose levels (DL) (50mg or 100mg po BID) combined with paclitaxel IV 80mg/m2 (day 1, 8 and 15) or eribulin IV 1.4mg/m2 (day1 and 8) for four 21-day cycles. Key eligibility includes histologically confirmed HER2 negative MBC. ≤ 2 non-taxane chemotherapy regimens are allowed for rebastinib plus paclitaxel arm, while ≥ 2 chemotherapy regimens (including a taxane) are required for eribulin plus rebastinib arm. ≥ 2 endocrine regimens, including an approved CDK4/6 inhibitor, is required for ER+ disease. Patients require ECOG PS 0 or 1 and normal organ and marrow function. Exclusion criteria include significant ocular disease, significant history of cardiac disease or concomitant use drugs that prolong QTc interval. Pharmacodynamic biomarkers to be measured during cycle 1-3 include CTCs, ANG 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients who have accessible tumors will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required. This trial has enrolled three patients assigned paclitaxel arm (DL1) and one patient in eribulin arm(DL1). Citation Format: Anampa JD, Xue X, Oktay M, Condeelis J, Sparano JA. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-04.

Management of Metastatic Sarcoma

Approximately 12,310 soft tissue sarcomas (STSs) were diagnosed in 2016. These tumors originate from mesenchymal cells throughout the body and account for less than 1% of all newly diagnosed cancers in adults. STSs comprise a heterogeneous group of tumors, with over 50 different histologic subtypes categorized based on the presumptive tissue of origin, each with varying individual characteristics and varying patterns of behavior. Most commonly, they originate in the extremity followed by the trunk as the second most common site of primary lesions. The likelihood of metastatic spread is highly variable among histologic subtype and primary disease site. Distant hematogenous metastases occur in up to 50% of patients with high-grade sarcomas but in only 5% of patients with low-grade sarcomas. Most metastases occur within 2 years following initial diagnosis. The risk of metastasis is dependent on several prognostic factors, including tumor depth, tumor size, and mitotic rate. The role of surgery in the management of metastatic disease is governed by careful patient selection in the context of a multidisciplinary plan including systemic treatment. Selection of patients for resection of sarcoma metastases is most appropriately based on consideration of factors associated with long-term survival. We review the role of surgery in the management of STS metastases, rational selection of patients for resection, and strategies for integrating surgery into multidisciplinary treatment planning for patients with metastatic STS. This review contains 3 figures, 3 tables and 60 references Key words: gastrointestinal stromal tumor, hepatic sarcoma metastases, metastatic sarcoma, pulmonary sarcoma metastases, retroperitoneal sarcoma, sarcoma, soft tissue sarcoma, surgical resection of sarcoma metastases

Management of Metastatic Sarcoma

Approximately 12,310 soft tissue sarcomas (STSs) were diagnosed in 2016. These tumors originate from mesenchymal cells throughout the body and account for less than 1% of all newly diagnosed cancers in adults. STSs comprise a heterogeneous group of tumors, with over 50 different histologic subtypes categorized based on the presumptive tissue of origin, each with varying individual characteristics and varying patterns of behavior. Most commonly, they originate in the extremity followed by the trunk as the second most common site of primary lesions. The likelihood of metastatic spread is highly variable among histologic subtype and primary disease site. Distant hematogenous metastases occur in up to 50% of patients with high-grade sarcomas but in only 5% of patients with low-grade sarcomas. Most metastases occur within 2 years following initial diagnosis. The risk of metastasis is dependent on several prognostic factors, including tumor depth, tumor size, and mitotic rate. The role of surgery in the management of metastatic disease is governed by careful patient selection in the context of a multidisciplinary plan including systemic treatment. Selection of patients for resection of sarcoma metastases is most appropriately based on consideration of factors associated with long-term survival. We review the role of surgery in the management of STS metastases, rational selection of patients for resection, and strategies for integrating surgery into multidisciplinary treatment planning for patients with metastatic STS. This review contains 3 figures, 3 tables and 60 references Key words: gastrointestinal stromal tumor, hepatic sarcoma metastases, metastatic sarcoma, pulmonary sarcoma metastases, retroperitoneal sarcoma, sarcoma, soft tissue sarcoma, surgical resection of sarcoma metastases

Two Uncommon Sites of Metastasis: Breast and Hypophysis Metastases of Head and Neck Adenoid Cystic Carcinoma Detected by FDG PET/CT.

Adenoid cystic carcinoma (ACC) is a rare epithelial malignancy arising from secretory glands, particularly the salivary glands. It tends to invade nerves and has a high potential for distant hematogenous metastasis, especially to the lungs, bone, liver and brain. The breast and hypophysis are not common sites of ACC metastatic disease. Herein, we report a case of ACC of the head and neck region with two unusual sites of metastases, the hypophysis and breast.

Treatment strategies in recurrent esophageal or junctional cancer.

Little evidence is available about survival rates in patients with recurrent disease after potentially curative surgery for esophageal or junctional cancer. Only in limited occasions, potentially curative salvage strategies are available. The aim of this study is to analyze survival rates and patterns of dissemination, and to identify independent prognostic factors in a consecutive series of patients who develop recurrent esophageal or junctional cancer. Between 1994 and 2015, patients who developed disease recurrence after neoadjuvant chemo(radio)therapy followed by radical esophagectomy for esophageal or junctional cancer were retrospectively analyzed. The Kaplan-Meier estimates were performed to calculate and compare overall survival between patients with different patterns of dissemination and to compare between different treatment strategies. Furthermore, univariate and multivariate Cox-regression analyses were performed to identify independent prognostic factors for post recurrence survival. In this study, we included 219 patients. The median overall survival of all included patients was 3.2 months (range: 0.0-101.1 months). The median overall survival in patients with exclusively locoregional recurrence (n =23, 10.8%) was 4.9 months (range: 0.1- 55.6) and 2.9 months (range: 0.0-101.1) in patients who had distant metastases (n =189, 89.2%), P=0.003. Patients who received treatment aimed at complete tumor eradication (n =28, 13.7%) had a median overall survival of 13.6 months (range: 1.1-101.1) and palliative treated patients (n =94, 46.1%) of 4.7 months (range: 0.3-25.6), P<0.001. In a selected group of patients survival of more than 20 months was achieved. Univariate and multivariate Cox-regression analysis showed that a higher age at the diagnosis of recurrent disease (hazard ratio: 1.087, P≤0.001), an irradical resection of the primary tumor (hazard ratio: 3.355, P= <0.001), the number of positive lymph nodes after neoadjuvant therapy (hazard ratios: ypN2 =1.724 (P=0.024) and ypN3 =2.082 (P=0.028) and the presence of a single hematogenous distant metastases (hazard ratio: 2.281, P=0.003) or more than one hematogenous distant metastasis (hazard ratio: 2.385, P=0.005) were associated with a shorter postrecurrence survival. The prognosis of patients who develop recurrent esophageal or junctional cancer is poor. In a selected group of patients however relatively long survival can be achieved. This offers new perspectives to improve treatment strategies and survival rates.

Abstract CT040: Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer

Abstract Background: Metastasis is the primary cause of death in breast cancer, yet no specific therapies are available that inhibit the metastatic process. TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. High TMEM score in the primary tumor is associated with higher risk of recurrence in ER+, HER2- early breast cancer. Paclitaxel induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy (NAC), and in the primary tumor and distant metastases in the PyMT rodent model and patient-derived xenograft (PDX) models. Intravasation of tumor cells is mediated by release of vascular endothelial growth factor (VEGF) that promotes focal vascular leakiness specifically at TMEM sites, and is derived from TMEM-associated Tie2HI/VEGFHI macrophages that release VEGF upon binding of the Tie2 receptor to angiopoietin, which is elaborated by TMEM-associated endothelial cells. The Tie2 inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either paclitaxel or eribulin. We therefore hypothesize that the addition of a potent Tie2 inhibitor (rebastinib) to antitubulin therapy with paclitaxel or eribulin in patients with HER2-negative metastatic breast cancer (MBC) will prevent hematogenous dissemination and distant metastasis by inhibiting TMEM function, reduce CTC burden, and improve clinical outcomes. Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of rebastinib (Tie2 inhibitor) in two dose levels (DL) (50mg or 100mg po BID) combined with paclitaxel IV 80mg/m2 (day 1, 8 and 15) or eribulin IV 1.4mg/m2 (day1 and 8) for four 21-day cycles. Key eligibility includes histologically confirmed HER2 negative MBC or not amenable to curative surgery. Up to two prior non-taxane chemotherapy regimens are allowed for rebastinib plus paclitaxel arm, while at least two chemotherapy regimens (including a taxane) are required for eribulin plus rebastinib arm. ER positive patients must have failed at least two lines of endocrine therapy including an approved CDK4/6 inhibitor. Patients require ECOG PS 0 or 1 and normal organ and marrow function. Exclusion criteria include significant ocular disease (retinal neovascularization, macular edema or macular degeneration), significant history of cardiac disease or concomitant use drugs that prolong QTc interval. Pharmacodynamic biomarkers to be measured during cycle 1(day1 and 15), cycle 2(day1 and 15) and cycle 3(day1) include CTCs, angiopoietin 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients who have accessible tumors will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required. This trial has enrolled two patients assigned to paclitaxel arm combined with rebastinib 50mg BID. Citation Format: Jesus D. Anampa, Xiaonan Xue, Maja oktay, John Condeelis, Joseph A. Sparano. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT040. doi:10.1158/1538-7445.AM2017-CT040

Pancreatic metastasis resulting from thymic neuroendocrine carcinoma: A case report.

Thymic neuroendocrine carcinoma (NEC) is a rare type of cancer. Unlike other thymic epithelial tumors and carcinoids originating in other locations, thymic NEC possesses a more aggressive biological behavior, including invasion to proximal structures, local recurrence and distant hematogenous metastasis. Distant metastasis is often observed in the bones, lungs, spleen, liver and adrenal glands. However, pancreatic metastasis resulting from thymic NEC is extremely uncommon, and only a few cases of patients with this disease have been reported. The current study presents the case of a patient with pancreatic metastasis resulting from thymic NEC. The patient was admitted to hospital with an anterior mediastinal neoplasm, which was identified using chest enhanced computed tomography. The patient underwent a monobloc excision of the tumor with resection of involved structures. Subsequently, a pathological diagnosis of atypical thymic carcinoid was provided, according to the morphological characteristics observed and the expression of neuroendocrine markers, as identified by immunohistochemistry. Following surgery, the patient received adjuvant chemotherapy and radiotherapy. However, ~2 years after surgery, metastasis at the pancreatic head was identified. The patient underwent a total pancreatectomy and splenectomy, and did not receive any post-operative therapies; however, the patient succumbed to the disease 9 months following surgery. Overall, the results from the present study demonstrate the clinical features of thymic NEC, which may aid with the diagnosis of this rare disease in other patients.

Tissue transglutaminase-interleukin-6 axis facilitates peritoneal tumor spreading and metastasis of human ovarian cancer cells.

Inflammation has recently been implicated in cancer formation and progression. As tissue transglutaminase (TG2) has been associated with both inflammatory signaling and tumor cell behavior, we propose that TG2 may be an important link inducing interleukin-6 (IL-6)-mediated cancer cell aggressiveness, including cancer stem cell-like characteristics and distant hematogenous metastasis. We evaluated the effect of differential TG2 and IL-6 expression on in vivo distant metastasis of human ovarian cancer cells. IL-6 production in human ovarian cancer cells was dependent on their TG2 expression levels. The size and efficiency of tumor sphere formation were correlated with TG2 expression levels and were dependent on TG2-mediated IL-6 secretion in human ovarian cancer cells. Primary tumor growth and propagation in the peritoneum and distant hematogenous metastasis into the liver and lung were also dependent on TG2 and downstream IL-6 expression levels in human ovarian cancer cells. In this report, we provide evidence that TG2 is an important link in IL-6-mediated tumor cell aggressiveness, and that TG2 and downstream IL-6 could be important mediators of distant hematogenous metastasis of human ovarian cancer cells. Intervention specific to TG2 and/or downstream IL-6 in ovarian cancer cells could provide a promising means to control tumor metastasis.

Case Report: Primary Leiomyosarcoma of the breast with unusual metastasis to the femur

With less than 40 cases reported, primary leiomyosarcoma is an extremely rare form of breast cancer (less than 0.0006% of cases) with unpredictable biological behavior that usually presents as a slow growing, mobile mass in middle age women. Most cases are low-grade and are cured by complete excision with wide margins. After surgical resection, late local recurrence and distant hematogenous metastasis to lungs and liver is, however, well-documented. To the best of our knowledge, bone metastasis has never been reported. Here we present a case of primary leiomyosarcoma of the breast metastatic to the femur.