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Sample records for metastatic lung tumor

  1. Applicability of Pulmonary Lobectomy in Treating Metastatic Lung Tumors

    PubMed Central

    Kitahara, Hirokazu; Shimamatsu, Shinichiro; Morodomi, Yosuke; Tagawa, Tetsuzo; Maehara, Yoshihiko

    2015-01-01

    Purpose: Although metastases to the lung from other organs are usually removed with limited lung resections (e.g., wedge resections or segmentectomies), pulmonary lobectomies are often required to remove whole pulmonary tumors. This study investigated the clinical applicability of pulmonary lobectomies to treat metastatic lung tumors. Methods: We retrospectively reviewed clinical records of 143 consecutive patients with metastatic tumors in the lung who underwent surgery in our department, including data sets for 100 patients treated for their first metastatic lung tumors. Results: Of the 100 patients, 23 received pulmonary lobectomies, 69 received wedge resections and eight received segmentectomies. Patients in the lobectomy group were more likely to be younger, have larger and/or multiple tumors, and to have tumors of musculoskeletal origin (sarcomas) than those who underwent segmentectomies or wedge resections (the limited resection group). The two groups did not significantly differ in survival (3-year survival rate; lobectomy vs limited resection: 75.2% vs 80.4%, P = 0.15), or post-operative morbidity, although the only post-operative morbidity was associated with post-operative prognosis in the lobectomy group. Conclusions: Pulmonary lobectomy is a safe and applicable surgical procedure for metastatic lung tumors when long survival is expected after the tumor resection. PMID:25641034

  2. Capnocytophaga Lung Abscess in a Patient with Metastatic Neuroendocrine Tumor

    PubMed Central

    Thirumala, Raghu; Babady, N. Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor. PMID:22075586

  3. Capnocytophaga lung abscess in a patient with metastatic neuroendocrine tumor.

    PubMed

    Thirumala, Raghu; Rappo, Urania; Babady, N Esther; Kamboj, Mini; Chawla, Mohit

    2012-01-01

    Capnocytophaga species are known commensals of the oral cavity of humans and animals (mainly dogs and cats) and are a rare cause of respiratory tract infections. We report a case of cavitary lung abscess caused by a Capnocytophaga species in a patient with a metastatic neuroendocrine tumor. PMID:22075586

  4. Pulmonar collision tumor: metastatic adenoid cystic carcinoma and lung adenocarcinoma.

    PubMed

    Blanco, M; García-Fontán, E; Ríos, J; Rivo, J E; Fernández-Martín, R; Cañizares, M A

    2012-01-01

    We report an extraordinary case of collision tumor consisting of a lung adenocarcinoma and a metastatic adenoid cystic carcinoma in a 56 year-old man. He was diagnosed with a pulmonary nodule 11 years after treatment of an adenoid cystic carcinoma of the right maxillary sinus. A non-small cell carcinoma was observed when a transbronchial biopsy was performed. The other component of the nodule was only diagnosed with pathological examination of the resection specimen. PMID:21802893

  5. Pulmonar collision tumor: metastatic adenoid cystic carcinoma and lung adenocarcinoma.

    PubMed

    Blanco, M; García-Fontán, E; Ríos, J; Rivo, J E; Fernández-Martín, R; Cañizares, M A

    2012-01-01

    We report an extraordinary case of collision tumor consisting of a lung adenocarcinoma and a metastatic adenoid cystic carcinoma in a 56 year-old man. He was diagnosed with a pulmonary nodule 11 years after treatment of an adenoid cystic carcinoma of the right maxillary sinus. A non-small cell carcinoma was observed when a transbronchial biopsy was performed. The other component of the nodule was only diagnosed with pathological examination of the resection specimen.

  6. Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs.

    PubMed

    Halvorsen, E C; Hamilton, M J; Young, A; Wadsworth, B J; LePard, N E; Lee, H N; Firmino, N; Collier, J L; Bennewith, K L

    2016-06-01

    Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.

  7. Volume change determination of metastatic lung tumors in CT images using 3-D template matching

    NASA Astrophysics Data System (ADS)

    Ambrosini, Robert D.; Wang, Peng; O'Dell, Walter G.

    2009-02-01

    The ability of a clinician to properly detect changes in the size of lung nodules over time is a vital element to both the diagnosis of malignant growths and the monitoring of the response of cancerous lesions to therapy. We have developed a novel metastasis sizing algorithm based on 3-D template matching with spherical tumor appearance models that were created to match the expected geometry of the tumors of interest while accounting for potential spatial offsets of nodules in the slice thickness direction. The spherical template that best-fits the overall volume of each lung metastasis was determined through the optimization of the 3-D normalized cross-correlation coefficients (NCCC) calculated between the templates and the nodules. A total of 17 different lung metastases were extracted manually from real patient CT datasets and reconstructed in 3-D using spherical harmonics equations to generate simulated nodules for testing our algorithm. Each metastasis 3-D shape was then subjected to 10%, 25%, 50%, 75% and 90% scaling of its volume to allow for 5 possible volume change combinations relative to the original size per each reconstructed nodule and inserted back into CT datasets with appropriate blurring and noise addition. When plotted against the true volume change, the nodule volume changes calculated by our algorithm for these 85 data points exhibited a high degree of accuracy (slope = 0.9817, R2 = 0.9957). Our results demonstrate that the 3-D template matching method can be an effective, fast, and accurate tool for automated sizing of metastatic tumors.

  8. Metastatic pleural tumor

    MedlinePlus

    ... persons. Alternative Names Tumor - metastatic pleural Images Pleural space References Arenberg D, Pickens A. Metastatic malignant tumors. In: Mason RJ, Murray JF, Broaddus VC, et al., eds. Murray and Nadel's Textbook of Respiratory Medicine . 5th ed. Philadelphia, PA: Elsevier Saunders; 2010:chap ...

  9. [Early diagnosis of metastatic spinal tumor is a key for effective palliative radiotherapy in patients with lung cancer].

    PubMed

    Isono, Hisayo; Kemmoku, Tomoko; Nakamura, Yusuke; Onose, Akira; Matsumoto, Yuka; Watanabe, Rinako; Haraguchi, Mizuha; Kasajima, Masashi; Takaya, Saho; Ishihara, Mikiko; Karigane, Daiki; Nagata, Hiroshi

    2011-12-01

    Patients with metastatic spinal tumor are the largest in number among the patients with bone tumor. It causes a severe bone pain, pathological fracture and spinal cord compression. Thus it harshly hampers patient's quality of life. We report 3 patients with lung cancer whose initial manifestation was metastatic spinal tumor. We treated the 3 patients with palliative radiotherapy and medication. Although the severe pain has improved on a numerical rating scale(NRS), but performance status(PS)and activity of daily living(ADL)of the 3 patients got worse because the disease was progressed and complicated. Generally, PS of cancer patients found by bone matastasis is low. However, it is difficult to take an effective treatment, which leads to ADL improvement. There are many choices for treating metastatic bone tumors including pain control, bisphosphonate administration, radiation therapy, strontium radiotherapy, bone cement, palliative surgery and orthotics. In addition, a development of molecular target drugs, such as Denosmab, is expected as future modality of palliative care. In conclusion, we should detect a bone metastasis in the patient with lung cancer as early as possible, and select an appropriate treatment in collaboration with each specialist for achieving the ADL and PS improvement. PMID:22189323

  10. Chinese expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors.

    PubMed

    Ye, Xin; Fan, Weijun; Chen, Jun-Hui; Feng, Wei-Jian; Gu, Shan-Zhi; Han, Yue; Huang, Guang-Hui; Lei, Guang-Yan; Li, Xiao-Guang; Li, Yu-Liang; Li, Zhen-Jia; Lin, Zheng-Yu; Liu, Bao-Dong; Liu, Ying; Peng, Zhong-Min; Wang, Hui; Yang, Wu-Wei; Yang, Xia; Zhai, Bo; Zhang, Jun

    2015-01-01

    Although surgical resection is the primary means of curing both primary and metastatic lung cancers, about 80% of lung cancers cannot be removed by surgery. As most patients with unresectable lung cancer receive only limited benefits from traditional radiotherapy and chemotherapy, many new local treatment methods have emerged, including local ablation therapy. The Minimally Invasive and Comprehensive Treatment of Lung Cancer Branch, Professional Committee of Minimally Invasive Treatment of Cancer of the Chinese Anti-Cancer Association has organized multidisciplinary experts to develop guidelines for this treatment modality. These guidelines aim at standardizing thermal ablation procedures and criteria for selecting treatment candidates and assessing outcomes; and for preventing and managing post-ablation complications. PMID:26273346

  11. Phase II Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer

    ClinicalTrials.gov

    2016-04-18

    Extensive Stage Small Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Tumors Metastatic to Brain; Metastatic Breast Cancer

  12. Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis

    PubMed Central

    Calvo, A; Catena, R; Noble, MS; Carbott, D; Gil-Bazo, I; Gonzalez-Moreno, O; Huh, J-I; Sharp, R; Qiu, T-H; Anver, MR; Merlino, G; Dickson, RB; Johnson, MD; Green, JE

    2009-01-01

    Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression profiling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C (TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-α-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a significant decrease (P < 0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer. PMID:18504437

  13. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells.

    PubMed

    Müller, Philipp; Rothschild, Sacha I; Arnold, Walter; Hirschmann, Petra; Horvath, Lukas; Bubendorf, Lukas; Savic, Spasenija; Zippelius, Alfred

    2016-01-01

    Tumor-infiltrating lymphocytes play an important role in cell-mediated immune destruction of cancer cells and tumor growth control. We investigated the heterogeneity of immune cell infiltrates between primary non-small cell lung carcinomas (NSCLC) and corresponding metastases. Formalin-fixed, paraffin-embedded primary tumors and corresponding metastases from 34 NSCLC patients were analyzed by immunohistochemistry for CD4, CD8, CD11c, CD68, CD163 and PD-L1. The percentage of positively stained cells within the stroma and tumor cell clusters was recorded and compared between primary tumors and metastases. We found significantly fewer CD4(+) and CD8(+) T cells within tumor cell clusters as compared with the stromal compartment, both in primary tumors and corresponding metastases. CD8(+) T cell counts were significantly lower in metastatic lesions than in the corresponding primary tumors, both in the stroma and the tumor cell islets. Of note, the CD8/CD4 ratio was significantly reduced in metastatic lesions compared with the corresponding primary tumors in tumor cell islets, but not in the stroma. We noted significantly fewer CD11c(+) cells and CD68(+) as well as CD163(+) macrophages in tumor cell islets compared with the tumor stroma, but no difference between primary and metastatic lesions. Furthermore, the CD8/CD68 ratio was higher in primary tumors than in the corresponding metastases. We demonstrate a differential pattern of immune cell infiltration in matched primary and metastatic NSCLC lesions, with a significantly lower density of CD8(+) T cells in metastatic lesions compared with the primary tumors. The lower CD8/CD4 and CD8/CD68 ratios observed in metastases indicate a rather tolerogenic and tumor-promoting microenvironment at the metastatic site.

  14. AAVrh.10-mediated genetic delivery of bevacizumab to the pleura to provide local anti-VEGF to suppress growth of metastatic lung tumors.

    PubMed

    Watanabe, M; Boyer, J L; Crystal, R G

    2010-08-01

    Vascular endothelial growth factor (VEGF) produced by tumor cells has a central role in stimulating angiogenesis required for tumor growth. Humanized monoclonal anti-VEGF antibody (bevacizumab, Avastin), approved as a treatment for non-squamous, non-small cell lung cancer, requires administration every 3 weeks. We hypothesized that an intrapleural administration of an adeno-associated virus (AAV) vector expressing an anti-VEGF-A antibody equivalent of bevacizumab would result in sustained anti-VEGF-A localized expression within the lung and suppress metastatic tumor growth. The AAV vector AAVrh.10alphaVEGF encodes the light chain and heavy chain complementary DNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF-A with the same antigen-binding site as bevacizumab. A metastatic lung tumor model was established in severe combined immunodeficient mice by intravenous administration of human DU145 prostate carcinoma cells. Intrapleural administration of AAVrh.10alphaVEGF directed long-term expression of the anti-human VEGF-A antibody in lung, as shown by sustained, high-level anti-human VEGF titers in lung epithelial lining fluid for 40 weeks, which was the duration of the study. In the AAVrh.10alphaVEGF-treated animals, tumor growth was significantly suppressed (P<0.05), the numbers of blood vessels and mitotic nuclei in the tumor was decreased (P<0.05) and there was increased survival (P<0.05). Thus, intrapleural administration of an AAVrh.10 vector, encoding the murine monoclonal antibody equivalent of bevacizumab, effectively suppresses the growth of metastatic lung tumors, suggesting AAV-mediated gene transfer to the pleura to deliver bevacizumab locally to the lung as a novel alternative platform to conventional monoclonal antibody therapy.

  15. Effects of letrozole on breast cancer micro-metastatic tumor growth in bone and lung in mice inoculated with murine 4T1 cells.

    PubMed

    Wang, Wendan; Belosay, Aashvini; Yang, Xujuan; Hartman, James A; Song, Huaxin; Iwaniec, Urszula T; Turner, Russell T; Churchwell, Mona I; Doerge, Daniel R; Helferich, William G

    2016-06-01

    Breast cancer (BC) is the leading cancer in women worldwide. Metastasis occurs in stage IV BC with bone and lung being common metastatic sites. Here we evaluate the effects of the aromatase inhibitor letrozole on BC micro-metastatic tumor growth in bone and lung metastasis in intact and ovariectomized (OVX) mice with murine estrogen receptor negative (ER-) BC cells inoculated in tibia. Forty-eight BALB/c mice were randomly assigned to one of four groups: OVX, OVX + Letrozole, Intact, and Intact + Letrozole, and injected with 4T1 cells intra-tibially. Letrozole was subcutaneously injected daily for 23 days at a dose of 1.75 µg/g body weight. Tumor progression was monitored by bioluminescence imaging (BLI). Following necropsy, inoculated tibiae were scanned via µCT and bone response to tumor was scored from 0 (no ectopic mineralization/osteolysis) to 5 (extensive ectopic mineralization/osteolysis). OVX mice had higher tibial pathology scores indicative of more extensive bone destruction than intact mice, irrespective of letrozole treatment. Letrozole decreased serum estradiol levels and reduced lung surface tumor numbers in intact animals. Furthermore, mice receiving letrozole had significantly fewer tumor colonies and fewer proliferative cells in the lung than OVX and intact controls based on H&E and Ki-67 staining, respectively. In conclusion, BC-inoculated OVX animals had higher tibia pathology scores than BC-inoculated intact animals and letrozole reduced BC metastases to lungs. These findings suggest that, by lowering systemic estrogen level and/or by interacting with the host organ, the aromatase inhibitor letrozole has the potential to reduce ER- BC metastasis to lung. PMID:27209469

  16. Surgical Outcomes of Hemorrhagic Metastatic Brain Tumors

    PubMed Central

    Yoo, Heon; Jung, Eugene; Gwak, Ho Shin; Shin, Sang Hoon

    2011-01-01

    Purpose Hemorrhagic metastatic brain tumors are not rare, but little is known about the surgical outcome following treatment. We conducted this study to determine the result of the surgical outcome of hemorrhagic metastatic brain tumors. Materials and Methods From July 2001 to December 2008, 21 patients underwent surgery for hemorrhagic metastatic brain tumors at our institution. 15 patients had lung cancer, 3 had hepatocellular carcinoma, and the rest had rectal cancer, renal cell carcinoma, and sarcoma. 20 patients had macroscopic hemorrhage in the tumors, and one patient had intracerebral hemorrhage surrounding the tumor. A retrospective clinical review was conducted focusing on the patterns of presenting symptoms and signs, as well as local recurrence following surgery. Results Among 21 hemorrhagic brain metastases, local recurrence developed in two patients. The 12 month progression free survival rate was 86.1%. Mean time to progression was 20.8 months and median survival time after surgery was 11.7 months. Conclusion The results of our study showed that hemorrhagic metastatic brain tumors rarely recurred after surgery. Surgery should be considered as a good treatment option for hemorrhagic brain metastasis, especially in cases with increased intracranial pressure or severe neurologic deficits. PMID:21811426

  17. Pulmonary tumor thrombotic microangiopathy from metastatic epithelioid angiosarcoma

    PubMed Central

    Cakir, Ebru; Yazici, Ulku; Tastepe, Irfan

    2013-01-01

    The lung is most common site for metastatic disease via hematogenous route. Tumor emboli of the vessels of the lung induces fibrocellular and fibromuscular intimal proliferation. These histopathological changes may cause pulmonary tumor trombotic microangiopaty. Few cases are diagnosed antemortem. We report a 60 year old woman with by metastatic epithelioid angiosarcoma involving the lung. Tumor cells were positive for VEGF and topoisomerase II. VEGF may be involved in the pathogenesis pulmonary tumor trombotic microangioapy and topoisomerase II positivity showed sensitivity against catalytic topoisomerase II inhibitors. PMID:23825782

  18. Detection of metastatic tumors after γ-irradiation using longitudinal molecular imaging and gene expression profiling of metastatic tumor nodules.

    PubMed

    Jang, Su Jin; Kang, Joo Hyun; Lee, Yong Jin; Kim, Kwang Il; Lee, Tae Sup; Choe, Jae Gol; Lim, Sang Moo

    2016-04-01

    A few recent reports have indicated that metastatic growth of several human cancer cells could be promoted by radiotherapy. C6-L cells expressing the firefly luciferase (fLuc) gene were implanted subcutaneously into the right thigh of BALB/c nu/nu mice. C6-L xenograft mice were treated locally with 50-Gy γ-irradiation (γ-IR) in five 10-Gy fractions. Metastatic tumors were evaluated after γ-IR by imaging techniques. Total RNA from non-irradiated primary tumor (NRPT), γ-irradiated primary tumor (RPT), and three metastatic lung nodule was isolated and analyzed by microarray. Metastatic lung nodules were detected by BLI and PET/CT after 6-9 weeks of γ-IR in 6 (17.1%) of the 35 mice. The images clearly demonstrated high [18F]FLT and [18F]FDG uptake into metastatic lung nodules. Whole mRNA expression patterns were analyzed by microarray to elucidate the changes among NRPT, RPT and metastatic lung nodules after γ-IR. In particular, expression changes in the cancer stem cell markers were highly significant in RPT. We observed the metastatic tumors after γ-IR in a tumor-bearing animal model using molecular imaging methods and analyzed the gene expression profile to elucidate genetic changes after γ-IR. PMID:26892334

  19. Lung Carcinoid Tumor: Surgery

    MedlinePlus

    ... for lung carcinoid tumor symptoms Surgery to treat lung carcinoid tumors Surgery is the main treatment for ... often be cured by surgery alone. Types of lung surgery Different operations can be used to treat ( ...

  20. Metastatic lung adenocarcinoma to the bladder: A case report

    PubMed Central

    YE, HAI-JUN; MA, JIAN; LIU, YING-JIE; YE, XIAO-FEI; ZHANG, LI-WANG; LI, JIN-GE

    2015-01-01

    Urothelial cancer is the most frequently diagnosed type of malignant tumor in the bladder, of which primary adenocarcinoma accounts for a small percentage. Secondary malignancies, in particular metastatic adenocarcinoma from the lung, are exceedingly rare, with only six cases previously reported in the literature. The present study describes the case of a 71-year-old Chinese male patient with known lung cancer for >2 years, who was diagnosed with metastatic adenocarcinoma to the bladder. The histopathological characteristics and immunohistochemical features of the patient are reported. It was proposed that pathologists should consider the possibility of metastatic adenocarcinoma from the lung, rather than assume a diagnosis of primary adenocarcinoma of the bladder or direct invasion of adenocarcinoma from the surrounding organs. Furthermore, it is essential to determine the medical history of each patient and observe the immunohistochemical features of all tumors prior to diagnosis. PMID:26622730

  1. GTI-2040 and Docetaxel in Treating Patients With Recurrent, Metastatic, or Unresectable Locally Advanced Non-Small Cell Lung Cancer, Prostate Cancer, or Other Solid Tumors

    ClinicalTrials.gov

    2013-01-23

    Recurrent Non-small Cell Lung Cancer; Recurrent Prostate Cancer; Stage III Prostate Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  2. Tumor-suppressive p53 Signaling Empowers Metastatic Inhibitor KLF17-dependent Transcription to Overcome Tumorigenesis in Non-small Cell Lung Cancer.

    PubMed

    Ali, Amjad; Bhatti, Muhammad Zeeshan; Shah, Abdus Saboor; Duong, Hong-Quan; Alkreathy, Huda Mohammad; Mohammad, Shah Faisal; Khan, Rahmat Ali; Ahmad, Ayaz

    2015-08-28

    Metastasis, which is controlled by concerted action of multiple genes, is a complex process and is an important cause of cancer death. Krüppel-like factor 17 (KLF17) is a negative regulator of metastasis and epithelial-mesenchymal transition (EMT) during cancer progression. However, the underlying molecular mechanism and biological relevance of KLF17 in cancer cells are poorly understood. Here, we show that tumor suppressor protein p53 plays an integral role to induce KLF17 expression in non-small cell lung cancer (NSCLC). p53 is recruited to the KLF17 promoter and results in the formation of p53-DNA complex. p53 enhances binding of p300 and favors histone acetylation on the KLF17 promoter. Mechanistically, p53 physically interacts with KLF17 and thereby enhances the anti-metastatic function of KLF17. p53 empowers KLF17-mediated EMT genes transcription via enhancing physical association of KLF17 with target gene promoters. Nutlin-3 recruits KLF17 to EMT target gene promoters and results in the formation of KLF17-DNA complex via a p53-dependent pathway. p53 depletion abrogates DNA binding affinity of KLF17 to EMT target gene promoters. KLF17 is critical for p53 cellular activities in NSCLC. Importantly, KLF17 enhances p53 transcription to generate a novel positive feedback loop. KLF17 depletion accelerates lung cancer cell growth in response to chemotherapy. Mechanistically, we found that KLF17 increases the expression of tumor suppressor genes p53, p21, and pRB. Functionally, KLF17 required p53 to suppress cancer cell invasion and migration in NSCLC. In conclusion, our study highlights a novel insight into the anti-EMT effect of KLF17 via a p53-dependent pathway in NSCLC, and KLF17 may be a new therapeutic target in NSCLC with p53 status.

  3. Malignant Pleural Effusion Supernatants Are Substitutes for Metastatic Pleural Tumor Tissues in EGFR Mutation Test in Patients with Advanced Lung Adenocarcinoma

    PubMed Central

    Wu, Ning; Nie, Xiaomeng; Xia, Yang; Han, Yiping; Li, Qiang; Zhu, Guanshan; Bai, Chong

    2014-01-01

    Background Though the possibility of using malignant pleural effusions (MPEs) as alternatives for metastatic pleural tumor tissues (MPTTs) in epidermal growth factor receptor (EGFR) mutation test has been examined, due to the lack of studies comparing the results in matching MPEs and MPTTs, the clinical value of MPEs for advanced adenocarcinoma patients with pleural effusions is not confirmed. Methods EGFR mutation statuses in matching MPTTs, MPE supernatants and cell blocks, of 41 patients with advanced lung adenocarcinoma as diagnosed by thoracoscopy were analyzed using amplification refractory mutation system (ARMS). Results EGFR mutations were detected in 46.3% (19/41) of MPTTs, 43.9% (18/41) of MPE supernatants and 56.3% (18/32) of MPE cell blocks by ARMS analysis. Generally, the same EGFR statuses were identified in both MPTTs and matching MPE cell blocks of 81.3% patients (26/32), whereas MPTTs and matching MPE supernatants of 87.8% (36/41) patients shared the same EGFR status. Compared with EGFR mutation detection in MPTTs, the sensitivity of EGFR mutation detection in MPE-cell blocks was 87.5% (14/16), specificity was 75.0% (12/16), while the sensitivity of EGFR mutation detection in MPE-supernatants was 84.2% (16/19), specificity was 90.9% (20/22). Conclusions The high concordance of EGFR mutation statuses between MPEs and MPTTs in lung adenocarcinoma patients with pleural metastasis as determined by ARMS analysis suggests that MPEs, particularly MPE supernatants, may be substitutes for MPTTs in EGFR mutation test. PMID:24587142

  4. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  5. Regorafenib in Treating Patients With Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2015-08-29

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma

  6. Hemangioblastoma in the Lung: Metastatic or Primary Lesions?

    PubMed Central

    Lu, Li; Drew, Peter A.; Yachnis, Anthony T.

    2014-01-01

    Hemangioblastoma primarily occurs in the CNS, most commonly in the posterior fossa. Extracranial locations are less common, and metastatic tumor involving the lung is exceedingly rare with only three cases previously reported. Two were autopsy studies in patients who died of complications of the CNS hemangioblastomas in 1943 and 1981, and the third was mentioned in a case report addendum providing follow-up information on hepatic hemangioblastoma in 1991. We report a case of a 48-year-old man who presented with multiple lung nodules treated by surgical excision. Pathological study revealed features classic for hemangioblastoma. The patient had a remote history of hemangioblastomas having been excised from the posterior fossa 7 and 20 years previously. This report details a fourth case of metastatic pulmonary hemangioblastoma. It is the first report on surgically resected hemangioblastomas from the lung of a living patient with histological and immunohistochemical characterization. PMID:25574414

  7. Oncolytic Reovirus in Combination With Chemotherapy in Metastatic or Recurrent Non–Small Cell Lung Cancer Patients With KRAS-Activated Tumors

    PubMed Central

    Villalona-Calero, Miguel A.; Lam, Elaine; Otterson, Gregory A.; Zhao, Weiqiang; Timmons, Matthew; Subramaniam, Deepa; Hade, Erinn M.; Gill, George M.; Coffey, Matthew; Selvaggi, Giovanni; Bertino, Erin; Chao, Bo; Knopp, Michael V.

    2016-01-01

    BACKGROUND The type 3 Dearing reovirus (Reolysin) is a naturally occurring virus that preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. It induces host immunity and cell cycle arrest and acts synergistically with cytotoxic agents. METHODS This study evaluated Reolysin combined with paclitaxel and carboplatin in patients with metastatic/recurrent KRAS-mutated or epidermal growth factor receptor (EGFR)–mutated/amplified non–small cell lung cancer. RESULTS Thirty-seven patients were treated. Molecular alterations included 20 KRAS mutations, 10 EGFR amplifications, 3 EGFR mutations, and 4 BRAF-V600E mutations. In total, 242 cycles (median, 4; range, 1-47) were completed. The initial doses were area under the curve (AUC) 6 mg/mL/min for carboplatin, 200 mg/m2 for paclitaxel on day 1, and 3×1010 50% tissue culture infective dose for Reolysin on days 1 to 5 of each 21-day cycle. Because of diarrhea and febrile neutropenia (in the first 2 patients), subsequent doses were reduced to 175 mg/m2 for paclitaxel and AUC 5 mg/mL/min for carboplatin. Toxicities included fatigue, diarrhea, nausea/vomiting, neutropenia, arthralgia/myalgia, anorexia, and electrolyte abnormalities. Response Evaluation Criteria in Solid Tumors 1.0 responses included the following: partial response for 11 patients, stable disease (SD) for 20 patients, progressive disease for 4 patients, and not evaluable for 2 patients (objective response rate, 31%; 90% 1-sided lower confidence interval, 21%). Four SD patients had >40% positron emission tomography standardized uptake value reductions. The median progression-free survival, median overall survival, and 12-month overall survival rate were 4 months, 13.1 months, and 57%, respectively. Seven patients were alive after a median follow-up of 34.2 months; they included 2 patients without disease progression at 37 and 50 months. CONCLUSIONS Reolysin in combination with paclitaxel and carboplatin was well tolerated. The

  8. Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  9. Pre-Clinical Mouse Models of Primary and Metastatic Pleural Cancers of the Lung and Breast and the Use of Bioluminescent Imaging to Monitor Pleural Tumor Burden (ms#CP-10-0176)

    PubMed Central

    Servais, Elliot L.; Colovos, Christos; Kachala, Stefan S.; Adusumilli, Prasad S.

    2015-01-01

    Malignant pleural disease (MPD) results in an estimated 150,000 cases of malignant pleural effusions (MPE) annually. The most common malignancies associated with MPD are primary malignant pleural mesothelioma (MPM) and metastatic lung cancer, breast cancer and lymphoma. MPM is a rare, regionally aggressive, malignancy whose incidence is increasing secondary to the latency of disease progression. MPD is characteristic of advanced stage pleural disease and portends a grave clinical prognosis with a median survival between 3 to 12 months. Treatment for MPD is primarily palliative by thoracentesis to drain the effusion or surgical procedures to liberate trapped lung and obliterate cavities in order to limit subsequent collection of pleural effusions. Systemic chemotherapy is typically ineffective due to dose-limiting toxicities and poor intratumoral penetration. Preclinical investigations conducted in flank and intraperitoneal tumor models do not fully recapitulate the pleural tumor microenvironment and the results are not directly translational to the clinically setting. An orthotopic model of pleural malignancy allows investigators to evaluate the efficacy of therapies against novel molecular targets in a microenvironment that mimics the clinical tumor milieu. The protocol described herein provides a mouse model of MPM and MPD from non-hematogenous tumors resulting in reproducible tumor location, tumor progression, animal survival, and histopathology. Pleural tumor growth in this model resembles the regionally aggressive clinical course and tumor microenvironment of human pleural cancers and provides an optimal animal model to investigate MPD biology and therapies. PMID:21898334

  10. Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

    PubMed

    Gorczynski, Reginald M; Erin, Nuray; Zhu, Fang

    2016-02-01

    Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential. PMID:26725371

  11. Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

    PubMed

    Gorczynski, Reginald M; Erin, Nuray; Zhu, Fang

    2016-02-01

    Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential.

  12. Pulmonary Metastatic Choriocarcinoma from a Burned-out Testicular Tumor.

    PubMed

    Nakazaki, Hirofumi; Tokuyasu, Hirokazu; Takemoto, Yu; Miura, Hiroshi; Yanai, Masaaki; Fukushima, Takehito; Shimizu, Eiji

    2016-01-01

    A 54-year-old man was referred to our hospital because of progressive dyspnea. Chest computed tomography showed multiple nodular shadows with a peripheral ground-glass halo. His clinical condition continued to deteriorate with the development of progressive respiratory failure requiring mechanical ventilation. A histological examination of a transbronchial lung biopsy revealed choriocarcinoma. The patient died within nine days of admission. A histological examination of the right testis during an autopsy revealed a burned-out testicular tumor consisting of a teratoma and a fibrous scar. We herein report a rare case of pulmonary multiple metastatic choriocarcinoma originating from a burned-out testicular tumor. PMID:27250057

  13. Lung metastases

    MedlinePlus

    Metastases to the lung; Metastatic cancer to the lung ... Metastatic tumors in the lungs are cancers that developed at other places in the body (or other parts of the lungs) and spread through the ...

  14. Malignant metastatic carcinoid presenting as brain tumor

    PubMed Central

    Sundar, I. Vijay; Jain, S. K.; Kurmi, Dhrubajyoti; Sharma, Rakesh; Chopra, Sanjeev; Singhvi, Shashi

    2016-01-01

    Carcinoid tumors are rarely known to metastasise to the brain. It is even more rare for such patients to present with symptoms related to metastases as the initial and only symptom. We present a case of a 60-year-old man who presented with hemiparesis and imaging features suggestive of brain tumor. He underwent surgery and the histopathology revealed metastatic malignant lesion of neuroendocrine origin. A subsequent work up for the primary was negative. Patient was treated with adjuvant radiotherapy. We present this case to highlight the pathophysiological features, workup and treatment options of this rare disease and discuss the methods of differentiating it from more common brain tumors. PMID:27366273

  15. Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma

    ClinicalTrials.gov

    2016-11-02

    Metastatic Ewing Sarcoma; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Bone Marrow; Metastatic Malignant Neoplasm in the Lung; Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone; Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

  16. Inhibition of metastatic tumor growth and metastasis via targeting metastatic breast cancer by chlorotoxin-modified liposomes.

    PubMed

    Qin, Chao; He, Bing; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Wang, Guangji; Yin, Lifang; Zhang, Qiang

    2014-10-01

    A liposome system modified with chlorotoxin (ClTx), a scorpion venom peptide previously utilized for targeting brain tumors, was established. Its targeting efficiency and antimetastasis behavior against metastatic breast cancer highly expressed MMP-2, the receptor of ClTx, were investigated. 4T1, a metastatic breast cancer cell line derived from a murine breast tumor, was selected as the cell model. As results, the ClTx-modified liposomes displayed specific binding to 4T1 as determined by flow cytometry and confocal imaging. The cytotoxicity assay revealed that the ClTx modification increased the toxicity compared with nonmodified liposomes. In addition, the modified liposomes also exhibited high in vivo targeting efficiency in the BALB/c mice bearing 4T1 tumors. Importantly, this system inhibited the growth of metastatic tumor and prevented the incidence of lung metastasis in mice bearing 4T1 tumors with only low systemic toxicity. The data obtained from the in vitro and in vivo studies confirmed that the ClTx-modified liposomes increased the drug delivery to metastatic breast cancers. This study proved that the ClTx-modified liposomes had targeting ability to metastatic breast cancer in addition to brain cancer, and displayed an obvious antimetastasis effect. Generally, it may provide a promising strategy for metastatic breast cancer therapy.

  17. Metastatic cardiac tumor manifested by persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography.

    PubMed

    Cheon, Dae Young; Park, Kyoung-Ha; Hong, Seong Eun; Lee, Soo Haeng; Jang, Seung Hun; Park, Woo Jung

    2014-01-01

    In cases with metastatic invasion of the heart, electrocardiographic abnormalities are commonly seen. However, most of these electrocardiographic changes are nonspecific; certain findings may be highly suggestive of myocardial involvement of the tumor. We report a patient with lung cancer who presented with persistent ST-segment elevation with coexisting reciprocal changes on electrocardiography due to myocardial invasion of the lung cancer.

  18. Pulmonary Hyalinizing Granuloma Mimicking Metastatic Lung Cancer

    PubMed Central

    Düzgün, Nuri; Kurtipek, Ercan; Esme, Hıdır; Eren Karanis, Meryem İlkay; Tolu, İsmet

    2015-01-01

    Pulmonary hyalinizing granuloma is a very rare benign condition, which usually manifests as solitary and sometimes as multiple pulmonary nodules. Deposition of immune complexes in the lung parenchyma due to hypersensitivity reactions is implicated in the etiology of pulmonary hyalinizing granuloma. A 59-year-old female patient who presented to our clinic with complaints of chest pain and cough had bilateral, multiple, and rounded lesions with regular margins suggesting metastatic lung disease. A transthoracic needle biopsy of the nodule was performed in the left pulmonary anterior segment. Biopsy showed no malignancy. Since no diagnosis was made by the biopsy, the patient underwent a video-assisted thoracic surgery. The wedge biopsy reported pulmonary hyalinizing granuloma. We aimed to present the diagnosis and treatment stages of our patient who was diagnosed with pulmonary hyalinizing granuloma in the light of literature review. PMID:26347384

  19. Pulmonary Hyalinizing Granuloma Mimicking Metastatic Lung Cancer.

    PubMed

    Düzgün, Nuri; Kurtipek, Ercan; Esme, Hıdır; Eren Karanis, Meryem İlkay; Tolu, İsmet

    2015-01-01

    Pulmonary hyalinizing granuloma is a very rare benign condition, which usually manifests as solitary and sometimes as multiple pulmonary nodules. Deposition of immune complexes in the lung parenchyma due to hypersensitivity reactions is implicated in the etiology of pulmonary hyalinizing granuloma. A 59-year-old female patient who presented to our clinic with complaints of chest pain and cough had bilateral, multiple, and rounded lesions with regular margins suggesting metastatic lung disease. A transthoracic needle biopsy of the nodule was performed in the left pulmonary anterior segment. Biopsy showed no malignancy. Since no diagnosis was made by the biopsy, the patient underwent a video-assisted thoracic surgery. The wedge biopsy reported pulmonary hyalinizing granuloma. We aimed to present the diagnosis and treatment stages of our patient who was diagnosed with pulmonary hyalinizing granuloma in the light of literature review. PMID:26347384

  20. Is the Blood-Brain Barrier Relevant in Metastatic Germ Cell Tumor?

    SciTech Connect

    Azar, Jose M. Schneider, Bryan P.; Einhorn, Lawrence H.

    2007-09-01

    Purpose: Germ cell tumors are uniquely chemosensitive and curable, even with advanced metastatic disease. Central nervous system recurrence can terminate a complete remission in other chemosensitive tumors, such as small cell lung cancer, because of the blood-brain barrier (BBB). We propose to document that the BBB is also relevant in germ cell tumors despite their dramatic chemosensitivity. Methods and Materials: We present five cases illustrating the concept of the BBB in patients with metastatic testicular cancer treated with chemotherapy. Results: In our large series of patients with metastatic testicular cancer treated with chemotherapy, we identified 5 unique patients. These patients were rendered free of disease only to experience relapse in the brain alone. This included 1 patient who initially had good-risk metastatic disease by means of the International Germ Cell Collaborative Group staging system at the onset of chemotherapy. Conclusions: The BBB is relevant in patients with metastatic testicular cancer.

  1. iTRAQ Quantitative Proteomic Comparison of Metastatic and Non-Metastatic Uveal Melanoma Tumors

    PubMed Central

    Crabb, John W.; Hu, Bo; Crabb, John S.; Triozzi, Pierre; Saunthararajah, Yogen; Singh, Arun D.

    2015-01-01

    Background Uveal melanoma is the most common malignancy of the adult eye. The overall mortality rate is high because this aggressive cancer often metastasizes before ophthalmic diagnosis. Quantitative proteomic analysis of primary metastasizing and non-metastasizing tumors was pursued for insights into mechanisms and biomarkers of uveal melanoma metastasis. Methods Eight metastatic and 7 non-metastatic human primary uveal melanoma tumors were analyzed by LC MS/MS iTRAQ technology with Bruch’s membrane/choroid complex from normal postmortem eyes as control tissue. Tryptic peptides from tumor and control proteins were labeled with iTRAQ tags, fractionated by cation exchange chromatography, and analyzed by LC MS/MS. Protein identification utilized the Mascot search engine and the human Uni-Prot/Swiss-Protein database with false discovery ≤ 1%; protein quantitation utilized the Mascot weighted average method. Proteins designated differentially expressed exhibited quantitative differences (p ≤ 0.05, t-test) in a training set of five metastatic and five non-metastatic tumors. Logistic regression models developed from the training set were used to classify the metastatic status of five independent tumors. Results Of 1644 proteins identified and quantified in 5 metastatic and 5 non-metastatic tumors, 12 proteins were found uniquely in ≥ 3 metastatic tumors, 28 were found significantly elevated and 30 significantly decreased only in metastatic tumors, and 31 were designated differentially expressed between metastatic and non-metastatic tumors. Logistic regression modeling of differentially expressed collagen alpha-3(VI) and heat shock protein beta-1 allowed correct prediction of metastasis status for each of five independent tumor specimens. Conclusions The present data provide new clues to molecular differences in metastatic and non-metastatic uveal melanoma tumors. While sample size is limited and validation required, the results support collagen alpha-3(VI) and

  2. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor.

    PubMed

    Velez-Cubian, Frank O; Gabordi, Robert C; Smith, Prudence V; Toloza, Eric M

    2016-06-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed.

  3. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor.

    PubMed

    Velez-Cubian, Frank O; Gabordi, Robert C; Smith, Prudence V; Toloza, Eric M

    2016-06-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  4. Tumor-to-tumor metastasis: an unusual case of breast cancer metastatic to a solitary fibrous tumor

    PubMed Central

    Velez-Cubian, Frank O.; Gabordi, Robert C.; Smith, Prudence V.

    2016-01-01

    Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm that most commonly involves the visceral or parietal pleura, but that has also been described arising from virtually all organs. This neoplasm exhibits rich vascularity, a characteristic it shares with renal cell carcinoma, making these tumors especially suitable for harboring metastases. We present a case of a 64-year-old woman with history of right breast cancer treated six years previously and who presents with a left pulmonary SFT containing metastatic invasive ductal breast carcinoma as well as a synchronous contralateral primary adenocarcinoma of the lung. The literature on tumor-to-tumor metastasis is then reviewed. PMID:27293861

  5. Suppressive effects of a proton beam on tumor growth and lung metastasis through the inhibition of metastatic gene expression in 4T1 orthotopic breast cancer model.

    PubMed

    Kwon, Yun-Suk; Lee, Kyu-Shik; Chun, So-Young; Jang, Tae Jung; Nam, Kyung-Soo

    2016-07-01

    A proton beam is a next generation tool to treat intractable cancer. Although the therapeutic effects of a proton beam are well known, the effect on tumor metastasis is not fully described. Here, we investigated the effects of a proton beam on metastasis in highly invasive 4T1 murine breast cancer cells and their orthotopic breast cancer model. Cells were irradiated with 2, 4, 8 or 16 Gy proton beam, and changes in cell proliferation, survival, and migration were observed by MTT, colony forming and wound healing assays. 4T1 breast cancer cell-implanted BALB/c mice were established and the animals were randomly divided into 4 groups when tumor size reached 200 mm3. Breast tumors were selectively irradiated with 10, 20 or 30 Gy proton beam. Breast tumor sizes were measured twice a week, and breast tumor and lung tissues were pathologically observed. Metastasis-regulating gene expression was assessed with quantitative RT-PCR. A proton beam dose-dependently decreased cell proliferation, survival and migration in 4T1 murine breast cancer cells. Also, growth of breast tumors in the 4T1 orthotopic breast cancer model was significantly suppressed by proton beam irradiation without significant change of body weight. Furthermore, fewer tumor nodules metastasized from breast tumor into lung in mice irradiated with 30 Gy proton beam, but not with 10 and 20 Gy, than in control. We observed correspondingly lower expression levels of urokinase plasminogen activator (uPA), uPA receptor, cyclooxygenase (COX)-2, and vascular endothelial growth factor (VEGF), which are important factors in cancer metastasis, in breast tumor irradiated with 30 Gy proton beam. Proton beam irradiation did not affect expressions of matrix metalloproteinase (MMP)-9 and MMP-2. Taken together, the data suggest that, although proton beam therapy is an effective tool for breast cancer treatment, a suitable dose is necessary to prevent metastasis-linked relapse and poor prognosis. PMID:27176787

  6. Urinary Bladder Paraganglioma and Concomitant Metastatic Lung Cancer. A Case Report.

    PubMed

    Gkikas, Christos; Ram, Manisha; Tsafrakidis, Petros

    2016-03-01

    We present a case of an organ confined urinary bladder paraganglioma and concomitant metastatic lung cancer to the liver diagnosed on a 66 year old man initially though to be metastatic bladder cancer. The patient was referred to our hospital for frank hematuria and a single solid bladder tumor was identified at flexible cystoscopy. We are also reviewing the literature on the diagnostic and therapeutic approach of extra-adrenal phaeochromocytoma.

  7. A nanoparticle formulation that selectively transfects metastatic tumors in mice

    PubMed Central

    Yang, Jian; Hendricks, William; Liu, Guosheng; McCaffery, J. Michael; Kinzler, Kenneth W.; Huso, David L.; Vogelstein, Bert; Zhou, Shibin

    2013-01-01

    Nanoparticle gene therapy holds great promise for the treatment of malignant disease in light of the large number of potent, tumor-specific therapeutic payloads potentially available for delivery. To be effective, gene therapy vehicles must be able to deliver their therapeutic payloads to metastatic lesions after systemic administration. Here we describe nanoparticles comprised of a core of high molecular weight linear polyethylenimine (LPEI) complexed with DNA and surrounded by a shell of polyethyleneglycol-modified (PEGylated) low molecular weight LPEI. Compared with a state-of-the-art commercially available in vivo gene delivery formulation, i.v. delivery of the core/PEGylated shell (CPS) nanoparticles provided more than a 16,000-fold increase in the ratio of tumor to nontumor transfection. The vast majority of examined liver and lung metastases derived from a colorectal cancer cell line showed transgene expression after i.v. CPS injection in an animal model of metastasis. Histological examination of tissues from transfected mice revealed that the CPS nanoparticles selectively transfected neoplastic cells rather than stromal cells within primary and metastatic tumors. However, only a small fraction of neoplastic cells (<1%) expressed the transgene, and the extent of delivery varied with the tumor cell line, tumor site, and host mouse strain used. Our results demonstrate that these CPS nanoparticles offer substantial advantages over previously described formulations for in vivo nanoparticle gene therapeutics. At the same time, they illustrate that major increases in the effectiveness of such approaches are needed for utility in patients with metastatic cancer. PMID:23959886

  8. Outcomes of Adolescent and Adult Patients with Lung Metastatic Osteosarcoma and Comparison of Synchronous and Metachronous Lung Metastatic Groups.

    PubMed

    Gok Durnali, Ayse; Paksoy Turkoz, Fatma; Ardic Yukruk, Fisun; Tokluoglu, Saadet; Yazici, Omer Kamil; Demirci, Ayse; Bal, Oznur; Gundogdu Buyukbas, Selay; Esbah, Onur; Oksuzoglu, Berna; Alkis, Necati

    2016-01-01

    Osteosarcomas with lung metastases are rather heterogenous group. We aimed to evaluate the clinicopathological characteristics and outcomes of osteosarcoma patients with lung metastases and to compare the synchronous and metachronous lung metastatic groups. A total of 93 adolescent and adult patients with lung metastatic osteosarcoma, from March 1995 to July 2011, in a single center, were included. Sixty-five patients (69.9%) were male. The median age was 19 years (range, 14-74). Thirty-nine patients (41.9%) had synchronous lung metastases (Group A) and 54 patients (58.1%) had metachronous lung metastases (Group B). The 5-year and 10-year post-lung metastases overall survival (PLM-OS) was 17% and 15%, respectively. In multivariate analysis for PLM-OS, time to lung metastases (p = 0.010), number of metastatic pulmonary nodules (p = 0.020), presence of pulmonary metastasectomy (p = 0.007) and presence of chemotherapy for lung metastases (p< 0.001) were found to be independent prognostic factors. The median PLM-OS of Group A and Group B was 16 months and 9 months, respectively. In Group B, the median PLM-OS of the patients who developed lung metastases within 12 months was 6 months, whereas that of the patients who developed lung metastases later was 16 months. Time to lung metastases, number and laterality of metastatic pulmonary nodules, chemotherapy for lung metastatic disease and pulmonary metastasectomy were independent prognostic factors for patients with lung metastatic osteosarcoma. The best PLM-OS was in the subgroup of patients treated both surgery and chemotherapy. The prognosis of the patients who developed lung metastases within 12 months after diagnosis was worst.

  9. Outcomes of Adolescent and Adult Patients with Lung Metastatic Osteosarcoma and Comparison of Synchronous and Metachronous Lung Metastatic Groups

    PubMed Central

    Gok Durnali, Ayse; Paksoy Turkoz, Fatma; Ardic Yukruk, Fisun; Tokluoglu, Saadet; Yazici, Omer Kamil; Demirci, Ayse; Bal, Oznur; Gundogdu Buyukbas, Selay; Esbah, Onur; Oksuzoglu, Berna; Alkis, Necati

    2016-01-01

    Osteosarcomas with lung metastases are rather heterogenous group. We aimed to evaluate the clinicopathological characteristics and outcomes of osteosarcoma patients with lung metastases and to compare the synchronous and metachronous lung metastatic groups. A total of 93 adolescent and adult patients with lung metastatic osteosarcoma, from March 1995 to July 2011, in a single center, were included. Sixty-five patients (69.9%) were male. The median age was 19 years (range, 14–74). Thirty-nine patients (41.9%) had synchronous lung metastases (Group A) and 54 patients (58.1%) had metachronous lung metastases (Group B). The 5-year and 10-year post-lung metastases overall survival (PLM-OS) was 17% and 15%, respectively. In multivariate analysis for PLM-OS, time to lung metastases (p = 0.010), number of metastatic pulmonary nodules (p = 0.020), presence of pulmonary metastasectomy (p = 0.007) and presence of chemotherapy for lung metastases (p< 0.001) were found to be independent prognostic factors. The median PLM-OS of Group A and Group B was 16 months and 9 months, respectively. In Group B, the median PLM-OS of the patients who developed lung metastases within 12 months was 6 months, whereas that of the patients who developed lung metastases later was 16 months. Time to lung metastases, number and laterality of metastatic pulmonary nodules, chemotherapy for lung metastatic disease and pulmonary metastasectomy were independent prognostic factors for patients with lung metastatic osteosarcoma. The best PLM-OS was in the subgroup of patients treated both surgery and chemotherapy. The prognosis of the patients who developed lung metastases within 12 months after diagnosis was worst. PMID:27167624

  10. Metastatic tumors to the pancreas: The role of surgery

    PubMed Central

    Sperti, Cosimo; Moletta, Lucia; Patanè, Giuseppe

    2014-01-01

    Pancreatic metastases from other primary malignancies are a rare entity. By far, the most common primary cancer site resulting in an isolated pancreatic metastasis is the kidney, followed by colorectal cancer, melanoma, breast cancer, lung carcinoma and sarcoma. Only few data on the surgical outcome of pancreatic resections performed for metastases from other primary tumor have been published, and there are no guidelines to address the surgical treatment for these patients. In this study, we performed a review of the published literature, focusing on the early and long-term results of surgery for the most frequent primary tumors metastasizing to the pancreas. Results for the Literature’s analysis show that in last years an increasing number of surgical resections have been performed in selected patients with limited pancreatic disease. Pancreatic resection for metastatic disease can be performed with acceptable mortality and morbidity rates. The usefulness of pancreatic resection is mainly linked to the biology of the primary tumor metastasizing to the pancreas. The benefit of metastasectomy in terms of patient survival has been observed for metastases from renal cell cancer, while for other primary tumors, such as lung and breast cancers, the role of surgery is mainly palliative. PMID:25320654

  11. In vivo subcellular resolution optical imaging in the lung reveals early metastatic proliferation and motility

    PubMed Central

    Entenberg, David; Rodriguez-Tirado, Carolina; Kato, Yu; Kitamura, Takanori; Pollard, Jeffrey W; Condeelis, John

    2016-01-01

    To better understand breast cancer metastatic cell seeding, we have employed multiphoton microscopy and a vacuum stabilized window which eliminates the need for complex registration software, video rate microscopy or specialized gating electronics to observe the initial steps of tumor cell seeding within the living, breathing lung. We observe that upon arrival to the lung, tumor cells are found exclusively in capillary vessels, completely fill their volume and display an initial high level of protrusive activity that dramatically reduces over time. Further, we observe a concomitant increase in positional stability during this same period. We employ several techniques accessible to most imaging labs for optimizing signal to noise and resolution which enable us to report the first direct observation, with subcellular resolution, of the arrival, proliferation, and motility of metastatic tumor cells within the lung. PMID:26855844

  12. Aberrant NRP-1 expression serves as predicator of metastatic endometrial and lung cancers

    PubMed Central

    Okon, Imoh S.; Ding, Ye; Coughlan, Kathleen A.; Wang, Qiongxin; Song, Ping; Benbrook, Doris M.; Zou, Ming-Hui

    2016-01-01

    Neuropilin-1 (NRP-1) has emerged as an important driver of tumor-promoting phenotypes of human malignancies. However, incomplete knowledge exists as to how this single-pass transmembrane receptor mediates pleiotropic tumor-promoting functions. The purpose of this study was to evaluate NRP-1 expression and metastatic properties in 94 endometrial cancer and matching serum specimens and in a lung cancer cell line. We found that NRP-1 expression significantly correlated with increased tumoral expression of vascular endothelial growth factor 2 (VEGFR2) and serum levels of hepatocyte growth factor (HGF) and cell growth-stimulating factor (C-GSF). Tumoral NRP-1 also was positively associated with expression of NEDD9, a pro-metastatic protein. In the highly metastatic lung cancer cell line (H1792), stable LKB1 depletion caused increased migration in vitro and accentuated NRP-1 and NEDD9 expression in vivo. Our findings demonstrate that perturbed expression of these targets correlate with metastatic potential of endometrial and lung tumors, providing clinically-relevant biomarker applications for diagnostic and therapeutic targeting. PMID:26701889

  13. An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency.

    PubMed

    Brady, Jennifer J; Chuang, Chen-Hua; Greenside, Peyton G; Rogers, Zoë N; Murray, Christopher W; Caswell, Deborah R; Hartmann, Ursula; Connolly, Andrew J; Sweet-Cordero, E Alejandro; Kundaje, Anshul; Winslow, Monte M

    2016-05-01

    The ability of cancer cells to establish lethal metastatic lesions requires the survival and expansion of single cancer cells at distant sites. The factors controlling the clonal growth ability of individual cancer cells remain poorly understood. Here, we show that high expression of the transcription factor ARNTL2 predicts poor lung adenocarcinoma patient outcome. Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture. Arntl2 drives metastatic self-sufficiency by orchestrating the expression of a complex pro-metastatic secretome. We identify Clock as an Arntl2 partner and functionally validate the matricellular protein Smoc2 as a pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments. PMID:27150038

  14. Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors

    ClinicalTrials.gov

    2016-11-04

    Atypical Carcinoid Tumor; Foregut Carcinoid Tumor; Hindgut Carcinoid Tumor; Lung Carcinoid Tumor; Metastatic Carcinoid Tumor; Metastatic Digestive System Neuroendocrine Tumor G1; Midgut Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Regional Digestive System Neuroendocrine Tumor G1

  15. Temsirolimus and Vinorelbine Ditartrate in Treating Patients With Unresectable or Metastatic Solid Tumors

    ClinicalTrials.gov

    2016-06-09

    Extensive Stage Small Cell Lung Cancer; Hereditary Paraganglioma; Male Breast Cancer; Malignant Paraganglioma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Endometrial Carcinoma; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pheochromocytoma; Recurrent Prostate Cancer; Recurrent Renal Cell Cancer; Recurrent Small Cell Lung Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Regional Pheochromocytoma; Stage III Cervical Cancer; Stage III Endometrial Carcinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Prostate Cancer; Stage III Renal Cell Cancer; Stage III Uterine Sarcoma; Stage IIIA Breast Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Breast Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Stage IV Endometrial Carcinoma; Stage IV Neuroendocrine Carcinoma of the Skin; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Ovarian Germ Cell Tumor; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Uterine Sarcoma; Stage IVA Cervical Cancer; Stage IVB Cervical Cancer; Thyroid Gland Medullary Carcinoma

  16. Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2013-06-03

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Pulmonary Carcinoid Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Regional Gastrointestinal Carcinoid Tumor; Somatostatinoma

  17. [Palliative radiotherapy for metastatic bone tumor].

    PubMed

    Yoshida, Kenji; Hiratsuka, Junichi

    2006-04-01

    Bone metastases are one of the most common conditions requiring radiation therapy today. Its main aim is relief of bone pain, prevention of pathological bone fractures as well as its healing, with anticipated effect upon improving mobility, function, and quality of life. For localized bone pain, external beam radiation therapy (EBRT) will be successful in reducing pain in some 80% of patients. However, optimal fraction dose and total doses of EBRT required for pain relief have been unknown. According to the recent reports, carbon ion radiotherapy seems to be a safe and effective modality in the management of metastatic bone tumor not eligible for conventional EBRT. For scattered painful metastases, the systemic administration of radioisotopes is thought to be effective. PMID:16582516

  18. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes.

    PubMed

    Nishikawa, Makiya; Hyoudou, Kenji; Kobayashi, Yuki; Umeyama, Yukari; Takakura, Yoshinobu; Hashida, Mitsuru

    2005-12-01

    To develop effective anti-metastatic therapy, targeted or sustained delivery of catalase was examined in mice. We found that mouse lung with metastatic colonies of adenocarcinoma colon26 cells exhibited reduced catalase activity. The interaction of the tumor cells with macrophages or hepatocytes generated detectable amounts of ROS, and increased the activity of matrix metalloproteinases. Hepatocyte-targeted delivery of catalase was successfully achieved by galactosylation, which was highly effective in inhibiting the hepatic metastasis of colon26 cells. PEGylation, which increased the retention of catalase in the circulation, effectively inhibited the pulmonary metastasis of the cells. To examine which processes in tumor metastasis are inhibited by catalase derivatives, the tissue distribution and proliferation of tumor cells in mice was quantitatively analyzed using firefly luciferase-expressing tumor cells. An injection of PEG-catalase just before the inoculation of melanoma B16-BL6/Luc cells significantly reduced the number of the tumor cells in the lung at 24 h. Daily dosing of PEG-catalase greatly inhibited the proliferation of the tumor cells, and increased the survival rate of the tumor-bearing mice. These results indicate that targeted or sustained delivery of catalase to sites where tumor cells metastasize is a promising approach for inhibiting metastatic tumor growth. PMID:16256238

  19. Clinical Outcomes of Biological Effective Dose-Based Fractionated Stereotactic Radiation Therapy for Metastatic Brain Tumors From Non-Small Cell Lung Cancer

    SciTech Connect

    Matsuyama, Tomohiko; Kogo, Kasei; Oya, Natsuo

    2013-03-15

    Purpose: To evaluate the efficacy and toxicity of fractionated stereotactic radiation therapy (FSRT) based on biological effective dose (BED), a novel approach to deliver a fixed BED irrespective of dose fractionation, for brain metastases from non-small cell lung cancer (NSCLC). Methods and Materials: Between March 2005 and March 2009 we treated 299 patients with 1 to 5 lesions from NSCLC (573 total brain metastases) with FSRT using Novalis. The dose fractionation schedules were individually determined to deliver a peripheral BED10 (α/β ratio = 10) of approximately 80 Gy{sub 10}. The median number of fractions was 3 (range, 2-10), the median peripheral BED10 was 83.2 Gy (range, 19.1-89.6 Gy). Patients were followed up with magnetic resonance imaging (MRI) studies performed at 1- to 2-month intervals. The local tumor control rate and overall local progression-free and intracranial relapse-free survival were calculated by the Kaplan-Meier method. Results: Local control rates for all 573 lesions at 6 and 12 months were 96.3% and 94.5%, respectively. By multivariate analysis the tumor diameter was the only factor predictive of the local control rate (P=.001). The median overall survival, local progression-free survival, and intracranial relapse-free survival were 17.1, 14.9, and 4.4 months, respectively. The overall survival, local progression-free survival, and intracranial relapse-free survival rates at 6 and 12 months were 78.5% and 63.3%, 74.3% and 57.8%, and 41.0% and 21.8%, respectively. Six patients (2%) manifested progressive radiation injury to the brain even during therapy with corticosteroids; they underwent hyperbaric oxygen therapy, and follow-up MRI showed improvement. Conclusions: This study showed that BED-based FSRT for brain metastases from NSCLC is a promising strategy that may yield excellent outcomes with acceptable toxicity. Criteria must be established to determine the optimal dose fractionation for individual patients.

  20. Mucoepidermoid tumors of the lung.

    PubMed

    Yousem, S A; Hochholzer, L

    1987-09-15

    Mucoepidermoid tumors of lung (MET) are rare tumors derived from the minor salivary gland tissue of the proximal tracheobronchial tree. The authors studied 58 cases of MET confined to the lung and used criteria derived from similar tumors of the salivary glands to separate them into low-grade and high-grade variants. The overwhelming majority of low-grade tumors behaved in a benign fashion, whereas 23% of high-grade tumors resulted in patient death. Prognostic factors which appeared to predict future aggressive behavior included high-grade classification, advanced stage at presentation, and perhaps lymph node metastases.

  1. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma

    PubMed Central

    Eyles, Jo; Puaux, Anne-Laure; Wang, Xiaojie; Toh, Benjamin; Prakash, Celine; Hong, Michelle; Tan, Tze Guan; Zheng, Lin; Ong, Lai Chun; Jin, Yi; Kato, Masashi; Prévost-Blondel, Armelle; Chow, Pierce; Yang, Henry; Abastado, Jean-Pierre

    2010-01-01

    Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients. PMID:20501944

  2. Diagnosis and treatment of neuroendocrine lung tumors.

    PubMed

    Sánchez de Cos Escuín, Julio

    2014-09-01

    Pulmonary neuroendocrine tumors (PNT) encompass a broad spectrum of tumors including typical carcinoid (TC) and atypical (AC) tumors, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Although no variety can be considered benign, AC and TC have a much lower metastatic potential, are usually diagnosed in early stages, and most are candidates for surgical treatment. Several chemotherapy (CT) regimens are available in the case of recurrence or in advanced stages, although scientific evidence is insufficient. LCNEC, which is currently classified alongside large-cell carcinomas, have molecular features, biological behavior and CT sensitivity profile closely resembling SCLC. Pathological diagnosis is often difficult, despite the availability of immunohistochemical techniques, and surgical specimens may be necessary. The diagnostic tests used are similar to those used in other lung tumors, with some differences in the optimal tracer in positron emission tomography. The new TNM classification is useful for staging these tumors. Carcinoid syndrome, very rare in PNT, may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs. Overall, with the exception of SCLC, new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage.

  3. Diagnosis and treatment of neuroendocrine lung tumors.

    PubMed

    Sánchez de Cos Escuín, Julio

    2014-09-01

    Pulmonary neuroendocrine tumors (PNT) encompass a broad spectrum of tumors including typical carcinoid (TC) and atypical (AC) tumors, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Although no variety can be considered benign, AC and TC have a much lower metastatic potential, are usually diagnosed in early stages, and most are candidates for surgical treatment. Several chemotherapy (CT) regimens are available in the case of recurrence or in advanced stages, although scientific evidence is insufficient. LCNEC, which is currently classified alongside large-cell carcinomas, have molecular features, biological behavior and CT sensitivity profile closely resembling SCLC. Pathological diagnosis is often difficult, despite the availability of immunohistochemical techniques, and surgical specimens may be necessary. The diagnostic tests used are similar to those used in other lung tumors, with some differences in the optimal tracer in positron emission tomography. The new TNM classification is useful for staging these tumors. Carcinoid syndrome, very rare in PNT, may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs. Overall, with the exception of SCLC, new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage. PMID:24685201

  4. Sweets for a bitter end: lung cancer cell surface protein glycosylation mediates metastatic colonization

    PubMed Central

    Arnal-Estapé, Anna; Nguyen, Don X.

    2015-01-01

    Summary Glycosylation is one of the most predominant forms of cell surface protein modifications and yet its de-regulation in cancer and contribution to tumor microenvironment interactions remains poorly understood. In this issue of Cancer Discovery, Reticker-Flynn and Bhatia characterize an enzymatic switch in lung cancer cells that triggers aberrant surface protein glycosylation patterns, adhesion to lectins on the surface of inflammatory cells, and subsequent metastatic colonization of the liver. PMID:25656895

  5. Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells

    PubMed Central

    1993-01-01

    Attachment of circulating tumor cells to endothelial cell adhesion molecules restricted to select vascular compartments is thought to be responsible for site-specific metastasis. Lung-metastatic rat R3230AC- MET breast and RPC-2 prostate carcinoma cells bound outside-out endothelial cell membrane vesicles, prepared by perfusion of the rat lung vasculature with a low-strength formaldehyde solution, in significantly higher numbers than their nonmetastatic counterparts R3230AC-LR and RPC-LR. In contrast, vesicles derived from the vasculature of a nonmetastasized organ (e.g., hind leg muscle) showed no binding preference for either of the four tumor cell lines. Lung- derived endothelial vesicles were used here to generate mAbs against lung endothelial cell adhesion molecules. The first group of mice were actively immunized against lung endothelial vesicles, whereas the second group was injected with syngeneic mouse antiserum against leg endothelial vesicles before active immunization with lung endothelial vesicles. 17 hybridoma supernatants obtained from the two fusions bound lung vesicles with at least a 10-fold higher affinity than leg vesicles. Seven (four obtained by a passive/active immunization protocol) stained rat capillary endothelia. One mAb, mAb 8.6A3, inhibited specific adhesion of lung-derived vesicles to lung-metastatic breast and prostate carcinoma cells. Purification of the antigen (endothelial cell adhesion molecule) from rat lung extracts revealed a protein with a 110-kD mol wt. NH2-terminal sequencing established identity with dipeptidyl peptidase IV which had been reported to serve as a fibronectin-binding protein. These results indicate that vesicles obtained from in situ perfused organs are a convenient immunogen for the production of antibodies to compartment-specific endothelial cell surface molecules, and reinforce the concept that endothelial cell surface components are selectively recognized by circulating cancer cells during metastasis

  6. Induction of the metastatic phenotype in a mouse tumor model by 5-azacytidine, and characterization of an antigen associated with metastatic activity.

    PubMed Central

    Olsson, L; Forchhammer, J

    1984-01-01

    The murine Lewis lung carcinoma is a long-term grafted tumor that, after subcutaneous inoculation, forms metastases to the lungs. Forty-two cell lines were established from a primary tumor site and 40 were established from lung metastatic foci. Cloned sublines were established from the original 82 lines, and 2 sublines among 405 were found to be tumorigenic but not metastatic (T+/M-), whereas the remaining 403 sublines were both tumorigenic and metastatic (T+/M+). The T+/M- phenotype was shown to be stable for greater than 2 yr. However, treatment of the T+/M- cell lines for 3 days with 3 microM 5-azacytidine resulted in reexpression of the metastatic phenotype in otherwise stable T+/M- lines. Also, 5-azacytidine treatment could result in loss of the metastatic phenotype in lines that had been stable T+/M+. The changes in tumorigenic and metastatic phenotypes were not associated with altered immunogenicity of the cells. Monoclonal antibodies were generated against T+/M+ cells, and one antibody ( M36D3 ) was found to bind only to T+/M+ cells. Reactivity of the antibody was found to co-vary with expression of the metastatic phenotype. The antigen recognized by M36D3 antibody thus seems to be associated with metastatic capability. The antigen was found by two-dimensional gel electrophoretic analysis to be a cellular protein of Mr approximately equal to 45,000 and pI approximately equal to 6.7. Images PMID:6203119

  7. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues

    PubMed Central

    Piffko, Andras; Hoffmann, Christian J.; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell—endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection. PMID:27603673

  8. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues.

    PubMed

    Broggini, Thomas; Piffko, Andras; Hoffmann, Christian J; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell-endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection. PMID:27603673

  9. FRIZZLED7 Is Required for Tumor Inititation and Metastatic Growth of Melanoma Cells

    PubMed Central

    Tiwary, Shweta; Xu, Lei

    2016-01-01

    Metastases are thought to arise from cancer stem cells and their tumor initiating abilities are required for the establishment of metastases. Nevertheless, in metastatic melanoma, the nature of cancer stem cells is under debate and their contribution to metastasis formation remains unknown. Using an experimental metastasis model, we discovered that high levels of the WNT receptor, FZD7, correlated with enhanced metastatic potentials of melanoma cell lines. Knocking down of FZD7 in a panel of four melanoma cell lines led to a significant reduction in lung metastases in animal models, arguing that FZD7 plays a causal role during metastasis formation. Notably, limiting dilution analyses revealed that FZD7 is essential for the tumor initiation of melanoma cells and FZD7 knockdown impeded the early expansion of metastatic melanoma cells shortly after seeding, in accordance with the view that tumor initiating ability of cancer cells is required for metastasis formation. FZD7 activated JNK in melanoma cell lines in vitro and the expression of a dominant negative JNK suppressed metastasis formation in vivo, suggesting that FZD7 may promote metastatic growth of melanoma cells via activation of JNK. Taken together, our findings uncovered a signaling pathway that regulates the tumor initiation of melanoma cells and contributes to metastasis formation in melanoma. PMID:26808375

  10. Combined Aortic Resection and Stent Graft Insertion for Local Recurrence of Metastatic Lung Carcinoma Following Stereotactic Radiotherapy: A Case Report

    PubMed Central

    Matsutani, Noriyuki; Imazuru, Tomohiro; Morita, Shigeki; Takahashi, Yusuke; Shimokawa, Tomoki; Kawamura, Masafumi

    2015-01-01

    Stereotactic radiotherapy (SRT) is a useful treatment for malignant ling tumors. However, SRT is associated with complications such as high local recurrence rate and radiation-induced lung injury. Herein, we report a case of combined aortic resection for after SRT. An 82-year-old man underwent SRT for the metastatic lung carcinoma of rectal cancer at left lower lobe. Three years later, chest computed tomography showed local recurrence at the site of radiotherapy, with suspected invasion of the descending aorta. Thoracotomy was performed after metastatic lung carcinoma interpolation of a stent graft in the descending aorta. Because the tumor firmly adhered to the aorta, left lower lung lobe and aortic wall resection was performed. Pathological findings revealed fibrous hypertrophy and adhesion between the visceral pleura and aorta. As shown in our case, combined aortic resection and stent graft insertion is an effective minimally invasive and safe treatment for SRT-induced tissue damage. PMID:26256818

  11. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor.

    PubMed

    Farhangi, Baharak; Alizadeh, Ali Mohammad; Khodayari, Hamid; Khodayari, Saeed; Dehghan, Mohammad Javad; Khori, Vahid; Heidarzadeh, Alemeh; Khaniki, Mahmood; Sadeghiezadeh, Majid; Najafi, Farhood

    2015-07-01

    Curcumin has been shown to inhibit migration and invasion of cancer angiogenesis via interacting with key regulatory molecules like NF-κB. Rapidly metabolized and conjugated in the liver, curcumin has the limited systemic bioavailability. Previous results have shown a new light of potential biocompatibility, biodegradability, as well as anti-cancer effects of dendrosomal curcumin (DNC) in biological systems. The present study aims to deliberate the protective effects of DNC on metastatic breast tumor in vitro and in vivo. After the dosing procedure, twenty-seven female mice were divided into 40 and 80mg/kg groups of DNC, along with a control group to investigate the anti-metastatic effects of DNC on mammary tumor-bearing mice. In vitro results showed that the different concentrations of DNC reduced the migration and the adhesion of 4T1 cells after 24h (P<0.05). Under the dosing procedure, DNC was safe at 80mg/kg and lower doses. The treated DNC animals had a higher survival rate and lower metastatic signs (14%) compared to control (100%) (P<0.05). The metastatic tumors were more common in control mice than the treated groups in the lung, the liver and the sternum tissues. Animals treated with DNC had smaller tumor volume in comparison with control group (P<0.05). Final mean tumor volume reached to approximately 1.11, 0.31 and 0.27cm(3) in the control, and 40 and 80mg/kg DNC groups, respectively (P<0.05). Furthermore, suppression of NF-κB expression by DNC led to down-regulation of VEGF, COX-2, and MMP-9 expressions in the breast tumor, the lung, the brain, the spleen and the liver tissues (P<0.05). These outcomes indicate that dendrosomal curcumin has a chemoprotective effect on the breast cancer metastasis through suppression of NF-κB and its regulated gene products. PMID:25863259

  12. Bronchial carcinoid tumors metastatic to the sella turcica and review of the literature.

    PubMed

    Moshkin, Olga; Rotondo, Fabio; Scheithauer, Bernd W; Soares, Mark; Coire, Claire; Smyth, Harley S; Goth, Miklos; Horvath, Eva; Kovacs, Kalman

    2012-06-01

    We review here the literature on neuroendocrine neoplasms metastatic to the pituitary and present an example of the disease. Metastasis of bronchial carcinoid tumors to the sellar region are rare. Herein, we describe the case of a 63-year-old woman who presented with constant cough and headaches. She had previously been operated for carcinoid tumor of the lung. During the preoperative investigation, a CT scan of the head revealed a sellar mass. Six months after a left lower lobectomy, the sellar lesion was removed by transsphenoidal surgery. The two tumors were evaluated by histology, immunohistochemistry and electron microscopy. Both showed identical morphologic features, those of carcinoid tumor. Immunohistochemistry revealed immunoreactivity for the endocrine markers, synaptophysin and chromogranin, as well as CD-56, serotonin, bombesin and vascular endothelial growth factor. The sellar neoplasm showed nuclear immunopositivity for thyroid transcription factor-1, supporting the diagnosis of a metastatic bronchial carcinoid tumor. In conclusion, this is the first report of a serotonin- and bombesin-immunopositive atypical bronchial carcinoid tumor metastatic to the sella. PMID:22485018

  13. How Are Lung Carcinoid Tumors Diagnosed?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » How are lung carcinoid tumors diagnosed? Share this Page Close Push escape to close share window. Print ...

  14. Circulating tumor cells in lung cancer.

    PubMed

    Young, Rachel; Pailler, Emma; Billiot, Fanny; Drusch, Françoise; Barthelemy, Amélie; Oulhen, Marianne; Besse, Benjamin; Soria, Jean-Charles; Farace, Françoise; Vielh, Philippe

    2012-01-01

    Circulating tumor cells (CTCs) have emerged as potential biomarkers in several cancers such as colon, prostate, and breast carcinomas, with a correlation between CTC number and patient prognosis being established by independent research groups. The detection and enumeration of CTCs, however, is still a developing field, with no universal method of detection suitable for all types of cancer. CTC detection in lung cancer in particular has proven difficult to perform, as CTCs in this type of cancer often present with nonepithelial characteristics. Moreover, as many detection methods rely on the use of epithelial markers to identify CTCs, the loss of these markers during epithelial-to-mesenchymal transition in certain metastatic cancers can render these methods ineffective. The development of personalized medicine has led to an increase in the advancement of molecular characterization of CTCs. The application of techniques such as FISH and RT-PCR to detect EGFR, HER2, and KRAS abnormalities in lung, breast, and colon cancer, for example, could be used to characterize CTCs in real time. The use of CTCs as a 'liquid biopsy' is therefore an exciting possibility providing information on patient prognosis and treatment efficacy. This review summarizes the state of CTC detection today, with particular emphasis on lung cancer, and discusses the future applications of CTCs in helping the clinician to develop new strategies in patient treatment. PMID:23207444

  15. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth

    PubMed Central

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  16. Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth.

    PubMed

    Halin Bergström, Sofia; Hägglöf, Christina; Thysell, Elin; Bergh, Anders; Wikström, Pernilla; Lundholm, Marie

    2016-01-01

    Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer. PMID:27550147

  17. Metastatic brain tumor from urothelial carcinoma of the prostatic urethra

    PubMed Central

    Morita, Kohei; Oda, Masashi; Koyanagi, Masaomi; Saiki, Masaaki

    2016-01-01

    Background: Urothelial carcinoma occurs in the bladder, upper urinary tract, and lower urinary tract, including prostatic urethra. A majority of the reported cases of intracranial metastasis from urothelial carcinoma originates from the bladder and upper urinary tract. Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. Case Description: A 72-year-old male presented with a metastatic brain tumor and a 3-year history of urothelial carcinoma of the prostatic urethra treated with cystourethrectomy and chemotherapy with gemcitabine-cisplatin. Pathological diagnosis for tumor removal was compatible with metastatic brain tumor from urothelial carcinoma. Conclusion: Brain metastasis from urothelial carcinoma of the prostatic urethra has not yet been reported in the literature. It is an extremely rare case, however, we should be careful of brain metastasis during follow-up for urothelial carcinoma in the lower urinary tract. PMID:27512612

  18. Assessment of anti-metastatic effects of anticoagulant and antiplatelet agents using animal models of experimental lung metastasis.

    PubMed

    Amirkhosravi, Ali; Mousa, Shaker A; Amaya, Mildred; Meyer, Todd; Davila, Monica; Robson, Theresa; Francis, John L

    2010-01-01

    It is well established that the blood coagulation system is activated in cancer. In addition, there is considerable evidence to suggest that clotting activation plays an important role in the biology of malignant tumors, including the process of blood-borne metastasis. For many years our laboratory has used experimental models of lung metastasis to study the events that follow the introduction of procoagulant-bearing tumor cells into circulating blood. This chapter focuses on the basic methods involved in assessing the anti-metastatic effects of anticoagulants and anti-platelet agents using rodent models of experimental metastasis. In addition, it summarizes our experience with these models, which collectively suggests that intravascular coagulation and platelet activation are a necessary prelude to lung tumor formation and that interruption of coagulation pathways or platelet aggregation may be an effective anti-metastatic strategy. PMID:20617422

  19. Clear-cell carcinoma of the lung metastatic to the hamate: a case report.

    PubMed

    Nissenbaum, M; Kutz, J E; Lister, G D

    1978-01-01

    Metastatic lesions of the hand are uncommon. A report of a solitary metastasis to the hamate seems not to have appeared previously in the literature. A 46-year-old factory worker presented a rare tumor, clear-cell carcinom of the lung, metastasizing to an unusual location, the hamate. The symptoms simulated sympathetic dystrophy and diagnosis was delayed because of the late appearance of radiographic changes over 6 months after symptoms first appeared. Early bone scanning in patients with chronic pain may provide useful information prior to the appearance of X-ray changes.

  20. Autophagy sensitivity of neuroendocrine lung tumor cells.

    PubMed

    Hong, Seung-Keun; Kim, Jin-Hwan; Starenki, Dmytro; Park, Jong-In

    2013-12-01

    Neuroendocrine (NE) phenotypes characterize a spectrum of lung tumors, including low-grade typical and intermediate-grade atypical carcinoid, high-grade large-cell NE carcinoma and small cell lung carcinoma. Currently, no effective treatments are available to cure NE lung tumors, demanding identification of biological features specific to these tumors. Here, we report that autophagy has an important role for NE lung tumor cell proliferation and survival. We found that the expression levels of the autophagy marker LC3 are relatively high in a panel of lung tumor cell lines expressing high levels of neuron-specific enolase (NSE), a key NE marker in lung tumors. In response to bafilomycin A1 and chloroquine, NE lung tumor cells exhibited cytotoxicity whereas non-NE lung tumor cells exhibited cytostasis, indicating a distinct role of autophagy for NE lung tumor cell survival. Intriguingly, in certain NE lung tumor cell lines, the levels of processed LC3 (LC3-II) were inversely correlated with AKT activity. When AKT activity was inhibited using AKTi or MK2206, the levels of LC3-II and SQSTM1/p62 were increased. In contrast, torin 1, rapamycin or mTOR knockdown increased p62 levels, suggesting that these two pathways have opposing effects on autophagy in certain NE lung tumors. Moreover, inhibition of one pathway resulted in reduced activity of the other, suggesting that these two pathways crosstalk in the tumors. These results suggest that NE lung tumor cells share a common feature of autophagy and are more sensitive to autophagy inhibition than non-NE lung tumor cells. PMID:24126619

  1. Early and multiple origins of metastatic lineages within primary tumors

    PubMed Central

    Zhao, Zi-Ming; Zhao, Bixiao; Bai, Yalai; Iamarino, Atila; Gaffney, Stephen G.; Schlessinger, Joseph; Lifton, Richard P.; Rimm, David L.; Townsend, Jeffrey P.

    2016-01-01

    Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. PMID:26858460

  2. Early and multiple origins of metastatic lineages within primary tumors.

    PubMed

    Zhao, Zi-Ming; Zhao, Bixiao; Bai, Yalai; Iamarino, Atila; Gaffney, Stephen G; Schlessinger, Joseph; Lifton, Richard P; Rimm, David L; Townsend, Jeffrey P

    2016-02-23

    Many aspects of the evolutionary process of tumorigenesis that are fundamental to cancer biology and targeted treatment have been challenging to reveal, such as the divergence times and genetic clonality of metastatic lineages. To address these challenges, we performed tumor phylogenetics using molecular evolutionary models, reconstructed ancestral states of somatic mutations, and inferred cancer chronograms to yield three conclusions. First, in contrast to a linear model of cancer progression, metastases can originate from divergent lineages within primary tumors. Evolved genetic changes in cancer lineages likely affect only the proclivity toward metastasis. Single genetic changes are unlikely to be necessary or sufficient for metastasis. Second, metastatic lineages can arise early in tumor development, sometimes long before diagnosis. The early genetic divergence of some metastatic lineages directs attention toward research on driver genes that are mutated early in cancer evolution. Last, the temporal order of occurrence of driver mutations can be inferred from phylogenetic analysis of cancer chronograms, guiding development of targeted therapeutics effective against primary tumors and metastases. PMID:26858460

  3. Peptide-based method for detection of metastatic transformation in primary tumors of breast cancer.

    PubMed

    Li, Hao; Huang, Yue; Yu, Yue; Li, Weiwei; Yin, Yongmei; Li, Genxi

    2015-09-15

    Detection of metastatic activity before the onset of the actual metastasis can be a promising method to combat metastasis, the foremost cause of death in cancer. Therefore, in this work, we have developed an assay method for the detection of metastatic tumor cells in primary tumor, by using a protein of the metastatic cell signaling as the biomarker. In this assay, a peptide-based probe targeting the marker protein and a sensitive nanoparticle doped graphene nanolabel are combined to enable the detection of metastatic cells. Consequently, the metastatic cells can be specifically detected and discriminated from primary tumor cells. By applying this assay method to clinical samples of primary tumor, a low amount of metastatic activity can be detected in the tumor sites, which may suggest the activity of local metastatic transformation. So, these results may point to the prospect of using the proposed method for controlling metastatic cancer.

  4. Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo.

    PubMed

    Nelson, Michaela; Yang, Ming; Millican-Slater, Rebecca; Brackenbury, William J

    2015-10-20

    Voltage-gated Na+ channels (VGSCs) mediate action potential firing and regulate adhesion and migration in excitable cells. VGSCs are also expressed in cancer cells. In metastatic breast cancer (BCa) cells, the Nav1.5 α subunit potentiates migration and invasion. In addition, the VGSC-inhibiting antiepileptic drug phenytoin inhibits tumor growth and metastasis. However, the functional activity of Nav1.5 and its specific contribution to tumor progression in vivo has not been delineated. Here, we found that Nav1.5 is up-regulated at the protein level in BCa compared with matched normal breast tissue. Na+ current, reversibly blocked by tetrodotoxin, was retained in cancer cells in tumor tissue slices, thus directly confirming functional VGSC activity in vivo. Stable down-regulation of Nav1.5 expression significantly reduced tumor growth, local invasion into surrounding tissue, and metastasis to liver, lungs and spleen in an orthotopic BCa model. Nav1.5 down-regulation had no effect on cell proliferation or angiogenesis within the in tumors, but increased apoptosis. In vitro, Nav1.5 down-regulation altered cell morphology and reduced CD44 expression, suggesting that VGSC activity may regulate cellular invasion via the CD44-src-cortactin signaling axis. We conclude that Nav1.5 is functionally active in cancer cells in breast tumors, enhancing growth and metastatic dissemination. These findings support the notion that compounds targeting Nav1.5 may be useful for reducing metastasis. PMID:26452220

  5. Injection of Syngeneic Murine Melanoma Cells to Determine Their Metastatic Potential in the Lungs

    PubMed Central

    Timmons, Joshua J.; Cohessy, Sean; Wong, Eric T.

    2016-01-01

    Approximately 90% of human cancer deaths are linked to metastasis. Despite the prevalence and relative harm of metastasis, therapeutics for treatment or prevention are lacking. We report a method for the establishment of pulmonary metastases in mice, useful for the study of this phenomenon. Tail vein injection of B57BL/6J mice with B16-BL6 is among the most used models for melanoma metastases. Some of the circulating tumor cells establish themselves in the lungs of the mouse, creating "experimental" metastatic foci. With this model it is possible to measure the relative effects of therapeutic agents on the development of cancer metastasis. The difference in enumerated lung foci between treated and untreated mice indicates the efficacy of metastases neutralization. However, prior to the investigation of a therapeutic agent, it is necessary to determine an optimal number of injected B16-BL6 cells for the quantitative analysis of metastatic foci. Injection of too many cells may result in an overabundance of metastatic foci, impairing proper quantification and overwhelming the effects of anti-cancer therapies, while injection of too few cells will hinder the comparison between treated and controls. PMID:27285567

  6. Endobronchial cryptococcosis induced by Cryptococcus gattii mimicking metastatic lung cancer.

    PubMed

    Nakashima, Kazuhisa; Akamatsu, Hiroaki; Endo, Masahiro; Kawamura, Ichiro; Nakajima, Takashi; Takahashi, Toshiaki

    2014-09-01

    A 41-year-old previously healthy Japanese man complained of cough for 2 months. A chest computed tomography scan revealed a mass in his left lung with multiple mediastinal lymphadenopathy. Brain magnetic resonance imaging showed many small, enhancing lesions. He was admitted to our hospital for further evaluation of an abnormal shadow suspicious for metastatic lung cancer. Bronchoscopy showed aggregated white nodes in the compressively stenosed left main bronchus. A specimen from transbronchial biopsy showed many foamy and yeast-like cells. Cultures and additional gene analysis identified these cells as C ryptococcus gattii. Antifungal treatment was commenced and his symptoms clearly improved. To our knowledge, this is the first case of an aggressive form of endobronchial cryptococcosis caused by C . gattii.

  7. [Therapy of Metastatic Non-small Cell Lung Cancer].

    PubMed

    Reinmuth, N; Gröschel, A; Schumann, C; Sebastian, M; Wiewrodt, R; Reck, M

    2016-09-01

    Lung cancer accounts for the leading cause of cancer deaths in Germany and is characterized by early metastasis formation. The majority of patients with non-small cell lung cancer (NSCLC) will receive systemic therapy for treatment of their disease. Importantly together with the identification of targetable oncogenic alterations, systemic treatment of NSCLC has dramatically changed in recent years with the implementation of various new agents such as tyrosine kinase inhibitors, anti angiogenic agents, and immune modulating drugs. However, these new therapeutic options also challenge the treating physician since molecular, histologic, and clinical factors need to be considered for the clinical decision-making. Moreover, supportive therapy including bronchoscopic therapy has evolved. The following therapy recommendations will summarize the up-to date treatment strategies for metastatic NSCLC. PMID:27603945

  8. How Are Lung Carcinoid Tumors Staged?

    MedlinePlus

    ... from the abdomen (diaphragm), the membranes surrounding the space between the lungs (mediastinal pleura), or membranes of ... tumor of any size has grown into the space between the lungs (mediastinum), the heart, the large ...

  9. Metastatic Hip Tumor in a Middle-Aged Woman.

    PubMed

    Callan, Brad

    2016-05-01

    A 44-year-old woman was referred to physical therapy by a podiatrist for "iliotibial band syndrome." No imaging had been done, and she denied all constitutional symptoms, but reported having breast cancer 5 years earlier. Following an increase in pain, radiographs and magnetic resonance imaging were performed, and biopsy confirmed a metastatic breast cancer tumor. J Orthop Sports Phys Ther 2016;46(5):400. doi:10.2519/jospt.2016.0407. PMID:27133943

  10. Suppressing effect of resveratrol on the migration and invasion of human metastatic lung and cervical cancer cells.

    PubMed

    Kim, Yoon Suk; Sull, Jae Woong; Sung, Ho Joong

    2012-09-01

    The antioxidant 3,4',5 tri-hydroxystilbene (resveratrol), a phytoalexin found in grapes, shows cancer preventive activities, including inhibition of migration and invasion of metastatic tumors. However, the molecular mechanism underlying the effect of resveratrol on tumor metastasis, especially in human metastatic lung and cervical cancers is not clear. A non-cytotoxic dosage of resveratrol causes a reduction in the generation of reactive oxygen species, and suppresses phorbol 12-myristate 13-acetate (PMA)-induced invasion and migration in both A549 and HeLa cells. Resveratrol also decreases both the expression and the enzymatic activity of matrix metalloproteinase-9 (MMP-9), and the promoter activity of PMA-stimulated MMP-9 is also inhibited. However, resveratrol does not affect either the expression or the proteolytic activity of MMP-2. Our results also show that resveratrol suppresses the transcription of MMP-9 by the inhibition of both NF-κB and AP-1 transactivation. These results indicate that resveratrol inhibits both NF-κB and AP-1 mediated MMP-9 expression, leading to suppression of migration and invasion of human metastatic lung and cervical cancer cells. Resveratrol has potential for clinical use in preventing invasion by human metastatic lung and cervical cancers.

  11. Autoantibodies targeting tumor-associated antigens in metastatic cancer

    PubMed Central

    Oaks, Martin; Taylor, Samuel; Shaffer, James

    2013-01-01

    In addition to the well-established effector functions of IgGs, including direct cytotoxicity and antibody-dependent cellular cytotoxicity, some populations of IgGs may exert anti-inflammatory effects. Here, we describe a population of antibodies that form in the natural course of metastatic cancer and contain glycans that terminate with sialic acid. We demonstrate that both the titer of these antibodies and their level of sialylation are relatively stable throughout the progression of metastatic melanoma. The sialylation pattern of these antibodies somehow correlates with their specificity for tumor-associated antigens, as IgGs targeting several antigens associated with infectious agents are relatively poor of sialic acid. We also show that some antibodies targeting the melanoma-associated antigen NY-ESO-1 bind to the human C-type lectin CD209 (DC-SIGN). We propose that these antibodies are candidate anti-inflammatory antibodies. The presence of anti-inflammatory antibodies in cancer patients may explain, at least in part, why tumors persist and spread in the host despite strong tumor-specific humoral responses. The elucidation of the cellular and molecular pathways involved in the induction of anti-inflammatory antibodies specific for tumor-associated antigens and their function may yield important insights into how tumors evade immune detection and progress. PMID:23894724

  12. [Hydatid cyst disease mimicking metastatic lung disease: a case report].

    PubMed

    Yiyit, Nurettin; Görür, Rauf; Candaş, Fatih Hikmet; Yıldızhan, Akın; Turhan, Vedat; Işıtmangil, Turgut

    2011-01-01

    Pulmonary hydatid cysts usually present as a single lesion, whereas multiple cases are rare. It is not easy to distinguish hydatid cyst and nodular lesions radiologically. Chest radiograph of a 22 years-old male patient who was admitted due to right sided chest pain, revealed bilateral pulmonary nodules. His computerized tomography (CT) showed 34 nodular densities in the right lung and 21 nodular densities in the left lung. At that time, metastatic lung disease was suggested . Tru-cut lung biopsy was non-diagnostic. Anti-E. granulosus IgG (ELISA) was positive and hydatid cyst disease (HCD) was set as a prediagnosis. A right thoracotomy was performed and more cysts in number than those in tomography were observed intraoperatively. Postoperatively, 800 mg per day albendazole treatment was started. CT at the second month of medical therapy revealed that the lesions were stable in number but their sizes were smaller. CT of the fourth month showed that some of the lesions became cavitary. HCD should be kept in to mind in case of doubtful radiological findings. Although main treatment modality is surgery for HCD, when all cysts can not remove with the surgical treatment in patient with multiple cysts, medical treatment can be administered. PMID:21776601

  13. Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

    SciTech Connect

    Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy; Chapman, Christopher; Rao, Aarti; Shen, John; Quinlan-Davidson, Sean; Filion, Edith J.; Wakelee, Heather A.; Colevas, A. Dimitrios; Whyte, Richard I.; and others

    2012-09-01

    Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume {>=}12 mL) received multifraction regimens with BED {>=}100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

  14. Recovery from Choriocarcinoma Syndrome Associated with a Metastatic Extragonadal Germ Cell Tumor Hemorrhage

    PubMed Central

    Komori, Koji; Takahari, Daisuke; Kimura, Kenya; Kinoshita, Takashi; Ito, Seiji; Abe, Tetsuya; Senda, Yoshiki; Misawa, Kazunari; Ito, Yuichi; Uemura, Norihisa; Natsume, Seiji; Kawakami, Jiro; Iwata, Yoshinori; Tsutsuyama, Masayuki; Shigeyoshi, Itaru; Akazawa, Tomoyuki; Hayashi, Daisuke; Ouchi, Akira; Shimizu, Yasuhiro

    2016-01-01

    A germ cell tumor is the most common form of malignancy in early male life, and can be classified as either seminomatous or nonseminomatous. Choriocarcinoma, comprised of nonseminomatous germ cells, is the most aggressive type of germ cell tumor and characteristically metastasizes to the retroperitoneal lymph nodes and less frequently to the lungs, liver, bone or brain [Shibuya et al., 2009;48: 551–554]. A 56-year-old man was admitted to another hospital complaining of abdominal distension. Symptoms included anorexia, vomiting, and diarrhea. The patient was diagnosed with an extragonadal germ cell tumor and referred to our hospital to receive chemotherapy. The day after admission, the patient's abdominal distension gradually worsened. An emergency operation revealed venous hemorrhage from the surface of a metastatic extragonadal germ cell tumor between the ligament of Treitz and the inferior mesenteric vein in a horizontal position. Hemostatic treatment was performed with 4-0 proline thread attached to a medicated cotton sponge, rather than using a simple proline thread, and the closure area was manually compressed. Chemotherapy was initiated on postoperative day 10. A metastatic extragonadal germ cell tumor that causes massive hemorrhage and gastrointestinal hemorrhage is very rare, and represents a life-threatening emergency. If the patient's condition carries a substantial risk of bleeding to death, it may be worthwhile to attempt abdominal operations. PMID:27403124

  15. Recovery from Choriocarcinoma Syndrome Associated with a Metastatic Extragonadal Germ Cell Tumor Hemorrhage.

    PubMed

    Komori, Koji; Takahari, Daisuke; Kimura, Kenya; Kinoshita, Takashi; Ito, Seiji; Abe, Tetsuya; Senda, Yoshiki; Misawa, Kazunari; Ito, Yuichi; Uemura, Norihisa; Natsume, Seiji; Kawakami, Jiro; Iwata, Yoshinori; Tsutsuyama, Masayuki; Shigeyoshi, Itaru; Akazawa, Tomoyuki; Hayashi, Daisuke; Ouchi, Akira; Shimizu, Yasuhiro

    2016-01-01

    A germ cell tumor is the most common form of malignancy in early male life, and can be classified as either seminomatous or nonseminomatous. Choriocarcinoma, comprised of nonseminomatous germ cells, is the most aggressive type of germ cell tumor and characteristically metastasizes to the retroperitoneal lymph nodes and less frequently to the lungs, liver, bone or brain [Shibuya et al., 2009;48: 551-554]. A 56-year-old man was admitted to another hospital complaining of abdominal distension. Symptoms included anorexia, vomiting, and diarrhea. The patient was diagnosed with an extragonadal germ cell tumor and referred to our hospital to receive chemotherapy. The day after admission, the patient's abdominal distension gradually worsened. An emergency operation revealed venous hemorrhage from the surface of a metastatic extragonadal germ cell tumor between the ligament of Treitz and the inferior mesenteric vein in a horizontal position. Hemostatic treatment was performed with 4-0 proline thread attached to a medicated cotton sponge, rather than using a simple proline thread, and the closure area was manually compressed. Chemotherapy was initiated on postoperative day 10. A metastatic extragonadal germ cell tumor that causes massive hemorrhage and gastrointestinal hemorrhage is very rare, and represents a life-threatening emergency. If the patient's condition carries a substantial risk of bleeding to death, it may be worthwhile to attempt abdominal operations. PMID:27403124

  16. Primary adrenal sarcomatoid carcinoma metastatic to the lung: Case report and review of the literature

    PubMed Central

    ZHU, CHUANGZHI; ZHENG, AIPING; MAO, XIANGMING; SHI, BENTAO; LI, XIANXIN

    2016-01-01

    Adrenal sarcomatoid carcinoma is a rare adrenal carcinoma. To the best of our knowledge, only 11 cases have been reported since 1987. Adrenal sarcomatoid carcinoma presents a diagnostic challenge due to its atypical symptoms and histological patterns. At the time of diagnosis, a large percentage of patients are already at the metastatic stage and succumb within a few months. The present study reports a case of a 59-year-old man presenting with asthenia and weight loss with adrenal sarcomatoid carcinoma metastatic to the lung. A computed tomography (CT) scan and ultrasonography of the patient's abdomen suggested a large homogeneous mass in the right adrenal gland, and a CT scan of his chest suggested lung metastasis. Right adrenalectomy was performed. Histological examination revealed that the tumor was composed of sarcomatous and carcinomatous differentiation elements. Immunohistochemical examination revealed tumor cell positivity for vimentin and cytokeratin. At the 6-month follow-up the patient exhibited no disease progression and refused further proposed treatment. The patient was alive at the time of writing the current report. The present case report additionally reviews the literature, for the purpose of raising awareness of these rare lesions and assisting in achieving accurate diagnoses and effective treatment. PMID:27123074

  17. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

    SciTech Connect

    Savion, N.; Disatnik, M.H.; Nevo, Z.

    1987-01-01

    Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the (/sup 35/S)O/sub 4//sup -/-labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of (/sup 35/S)O/sub 4//sup -/-labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10..mu..g/ml), arteparon (10..mu..g/ml), and heparin at a concentration of 3 ..mu..g/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

  18. Diffuse alveolar hemorrhage due to metastatic angiosarcoma of the lung: A case report

    PubMed Central

    PAN, ZHIJIE; AN, ZHOU; LI, YANYUAN; ZHOU, JIANYING

    2015-01-01

    Angiosarcoma is a rare, heterogeneous malignant tumor that derives from endothelial cells, and it has aggressive characteristics with a marked tendency for distant metastasis. Diffuse alveolar hemorrhage (DAH) is a catastrophic clinical syndrome, however, it is rare as the presentation of pulmonary angiosarcoma. To increase awareness with regard to angiosarcoma and DAH, the current study presents a case of angiosarcoma that originated from the subcutaneous soft tissue of the mastoid process, but was subject to a delayed diagnosis and rapid invasion into the brain and lung. The metastatic angiosarcoma of the lung presented with DAH as the initial manifestation. The pathological examination of a biopsy of the subcutaneous mass and pulmonary lesions confirmed the diagnosis of angiosarcoma. The patient succumbed to respiratory failure at 1 month post-diagnosis. PMID:26788222

  19. Metastatic melanoma mimicking solitary fibrous tumor: report of two cases.

    PubMed

    Bekers, Elise M; van Engen-van Grunsven, Adriana C H; Groenen, Patricia J T A; Westdorp, Harm; Koornstra, Rutger H T; Bonenkamp, Johannes J; Flucke, Uta; Blokx, Willeke A M

    2014-02-01

    Malignant melanomas are known for their remarkable morphological variation and aberrant immunophenotype with loss of lineage-specific markers, especially in recurrences and metastases. Hot spot mutations in BRAF, NRAS, GNAQ, and GNA11 and mutations in KIT are oncogenic events in melanomas. Therefore, genotyping can be a useful ancillary diagnostic tool. We present one case each of recurrent and metastatic melanoma, both showing histological and immunohistochemical features of solitary fibrous tumor (SFT). Mutational analysis detected BRAF and NRAS mutations in the primary and secondary lesions, respectively. This result confirmed the diagnosis of recurrent/metastastic melanoma.

  20. Theranostic tumor homing nanocarriers for the treatment of lung cancer

    PubMed Central

    Patel, Apurva R; Chougule, Mahavir B.; Lim, Ed; Francis, Kevin P; Safe, Stephen; Singh, Mandip

    2014-01-01

    The drugs/strategies to selectively inhibit tumor blood supply has generated interest in recent years for enhancement of cancer therapeutics. The objective of this study was to formulate tumor homing PEGylated CREKA peptide conjugated theranostic nanoparticles of DIM-C-pPhC6H5 (DIM-P) and investigate in vivo antitumor activity as well as evaluate the targeted efficiency to lung tumors using imaging techniques. DIM-P loaded Nanoparticles (NCs-D) were prepared using lipids, and DOGS-NTA-Ni and the surface of NCs-D was modified with PEGylated CREKA peptide (PCNCs-D). PCNCs-D showed 3 fold higher binding to clotted plasma proteins in tumor vasculature compared to NCs-D. PCNCs-D showed 26±4% and 22±5% increase in tumor reduction compare to NCs-D in metastatic and orthotopic models respectively. In-vivo imaging studies showed ~40 folds higher migration of PCNCs-Di in tumor vasculature than NCs-Di. Our studies demonstrate the role of PCNCs-D as theranostic tumor homing drug delivery and imaging systems for lung cancer diagnosis and treatment. PMID:24355163

  1. Management of non metastatic phyllodes tumors of the breast: review of the literature.

    PubMed

    Khosravi-Shahi, Parham

    2011-12-01

    Phyllodes tumors of the breast are rare tumors, accounting for less than 0.5% of all breast tumors. These tumors are comprised of both stromal and epithelial elements; and traditionally they are graded by the use of a set of histologic features into benign, borderline, and malignant subtypes. Unfortunately, the histologic classification of phyllodes tumors does not reliably predict clinical behavior. The mainstay of treatment of non metastatic phyllodes tumors of the breast is complete surgical resection with wide resection margins. Lumpectomy or partial mastectomy is the preferred surgical therapy. However, despite the complete surgical resection, local failure rate may be high; and 22% of malignant tumors may give rise to haematogenous metastases. The most frequent site of distant metastases is the lungs. Several predictive factors of recurrence and metastases have been described in the literature, such as positive surgical margins, increased stromal cellularity, stromal overgrowth, stromal atypia and increased mitotic activity. Nevertheless, the role of adjuvant therapies (radiotherapy and chemotherapy) is presently undefined and should be tested in multicenter, prospective, randomized trials.

  2. Lung Tumor Radiofrequency Ablation: Where Do We Stand?

    SciTech Connect

    Baere, Thierry de

    2011-04-15

    Today, radiofrequency ablation (RFA) of primary and metastatic lung tumor is increasingly used. Because RFA is most often used with curative intent, preablation workup must be a preoperative workup. General anesthesia provides higher feasibility than conscious sedation. The electrode positioning must be performed under computed tomography for sake of accuracy. The delivery of RFA must be adapted to tumor location, with different impedances used when treating tumors with or without pleural contact. The estimated rate of incomplete local treatment at 18 months was 7% (95% confidence interval, 3-14) per tumor, with incomplete treatment depicted at 4 months (n = 1), 6 months (n = 2), 9 months (n = 2), and 12 months (n = 2). Overall survival and lung disease-free survival at 18 months were, respectively, 71 and 34%. Size is a key point for tumor selection because large size is predictive of incomplete local treatment and poor survival. The ratio of ablation volume relative to tumor volume is predictive of complete ablation. Follow-up computed tomography that relies on the size of the ablation zone demonstrates the presence of incomplete ablation. Positron emission tomography might be an interesting option. Chest tube placement for pneumothorax is reported in 8 to 12%. Alveolar hemorrhage and postprocedure hemoptysis occurred in approximately 10% of procedures and rarely required specific treatment. Death was mostly related to single-lung patients and hilar tumors. No modification of forced expiratory volume in the first second between pre- and post-RFA at 2 months was found. RFA in the lung provides a high local efficacy rate. The use of RFA as a palliative tool in combination with chemotherapy remains to be explored.

  3. Modulation of oxidative stress by functionalized fullerene materials in the lung tissues of female C57/BL mice with a metastatic Lewis lung carcinoma.

    PubMed

    Jiao, Fang; Qu, Ying; Zhou, Guoqiang; Liu, Ying; Li, Wei; Ge, Cuicui; Li, Yufeng; Hu, Wei; Li, Bai; Gao, Yuxi; Chen, Chunying

    2010-12-01

    Oxidative stress is considered to be one of the important mechanisms involved in carcinogenesis. To investigate the effect of [Gd@C82(OH)22]n and [C60(OH)20]n nanoparticles on the oxidative stress in the tumor-bearing mice, several antioxidative enzymes and antioxidants were tested for mice with or without tumor inoculation. Transplanted tumors were grown in mice by subcutaneous inoculation of a metastatic Lewis lung carcinoma in female C57/BL mice. More importantly, the tumor cells can metastasize into the normal lung tissues gradually. Therefore, in present paper, the activities of copper-zinc superoxide dismutase (CuZn-SOD), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST), as well as the levels of reduced glutathione (GSH) and malondialdehyde (MDA) in the tumor-invaded lung tissues of the tumor-bearing mice were compared to the nomal lung tissues of normal mice. After treatment with nanoparticles, the activities of GSH-Px and GST and other parameters related to the oxidative stress were downregulated and tended closely to the normal levels. Pulmonary histopathological results also showed that two different types of water-soluble fullerenes can prevent lungs from inflammatory lesion and tumor invasion. These findings indicate two different types of water-soluble fullerenes materials can downregulate the oxidative stress status by scavenging excessive free radicals and inhibiting the lipid peroxidation in tumor-bearing mice, which can partly explain their protective roles on the pulmonary oxidative-damage induced by the tumor metastasis to lung tissues.

  4. Near-infrared pH-activatable fluorescent probes for imaging primary and metastatic breast tumors.

    PubMed

    Lee, Hyeran; Akers, Walter; Bhushan, Kumar; Bloch, Sharon; Sudlow, Gail; Tang, Rui; Achilefu, Samuel

    2011-04-20

    Highly tumor selective near-infrared (NIR) pH-activatable probe was developed by conjugating pH-sensitive cyanine dye to a cyclic arginine-glycine-aspartic acid (cRGD) peptide targeting α(v)β(3) integrin (ABIR), a protein that is highly overexpressed in endothelial cells during tumor angiogenesis. The NIR pH-sensitive dye used to construct the probe exhibits high spectral sensitivity with pH changes. It has negligible fluorescence above pH 6 but becomes highly fluorescent below pH 5, with a pK(a) of 4.7. This probe is ideal for imaging acidic cell organelles such as tumor lysosomes or late endosomes. Cell microscopy data demonstrate that binding of the cRGD probe to ABIR facilitated the endocytosis-mediated lysosomal accumulation and subsequent fluorescence enhancement of the NIR pH-activatable dye in tumor cells (MDA-MB-435 and 4T1/luc). A similar fluorescence enhancement mechanism was observed in vivo, where the tumors were evident within 4 h post injection. Moreover, lung metastases were also visualized in an orthotopic tumor mouse model using this probe, which was further confirmed by histologic analysis. These results demonstrate the potential of using the new integrin-targeted pH-sensitive probe for the detection of primary and metastatic cancer.

  5. Diagnostic dilemma involving a mass in the parapharyngeal space: A metastatic breast carcinoma masquerading as a malignant salivary gland tumor.

    PubMed

    Murhekar, Kanchan; Majhi, Urmila; Krishnamurthy, Arvind; Ramshankar, Vijayalakshmi

    2015-01-01

    Parapharyngeal space (PPS) tumors are rare and account for about 0.5% of all head and neck neoplasms. Most PPS tumors are benign (up to 80%) while the remaining 20% are malignant. These tumors are either primaries; most commonly arising from salivary glands or metastatic tumors or due to direct extension of tumors from the adjacent sites. Distant metastasis from breast cancers more commonly involves the lungs, bones, brain and liver. Metastasis to the PPS from a primary breast carcinoma is rare, with only one case reported in literature. We, to the best of our knowledge report the second case of a carcinoma breast metastasizing to the PPS and further discuss the diagnostic and therapeutic challenges involved in its management. A fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan apart from explicitly defining the extent of the PPS tumor, majorly influenced the therapeutic decision making process by ruling out other sites of metastasis.

  6. SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice

    PubMed Central

    Hamilton, Melisa J.; Halvorsen, Elizabeth C.; LePard, Nancy E.; Bosiljcic, Momir; Ho, Victor W.; Lam, Vivian; Banáth, Judit

    2016-01-01

    SH2-containing-inositol-5′-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP−/− BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP−/− BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP−/− mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP−/− mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer. PMID:26683227

  7. SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice.

    PubMed

    Hamilton, Melisa J; Halvorsen, Elizabeth C; LePard, Nancy E; Bosiljcic, Momir; Ho, Victor W; Lam, Vivian; Banáth, Judit; Bennewith, Kevin L; Krystal, Gerald

    2016-01-26

    SH2-containing-inositol-5'-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP-/- BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP-/- BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP-/- mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP-/- mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer.

  8. Orally Administered Chitosan-Coated Polycaprolactone Nanoparticles Containing Curcumin Attenuate Metastatic Melanoma in the Lungs.

    PubMed

    Loch-Neckel, Gecioni; Santos-Bubniak, Lorena; Mazzarino, Letícia; Jacques, Amanda V; Moccelin, Bárbara; Santos-Silva, Maria Claúdia; Lemos-Senna, Elenara

    2015-10-01

    The study was aimed to evaluate the effect of orally administered chitosan-coated nanoparticles containing curcumin on metastatic melanoma. Chitosan-coated nanoparticles containing curcumin were prepared, and their antimetastatic activity was investigated both in vitro and in vivo. Curcumin decreased cell viability and induced apoptosis of B16F10 melanoma cells. We observed that curcumin significantly decreased the expression of metalloproteinases, which are known to be associated with migration and proliferation of cancer cells. Importantly, treatment with chitosan-coated nanoparticles containing curcumin decreased pulmonary tumor formation in a murine model of experimental metastasis. Histological analyses confirmed the macroscopic results in which lungs of mice treated with curcumin-loaded chitosan-coated polycaprolactone nanoparticles had only a few small nodules and most of them were free of melanoma. Our findings indicate that nanoparticles coated with the mucoadhesive polymer chitosan containing curcumin may be a promising approach and/or intervention for the treatment of malignant melanoma.

  9. Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Lorigan, Paul; Zhou, Cong; Lancashire, Matthew; Booth, Jessica; Cummings, Jeff; Califano, Raffaele; Clack, Glen; Hughes, Andrew; Dive, Caroline

    2013-06-01

    The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients. PMID:23223143

  10. Efficient Gene Silencing in Metastatic Tumor by siRNA Formulated in Surface-modified Nanoparticles

    PubMed Central

    Li, Shyh-Dar; Chono, Sumio; Huang, Leaf

    2009-01-01

    We have developed a nanoparticle (NP) formulation for systemically delivering siRNA into metastatic tumors. The NP, composed of nucleic acids, a polycationic peptide and cationic liposome, was prepared in a self-assembling process. The NP was then modified by PEG-lipid containing a targeting ligand, anisamide, and thus was decorated for targeting sigma receptor expressing B16F10 tumor. The activity of the targeted NP was compared with the naked NP (no PEGylation) and non-targeted NP (no ligand). The delivery efficiency of the targeted NP was 4-fold higher than the non-targeted NP and could be competed by excess free ligand. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene, in a lung metastasis model. The gene silencing activity of the targeted NP was significantly higher than the other formulations and lasted for 4 days. While confocal microscopy showed the naked NP provided no tissue selectivity and non-targeted NP was ineffective for tumor uptake, the targeted NP effectively penetrated the lung metastasis, but not the liver. It resulted in 70-80% gene silencing in the metastasis model after a single i.v. injection (150 μg siRNA/kg). This effective formulation also showed very little immunotoxicity. PMID:18083264

  11. Promotion of lung tumors in mice

    SciTech Connect

    Witschi, H.P.

    1981-01-01

    Several elements of two-stage carcinogenesis apply to the development of lung tumors in mice. At least three agents, identified as promoters, will also enhance tumor formation in lung: phorbol, saccharin, and butylated hydroxytoluene (BHT). The antioxidant BHT is effective only if animals are treated after exposure to an initiating agent. Administration can be delayed up to 5 months after urethan treatment and still enhance tumor formation. BHT enhances lung tumor formation regardless of its route of administration. The lowest dose required to produce an effect has not yet been determined. In at least one mouse strain, BHT also enhances tumor formation in animals initiated with 3-methylcholanthren or diethylnitrosaine. No evidence is available yet to show that BHT would enhance tumor development in animals treated with subcarcinogenic doses of an initiating compound. Nor has it been possible to produce more tumors with BHT in mouse strains which have a low spontaneous tumor incidence and respond poorly to urethan. Neveretheless, the data collected on the effects of BHT on mouse lung tumor development have broadened the concept of two-stage carcinogenesis and complement the evidence for initiation-promotion available for other epithelial tissues. (ERB)

  12. Evaluation of Lung Metastasis in Mouse Mammary Tumor Models by Quantitative Real-time PCR

    PubMed Central

    Abt, Melissa A.; Grek, Christina L.; Ghatnekar, Gautam S.; Yeh, Elizabeth S.

    2016-01-01

    Metastatic disease is the spread of malignant tumor cells from the primary cancer site to a distant organ and is the primary cause of cancer associated death 1. Common sites of metastatic spread include lung, lymph node, brain, and bone 2. Mechanisms that drive metastasis are intense areas of cancer research. Consequently, effective assays to measure metastatic burden in distant sites of metastasis are instrumental for cancer research. Evaluation of lung metastases in mammary tumor models is generally performed by gross qualitative observation of lung tissue following dissection. Quantitative methods of evaluating metastasis are currently limited to ex vivo and in vivo imaging based techniques that require user defined parameters. Many of these techniques are at the whole organism level rather than the cellular level 3–6. Although newer imaging methods utilizing multi-photon microscopy are able to evaluate metastasis at the cellular level 7, these highly elegant procedures are more suited to evaluating mechanisms of dissemination rather than quantitative assessment of metastatic burden. Here, a simple in vitro method to quantitatively assess metastasis is presented. Using quantitative Real-time PCR (QRT-PCR), tumor cell specific mRNA can be detected within the mouse lung tissue. PMID:26862835

  13. Metastatic solitary fibrous tumor of the meninges. Case report.

    PubMed

    Ng, H K; Choi, P C; Wong, C W; To, K F; Poon, W S

    2000-09-01

    Solitary fibrous tumor (SFT) is a unique tumor composed of interstitial dendritic cells that was first described in the thorax and subsequently reported in diverse organs. Extrathoracic SFTs are predominantly benign but rare malignant cases have been documented. In the nervous system, SFT has been described as a meningeal lesion although all 14 previously reported cases were benign. The authors report the first case of a meningeal SFT occurring in a 55-year-old woman. The tumor first presented as a meningeal lesion that after three recurrences over a 10-year period metastasized to the soft tissues and lungs. The potentially malignant nature of cranial SFTs, especially those with atypical histological features and high mitotic counts, should be recognized.

  14. [Combined use of lentinan with X-ray therapy in an experimental mouse tumor system (Part 3). Combined effect on metastatic tumors].

    PubMed

    Shiio, T; Ohishi, K; Niitsu, I; Hayashibara, H; Tsuchiya, Y; Yoshihama, T; Moriyuki, H

    1988-03-01

    Combination effect of lentinan with X-ray irradiation on the metastatic mouse tumors, L1210, KLN205 and Lewis lung carcinoma were studied. Combination use of lentinan with X-ray therapy prolonged the life of BDF1 mice bearing L1210 leukemia in the suitable combination conditions. Combination effects of lentinan with X-ray therapy were also observed on the suppression of the growth of KLN205 squamous cell carcinoma and on the suppression of the metastasis of Lewis lung carcinoma. Especially, in the case that lentinan was administered before or after X-ray local irradiation in the pulmonary metastasis system of Lewis lung carcinoma, a marked suppression of pulmonary metastasis was observed and 2 to 4 mice among 8 tested mice were tumor free.

  15. Vaccine Therapy Plus Biological Therapy in Treating Adults With Metastatic Solid Tumors

    ClinicalTrials.gov

    2013-06-19

    Colorectal Cancer; Endometrial Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Melanoma (Skin); Pancreatic Cancer; Testicular Germ Cell Tumor; Unspecified Adult Solid Tumor, Protocol Specific

  16. Tumor-specific Anti-Nucleosome Antibody Improves Therapeutic Efficacy of Doxorubicin-Loaded Long-Circulating Liposomes against Primary and Metastatic Tumor in Mice

    PubMed Central

    ElBayoumi, Tamer A.; Torchilin, Vladimir P.

    2009-01-01

    The efficacy of drug delivery systems can be significantly enhanced by making them target-specific via the attachment of various ligands to their surface. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded long-circulating liposomes (Doxil®, ALZA Corp.) by coupling to their surface the anti-cancer monoclonal antibody 2C5 (mAb 2C5) with nuclesome (NS)-restricted activity, that can recognize the surface of various tumor but not normal cells via the surface-bound nucleosomes released from the apoptotically dying neighboring tumor cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Antibody coupling to PEGylated doxorubicin-liposomes was performed by the “post-insertion” technique. The pharmacokinetics of plain and immuno-targeted Doxil®-mimicking liposomes, as well as their accumulation in primary Lewis Lung Carcinoma (LLC) tumors in mice was followed by real-time gamma-scintigraphy upon liposomal membrane labeling with 111In. Therapeutic action of various liposomal formulations was followed by registering primary tumor growth, determining tumor weigh upon mice sacrifice, and by counting the number of metastases in the liver and lungs. 2C5 antibody-targeted liposomes demonstrate significantly enhanced accumulation in LLC tumors. Targeted doxorubicin-loaded PEG-liposomes were significantly more effective in inhibiting tumor growth and metastatic process in the LLC tumor models in mice. Our results clearly show the remarkable capability of 2C5-targeted Doxil® to specifically deliver its cargo into various tumor manifestations (solid and metastatic) significantly increasing the efficacy of therapy. PMID:19049322

  17. Metastatic alveolar soft part sarcoma of the lung: Metastatic alveolar soft part sarcoma of the lung-a morphologic pitfall on cytology and aberrant CD10 expression on histology.

    PubMed

    Nambirajan, Aruna; Jain, Deepali; Malik, Prabhat; Arava, Sudheer; Mathur, Sandeep R

    2016-03-01

    Alveolar soft part sarcoma (ASPS) is a rare aggressive soft tissue sarcoma of young adults, typically arising in the deep soft tissue of lower extremities. Although cytomorphology is characteristic enough for an accurate diagnosis in typical clinical scenarios, problems arise when it occurs in older patients, atypical sites, or in primary evaluation at metastatic sites. A 48-year-old smoker presented with breathlessness and headache for 2 months. Imaging showed a heterogeneous enhancing lesion of 6 cm × 6 cm in right middle lobe of lung, smaller miliary nodules in bilateral lungs, multiple bilateral cerebral lesions, and a mass of 3 cm × 3 cm in the left thigh. Primary lung carcinoma with brain and thigh metastases was the clinical diagnosis. Fine-needle aspiration smears of the lung lesion showed cohesive fragments of large cells with a prominent traversing branching capillary network and discohesion at periphery resulting in a pseudo-papillary appearance. Tumor cells had fine granular to vacuolated cytoplasm, frayed borders, and prominent nucleoli. Trucut biopsy from the same showed a tumor arranged in nests composed of large polygonal cells, immunopositive for CD10. Possibility of metastatic renal cell carcinoma (RCC) was offered. Abdominal imaging was, however, normal. Core biopsy from thigh showed a similar tumor, immunonegative for epithelial markers, with cytoplasmic periodic-acid-schiff positive rhomboid crystals, clinching the final diagnosis of ASPS with lung and brain metastases. There is considerable morphological and immunohistochemical overlap between ASPS and RCC. Bare nuclei on air dried smears, binucleation, metachromatic basement membrane material are subtle pointers toward ASPS. PMID:26693959

  18. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas

    PubMed Central

    Wu, Kui; Zhang, Xin; Li, Fuqiang; Xiao, Dakai; Hou, Yong; Zhu, Shida; Liu, Dongbing; Ye, Xiaofei; Ye, Mingzhi; Yang, Jie; Shao, Libin; Pan, Hui; Lu, Na; Yu, Yuan; Liu, Liping; Li, Jin; Huang, Liyan; Tang, Hailing; Deng, Qiuhua; Zheng, Yue; Peng, Lihua; Liu, Geng; Gu, Xia; He, Ping; Gu, Yingying; Lin, Weixuan; He, Huiming; Xie, Guoyun; Liang, Han; An, Na; Wang, Hui; Teixeira, Manuel; Vieira, Joana; Liang, Wenhua; Zhao, Xin; Peng, Zhiyu; Mu, Feng; Zhang, Xiuqing; Xu, Xun; Yang, Huanming; Kristiansen, Karsten; Wang, Jian; Zhong, Nanshan; Wang, Jun; Pan-Hammarström, Qiang; He, Jianxing

    2015-01-01

    The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma. PMID:26647728

  19. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

    PubMed

    Wu, Kui; Zhang, Xin; Li, Fuqiang; Xiao, Dakai; Hou, Yong; Zhu, Shida; Liu, Dongbing; Ye, Xiaofei; Ye, Mingzhi; Yang, Jie; Shao, Libin; Pan, Hui; Lu, Na; Yu, Yuan; Liu, Liping; Li, Jin; Huang, Liyan; Tang, Hailing; Deng, Qiuhua; Zheng, Yue; Peng, Lihua; Liu, Geng; Gu, Xia; He, Ping; Gu, Yingying; Lin, Weixuan; He, Huiming; Xie, Guoyun; Liang, Han; An, Na; Wang, Hui; Teixeira, Manuel; Vieira, Joana; Liang, Wenhua; Zhao, Xin; Peng, Zhiyu; Mu, Feng; Zhang, Xiuqing; Xu, Xun; Yang, Huanming; Kristiansen, Karsten; Wang, Jian; Zhong, Nanshan; Wang, Jun; Pan-Hammarström, Qiang; He, Jianxing

    2015-01-01

    The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma. PMID:26647728

  20. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas.

    PubMed

    Wu, Kui; Zhang, Xin; Li, Fuqiang; Xiao, Dakai; Hou, Yong; Zhu, Shida; Liu, Dongbing; Ye, Xiaofei; Ye, Mingzhi; Yang, Jie; Shao, Libin; Pan, Hui; Lu, Na; Yu, Yuan; Liu, Liping; Li, Jin; Huang, Liyan; Tang, Hailing; Deng, Qiuhua; Zheng, Yue; Peng, Lihua; Liu, Geng; Gu, Xia; He, Ping; Gu, Yingying; Lin, Weixuan; He, Huiming; Xie, Guoyun; Liang, Han; An, Na; Wang, Hui; Teixeira, Manuel; Vieira, Joana; Liang, Wenhua; Zhao, Xin; Peng, Zhiyu; Mu, Feng; Zhang, Xiuqing; Xu, Xun; Yang, Huanming; Kristiansen, Karsten; Wang, Jian; Zhong, Nanshan; Wang, Jun; Pan-Hammarström, Qiang; He, Jianxing

    2015-12-09

    The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.

  1. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer.

    PubMed

    Nurwidya, Fariz; Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-09-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer. PMID:27689025

  2. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer

    PubMed Central

    Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-01-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer. PMID:27689025

  3. Circulating Tumor Cell and Cell-free Circulating Tumor DNA in Lung Cancer

    PubMed Central

    Zaini, Jamal; Putra, Andika Chandra; Andarini, Sita; Hudoyo, Achmad; Syahruddin, Elisna; Yunus, Faisal

    2016-01-01

    Circulating tumor cells (CTCs) are tumor cells that are separated from the primary site or metastatic lesion and disseminate in blood circulation. CTCs are considered to be part of the long process of cancer metastasis. As a 'liquid biopsy', CTC molecular examination and investigation of single cancer cells create an important opportunity for providing an understanding of cancer biology and the process of metastasis. In the last decade, we have seen dramatic development in defining the role of CTCs in lung cancer in terms of diagnosis, genomic alteration determination, treatment response and, finally, prognosis prediction. The aims of this review are to understand the basic biology and to review methods of detection of CTCs that apply to the various types of solid tumor. Furthermore, we explored clinical applications, including treatment monitoring to anticipate therapy resistance as well as biomarker analysis, in the context of lung cancer. We also explored the potential use of cell-free circulating tumor DNA (ctDNA) in the genomic alteration analysis of lung cancer.

  4. Primary tumor prevalence has an impact on the constituent ratio of metastases to the jaw but not on metastatic sites

    PubMed Central

    Zhang, Fu-gui; Hua, Cheng-ge; Shen, Mo-lun; Tang, Xiu-fa

    2011-01-01

    This article provides an overview of metastases to jaws (MJ), mainly concerning the differences between American and Chinese patients, and exploring the relationship between the primary tumors' prevalence (PTP) and constituent ratio of MJ. Information concerning of 399 MJ cases in 215 papers, including one new case in our hospital, was subjected to statistic analysis. The main clinical features of MJ, such as constituent ratio of PTP and that of MJ, metastatic sites, treatments, and prognosis were summarized. Breast, lung, kidney, prostate and thyroid (in descending order) were the leading primary sites of MJ. Furthermore, the constituent ratio of MJ was found to be correlated with that of PTP in all subjects including American and Chinese subjects in our study. As to metastatic sites in the mandible, a specific “M” shaped pattern appeared regardless of the tumor type or constituent ratios of MJ were in all subjects. Almost all subjects received traditionally palliative treatments, and the prognosis was quite poor. The PTP had a significant impact on the constituent ratio of MJ. However, it was the properties of the microenvironment rather than characteristics or constituent ratios of tumor cells, that decided the metastatic sites in various tumor subjects. PMID:21789963

  5. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors.

    PubMed

    Pelosi, Giuseppe; Papotti, Mauro; Rindi, Guido; Scarpa, Aldo

    2014-06-01

    Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations

  6. Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates.

    PubMed

    Shamay, Yosi; Raviv, Lior; Golan, Moran; Voronov, Elena; Apte, Ron N; David, Ayelet

    2015-11-10

    There is currently no effective means to prevent or control metastatic dissemination of cancer cells. E-selectin, an adhesion molecule expressed exclusively on inflamed and angiogenic blood vessels, plays an important role in several rate-limiting steps of cancer metastasis. In this study, we assessed the in vivo antitumor efficacy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to an E-selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped with the chemotherapeutic drug doxorubicin (P-(Esbp)-DOX) or with the proapoptotic peptide D(KLAKLAK)2 (P-(Esbp)-KLAK). Following a single intravenous injection, P-(Esbp)-DOX reduced tumor growth rate and prolonged the survival of mice bearing primary Lewis lung carcinoma (3LL) tumors significantly more than treatment with a non-targeted copolymer (P-DOX) or with free DOX. In an experimental B16-F10 lung metastasis model, a single intravenous dose of P-(Esbp)-DOX or P-(Esbp)-KLAK prolonged mice survival time significantly more than the non-targeted copolymers or the free drugs, and the percentage of complete tumor regression increased with increasing doses and with dosing frequency. In addition, mice pretreated with an E-selectin-targeted "drug-free" copolymer (P-(Esbp)-FITC) exhibited significantly fewer B16-F10 tumor foci in the lungs as compared with non-treated mice, demonstrating the anti-metastatic properties of the copolymer and its ability to control cancer spread through E-selectin-mediated interactions. Biodistribution analysis further confirmed the preferential accumulation of the E-selectin-targeted near-infrared fluorescently-labeled copolymer P-(Esbp)-IR783 in B16-F10 lung metastases. Taken together, this study demonstrates, for the first time, that the E-selectin targeted copolymer-drug conjugates can inhibit primary tumor growth and prevent metastases in vivo. PMID:26297207

  7. Inhibition of primary and metastatic tumors in mice by E-selectin-targeted polymer-drug conjugates.

    PubMed

    Shamay, Yosi; Raviv, Lior; Golan, Moran; Voronov, Elena; Apte, Ron N; David, Ayelet

    2015-11-10

    There is currently no effective means to prevent or control metastatic dissemination of cancer cells. E-selectin, an adhesion molecule expressed exclusively on inflamed and angiogenic blood vessels, plays an important role in several rate-limiting steps of cancer metastasis. In this study, we assessed the in vivo antitumor efficacy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers conjugated to an E-selectin binding peptide (Esbp, DITWDQLWDLMK) and equipped with the chemotherapeutic drug doxorubicin (P-(Esbp)-DOX) or with the proapoptotic peptide D(KLAKLAK)2 (P-(Esbp)-KLAK). Following a single intravenous injection, P-(Esbp)-DOX reduced tumor growth rate and prolonged the survival of mice bearing primary Lewis lung carcinoma (3LL) tumors significantly more than treatment with a non-targeted copolymer (P-DOX) or with free DOX. In an experimental B16-F10 lung metastasis model, a single intravenous dose of P-(Esbp)-DOX or P-(Esbp)-KLAK prolonged mice survival time significantly more than the non-targeted copolymers or the free drugs, and the percentage of complete tumor regression increased with increasing doses and with dosing frequency. In addition, mice pretreated with an E-selectin-targeted "drug-free" copolymer (P-(Esbp)-FITC) exhibited significantly fewer B16-F10 tumor foci in the lungs as compared with non-treated mice, demonstrating the anti-metastatic properties of the copolymer and its ability to control cancer spread through E-selectin-mediated interactions. Biodistribution analysis further confirmed the preferential accumulation of the E-selectin-targeted near-infrared fluorescently-labeled copolymer P-(Esbp)-IR783 in B16-F10 lung metastases. Taken together, this study demonstrates, for the first time, that the E-selectin targeted copolymer-drug conjugates can inhibit primary tumor growth and prevent metastases in vivo.

  8. Expression Profiling of Primary and Metastatic Ovarian Tumors Reveals Differences Indicative of Aggressive Disease

    PubMed Central

    Brodsky, Alexander S.; Fischer, Andrew; Miller, Daniel H.; Vang, Souriya; MacLaughlan, Shannon; Wu, Hsin-Ta; Yu, Jovian; Steinhoff, Margaret; Collins, Colin; Smith, Peter J. S.; Raphael, Benjamin J.; Brard, Laurent

    2014-01-01

    The behavior and genetics of serous epithelial ovarian cancer (EOC) metastasis, the form of the disease lethal to patients, is poorly understood. The unique properties of metastases are critical to understand to improve treatments of the disease that remains in patients after debulking surgery. We sought to identify the genetic and phenotypic landscape of metastatic progression of EOC to understand how metastases compare to primary tumors. DNA copy number and mRNA expression differences between matched primary human tumors and omental metastases, collected at the same time during debulking surgery before chemotherapy, were measured using microarrays. qPCR and immunohistochemistry validated findings. Pathway analysis of mRNA expression revealed metastatic cancer cells are more proliferative and less apoptotic than primary tumors, perhaps explaining the aggressive nature of these lesions. Most cases had copy number aberrations (CNAs) that differed between primary and metastatic tumors, but we did not detect CNAs that are recurrent across cases. A six gene expression signature distinguishes primary from metastatic tumors and predicts overall survival in independent datasets. The genetic differences between primary and metastatic tumors, yet common expression changes, suggest that the major clone in metastases is not the same as in primary tumors, but the cancer cells adapt to the omentum similarly. Together, these data highlight how ovarian tumors develop into a distinct, more aggressive metastatic state that should be considered for therapy development. PMID:24732363

  9. Anti-tumor immunity generated by photodynamic therapy in a metastatic murine tumor model

    NASA Astrophysics Data System (ADS)

    Castano, Ana P.; Hamblin, Michael R.

    2005-04-01

    Photodynamic therapy (PDT) is a modality for the treatment of cancer involving excitation of photosensitizers with harmless visible light producing reactive oxygen species. The major biological effects of PDT are apoptosis of tumor cells, destruction of the blood supply and activation of the immune system. The objective of this study is to compare in an animal model of metastatic cancer, PDT alone and PDT combined with low-dose cyclophosphamide (CY). Since the tumor we used is highly metastatic, it is necessary to generate anti-tumor immunity using PDT to both cure the primary tumor and prevent death from metastasis. This immunity may be potentiated by low dose CY. In our model we used J774 cells (a Balb/c reticulum cell sarcoma line with the characteristics of macrophages) and the following PDT regimen: benzoporphyrin derivative monoacid ring A (BPD, 2mg/kg injected IV followed after 15 min by 150 J/cm2 of 690-nm light). CY (50 mg/kg i.p.) was injected 48 hours before light delivery. BPD-PDT led to complete regression of the primary tumor in more than half the mice but no permanent cures were obtained. BPD-PDT in combination with CY led to 60% permanent cures. CY alone gave no permanent cures but did provide a survival advantage. To probe permanent immunity cured animals were rechallenged with the same tumor cell line and the tumors were rejected in 71% of mice cured with BPD-PDT plus CY. We conclude that BPD-PDT in combination with CY gives best overall results and that this is attributable to immunological response activation in addition to PDT-mediated destruction of the tumor.

  10. Multimodal Approach to the Management of Metastatic Epidural Spinal Cord Compression (MESCC) Due to Solid Tumors

    SciTech Connect

    Tancioni, Flavio; Navarria, Pierina; Lorenzetti, Martin A.; Pedrazzoli, Paolo; Masci, Giovanna; Mancosu, Pietro; Alloisio, Marco; Morenghi, Emanuela; Santoro, Armando; Rodriguez y Baena, Riccardo; Scorsetti, Marta

    2010-12-01

    Purpose: To assess the impact of a multidisciplinary approach for treatment of patients with metastatic epidural spinal cord compression in terms of feasibility, local control, and survival. Methods and Materials: Eighty-nine consecutive patients treated between January 2004 and December 2007 were included. The most common primary cancers were lung, breast, and kidney cancers. Ninety-eight surgical procedures were performed. Radiotherapy was performed within the first month postoperatively. Clinical outcome was evaluated by modified visual analog scale for pain, Frankel scale for neurologic deficit, and magnetic resonance imaging or computed tomography scan. Nearly all patients (93%) had back pain before treatment, whereas major or minor preoperative neurologic deficit was present in 62 cases (63%). Results: Clinical remission of pain was obtained in the vast majority of patients (91%). Improvement of neurologic deficit was observed in 45 cases (72.5%). Local relapse occurred in 10%. Median survival was 11 months (range, 0-46 months). Overall survival at 1 year was 43.6%. Type of primary tumor significantly affected survival. Conclusions: In patients with metastatic epidural spinal cord compression, the combination of surgery plus radiotherapy is feasible and provides clinical benefit in most patients. The discussion of each single case within a multidisciplinary team has been of pivotal importance in implementing the most appropriate therapeutic approach.

  11. Circulating tumor DNA and circulating tumor cells in metastatic triple negative breast cancer patients.

    PubMed

    Madic, Jordan; Kiialainen, Anna; Bidard, Francois-Clement; Birzele, Fabian; Ramey, Guillemette; Leroy, Quentin; Rio Frio, Thomas; Vaucher, Isabelle; Raynal, Virginie; Bernard, Virginie; Lermine, Alban; Clausen, Inga; Giroud, Nicolas; Schmucki, Roland; Milder, Maud; Horn, Carsten; Spleiss, Olivia; Lantz, Olivier; Stern, Marc-Henri; Pierga, Jean-Yves; Weisser, Martin; Lebofsky, Ronald

    2015-05-01

    Circulating tumor DNA (ctDNA) is a new circulating tumor biomarker which might be used as a prognostic biomarker in a way similar to circulating tumor cells (CTCs). Here, we used the high prevalence of TP53 mutations in triple negative breast cancer (TNBC) to compare ctDNA and CTC detection rates and prognostic value in metastatic TNBC patients. Forty patients were enrolled before starting a new line of treatment. TP53 mutations were characterized in archived tumor tissues and in plasma DNA using two next generation sequencing (NGS) platforms in parallel. Archived tumor tissue was sequenced successfully for 31/40 patients. TP53 mutations were found in 26/31 (84%) of tumor samples. The same mutation was detected in the matched plasma of 21/26 (81%) patients with an additional mutation found only in the plasma for one patient. Mutated allele fractions ranged from 2 to 70% (median 5%). The observed correlation between the two NGS approaches (R(2) = 0.903) suggested that ctDNA levels data were quantitative. Among the 27 patients with TP53 mutations, CTC count was ≥1 in 19 patients (70%) and ≥5 in 14 patients (52%). ctDNA levels had no prognostic impact on time to progression (TTP) or overall survival (OS), whereas CTC numbers were correlated with OS (p = 0.04) and marginally with TTP (p = 0.06). Performance status and elevated LDH also had significant prognostic impact. Here, absence of prognostic impact of baseline ctDNA level suggests that mechanisms of ctDNA release in metastatic TNBC may involve, beyond tumor burden, biological features that do not dramatically affect patient outcome.

  12. Efficient gene silencing in metastatic tumor by siRNA formulated in surface-modified nanoparticles.

    PubMed

    Li, Shyh-Dar; Chono, Sumio; Huang, Leaf

    2008-02-18

    We have developed a nanoparticle (NP) formulation for systemically delivering siRNA into metastatic tumors. The NP, composed of nucleic acids, a polycationic peptide and cationic liposome, was prepared in a self-assembling process. The NP was then modified by PEG-lipid containing a targeting ligand, anisamide, and thus was decorated for targeting sigma receptor expressing B16F10 tumor. The activity of the targeted NP was compared with the naked NP (no PEGylation) and non-targeted NP (no ligand). The delivery efficiency of the targeted NP was 4-fold higher than the non-targeted NP and could be competed by excess free ligand. Luciferase siRNA was used to evaluate the gene silencing activity in the B16F10 cells, which were stably transduced with a luciferase gene. The gene silencing activity of the targeted NP was significantly higher than the other formulations and lasted for 4 days. While confocal microscopy showed that the naked NP provided no tissue selectivity and non-targeted NP was ineffective for tumor uptake, the targeted NP effectively penetrated the lung metastasis, but not the liver. It resulted in 70-80% gene silencing in the metastasis model after a single i.v. injection (150 microg siRNA/kg). This effective formulation also showed very little immunotoxicity.

  13. [Advanced and Metastatic Lung Cancer – What is new in the Diagnosis and Therapy?].

    PubMed

    Rothschild, Sacha I

    2015-07-01

    Lung cancer is one of the most common types of malignancies worldwide. The majority of patients are diagnosed with an incurable advanced/metastatic stage disease. Palliative treatment approaches improve the survival and the quality of life of these patients. Lung cancer is subdivided according to histology and molecular biology. The most important classification separates small cell from non-small cell lung cancer. In the subgroup of non-small cell lung cancer novel treatment approaches coming along with an improved prognosis have been established during the last decade. The current manuscript provides an overview on current treatment options for metastatic lung cancer. Furthermore, an outlook on promising future treatment options is provided.

  14. What Are the Key Statistics for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What are the key statistics about lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  15. What Are the Risk Factors for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What are the risk factors for lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  16. What Should You Ask Your Doctor about Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What should you ask your doctor about lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  17. What Happens after Treatment for Lung Carcinoid Tumors?

    MedlinePlus

    ... Research Get Involved Find Local ACS Learn About Cancer » Lung Carcinoid Tumor » Detailed Guide » What happens after treatment for lung carcinoid tumors? Share this Page Close Push escape to close share window. Print ...

  18. What's New in Lung Carcinoid Tumor Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for lung carcinoid tumors What’s new in lung carcinoid tumor research and treatment? Many ... controlling when our cells grow and divide into new cells. Certain genes that cause cells to grow, ...

  19. Imaging Features of Primary Tumors and Metastatic Patterns of the Extraskeletal Ewing Sarcoma Family of Tumors in Adults: A 17-Year Experience at a Single Institution

    PubMed Central

    Huh, Jimi; Park, Seong Joon; Kim, Hyoung Jung; Lee, Jong Seok; Ha, Hyun Kwon; Tirumani, Sree Harsha; Ramaiya, Nikhil H.

    2015-01-01

    Objective To comprehensively analyze the spectrum of imaging features of the primary tumors and metastatic patterns of the Extraskeletal Ewing sarcoma family of tumors (EES) in adults. Materials and Methods We performed a computerized search of our hospital's data-warehouse from 1996 to 2013 using codes for Ewing sarcoma and primitive neuroectodermal tumors as well as the demographic code for ≥ 18 years of age. We selected subjects who were histologically confirmed to have Ewing sarcoma of extraskeletal origin. Imaging features of the primary tumor and metastatic disease were evaluated for lesion location, size, enhancement pattern, necrosis, margin, and invasion of adjacent organs. Results Among the 70 patients (mean age, 35.8 ± 15.6 years; range, 18-67 years) included in our study, primary tumors of EES occurred in the soft tissue and extremities (n = 20), abdomen and pelvis (n = 18), thorax (n = 14), paravertebral space (n = 8), head and neck (n = 6), and an unknown primary site (n = 4). Most primary tumors manifested as large and bulky soft-tissue masses (mean size, 9.0 cm; range, 1.3-23.0 cm), frequently invading adjacent organs (45.6%) and showed heterogeneous enhancement (73.7%), a well-defined (66.7%) margin, and partial necrosis/cystic degeneration (81.9%). Notably, 29 patients had metastatic disease detected at their initial diagnosis. The most frequent site of metastasis was lymph nodes (75.9%), followed by bone (31.0%), lung (20.7%), abdominal solid organs (13.8%), peritoneum (13.8%), pleura (6.9%), and brain (3.4%). Conclusion Primary tumors of EES can occur anywhere and mostly manifest as large and bulky, soft-tissue masses. Lymph nodes are the most frequent metastasis sites. PMID:26175577

  20. Tumor Therapeutic Response and Vessel Tortuosity: Preliminary Report in Metastatic Breast Cancer

    PubMed Central

    Bullitt, Elizabeth; Lin, Nancy U.; Ewend, Matthew G.; Zeng, Donglin; Winer, Eric P.; Carey, Lisa A.; Smith, J. Keith

    2008-01-01

    No current non-invasive method is capable of assessing the efficacy of brain tumor therapy early during treatment. We outline an approach that evaluates tumor activity via statistical analysis of vessel shape using vessels segmented from MRA. This report is the first to describe the changes in vessel shape that occur during treatment of metastatic brain tumors as assessed by sequential MRA. In this preliminary study of 16 patients undergoing treatment for metastatic breast cancer we conclude that vessel shape may predict tumor response several months in advance of traditional methods. PMID:17354817

  1. The Effect of Flattening Filter Free on Three-dimensional Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT) Plans for Metastatic Brain Tumors from Non-small Cell Lung Cancer.

    PubMed

    Shi, Li-Wan; Lai, You-Qun; Lin, Qin; Ha, Hui-Ming; Fu, Li-Rong

    2015-07-01

    Flattening filter free (FFF) may affect outcome measures of radiotherapy. The objective of this study is to compare the dosimetric parameters in three types of radiotherapy plans, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), with or without the flattening filter (FF), developed for the treatment of metastatic brain tumors from non-small cell lung cancer (NSCLC). From July 2013 to October 2013, 3D-CRT, IMRT, and VMAT treatment plans were designed using 6 MV and 10 MV, with and without FF, for 10 patients with brain metastasis from NSCLC. The evaluation of the treatment plans included homogeneity index (HI), conformity index (CI), monitor units (MU), mean dose (Dmean), treatment time, and the influence of FFF on volumes. There was no difference in CI or HI between FFF and FF models with 3D-CRT, IMRT, and VMAT plans. At 6 MV, a lower Dmean was seen in the FFF model of 3D-CRT and in the VMAT plan at 10 MV. In the IMRT 6 MV, IMRT 10 MV, and VMAT 10 MV plans, higher MUs were seen in the FFF models. FFF treatments are similar in quality to FF plans, generally lead to more monitor units, and are associated with shorter treatment times. FFF plans ranked by the order of superiority in terms of a time advantage are VMAT, 3D-CRT, and IMRT.

  2. The Effect of Flattening Filter Free on Three-dimensional Conformal Radiation Therapy (3D-CRT), Intensity-Modulated Radiation Therapy (IMRT), and Volumetric Modulated Arc Therapy (VMAT) Plans for Metastatic Brain Tumors from Non-small Cell Lung Cancer.

    PubMed

    Shi, Li-Wan; Lai, You-Qun; Lin, Qin; Ha, Hui-Ming; Fu, Li-Rong

    2015-07-01

    Flattening filter free (FFF) may affect outcome measures of radiotherapy. The objective of this study is to compare the dosimetric parameters in three types of radiotherapy plans, three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT), with or without the flattening filter (FF), developed for the treatment of metastatic brain tumors from non-small cell lung cancer (NSCLC). From July 2013 to October 2013, 3D-CRT, IMRT, and VMAT treatment plans were designed using 6 MV and 10 MV, with and without FF, for 10 patients with brain metastasis from NSCLC. The evaluation of the treatment plans included homogeneity index (HI), conformity index (CI), monitor units (MU), mean dose (Dmean), treatment time, and the influence of FFF on volumes. There was no difference in CI or HI between FFF and FF models with 3D-CRT, IMRT, and VMAT plans. At 6 MV, a lower Dmean was seen in the FFF model of 3D-CRT and in the VMAT plan at 10 MV. In the IMRT 6 MV, IMRT 10 MV, and VMAT 10 MV plans, higher MUs were seen in the FFF models. FFF treatments are similar in quality to FF plans, generally lead to more monitor units, and are associated with shorter treatment times. FFF plans ranked by the order of superiority in terms of a time advantage are VMAT, 3D-CRT, and IMRT. PMID:26011493

  3. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors

    PubMed Central

    Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-01-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3–15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase. PMID:27652204

  4. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors.

    PubMed

    Dorantes-Heredia, Rita; Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-08-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase. PMID:27652204

  5. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors.

    PubMed

    Dorantes-Heredia, Rita; Ruiz-Morales, José Manuel; Cano-García, Fernando

    2016-08-01

    Lung cancer is the principal cause of cancer-related death worldwide. The use of targeted therapies, especially tyrosine kinase inhibitors (TKIs), in specific groups of patients has dramatically improved the prognosis of this disease, although inevitably some patients will develop resistance to these drugs during active treatment. The most common cancer-associated acquired mutation is the epidermal growth factor receptor (EGFR) Thr790Met (T790M) mutation. During active treatment with targeted therapies, histopathological transformation to small-cell lung carcinoma (SCLC) can occur in 3-15% of patients with non-small-cell lung carcinoma (NSCLC) tumors. By definition, SCLC is a high-grade tumor with specific histological and genetic characteristics. In the majority of cases, a good-quality hematoxylin and eosin (H&E) stain is enough to establish a diagnosis. Immunohistochemistry (IHC) is used to confirm the diagnosis and exclude other neoplasia such as sarcomatoid carcinomas, large-cell carcinoma, basaloid squamous-cell carcinoma, chronic inflammation, malignant melanoma, metastatic carcinoma, sarcoma, and lymphoma. A loss of the tumor-suppressor protein retinoblastoma 1 (RB1) is found in 100% of human SCLC tumors; therefore, it has an essential role in tumorigenesis and tumor development. Other genetic pathways probably involved in the histopathological transformation include neurogenic locus notch homolog (NOTCH) and achaete-scute homolog 1 (ASCL1). Histological transformation to SCLC can be suspected in NSCLC patients who clinically deteriorate during active treatment. Biopsy of any new lesion in this clinical setting is highly recommended to rule out a SCLC transformation. New studies are trying to assess this histological transformation by noninvasive measures such as measuring the concentration of serum neuron-specific enolase.

  6. In vivo quantification of metastatic tumor cell adhesion in the pulmonary microvasculature.

    PubMed

    Bartsch, F; Kang, M L; Mees, S T; Haier, J; Gassmann, P

    2013-01-01

    In vivo and ex vivo fluorescence video microscopy used to be a well-established method in life science with a variety of applications, such as in inflammation or cancer research. In this book chapter, we describe a model of in vivo fluorescence microscopy of the rat's lung with the exclusive advantage of qualitative and quantitative in vivo analysis of cell adhesion within the complex microenvironment of the ventilated and perfused lung. Observation can include real-time, time-lapse, or fast-motion analysis. In our laboratory, we have used the model for qualitative and quantitative real-time analyses of metastatic colon cancer cell adhesion within the rat's pulmonary microcirculation. Using some modifications in another series, we have also applied the model to analyze thrombocyte and leucocyte adhesion within the pulmonary capillaries in experimental sepsis. For interventional studies, injected cells or animals may be pretreated with various reagents or drugs for further analysis of adhesion molecules involved in tumor cell-endothelial cell interactions. PMID:23955736

  7. Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer.

    PubMed

    Dang, Thu Oanh; Ogunniyi, Adebayo; Barbee, Meagan S; Drilon, Alexander

    2016-01-01

    The emergence of immune checkpoint inhibitors marked an important advancement in the development of cancer therapeutics. Pembrolizumab is a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 (PD-1) receptor, an integral component of immune checkpoint regulation in the tumor microenvironment. The drug is currently approved by the Food and Drug Administration for the treatment of advanced melanoma and metastatic squamous and nonsquamous non-small cell lung cancer (NSCLC). Several published studies demonstrate that single-agent pembrolizumab is safe and has efficacy in patients with NSCLC. Many ongoing protocols are investigating the role of pembrolizumab in combination with other agents in lung cancer and various other cancer types. We review the available data on pembrolizumab in NSCLC and examine the role of potential predictive biomarkers of response to therapy.

  8. Total En Bloc Spondylectomy for Primary and Metastatic Spine Tumors.

    PubMed

    Mesfin, Addisu; El Dafrawy, Mostafa H; Jain, Amit; Hassanzadeh, Hamid; Kebaish, Khaled M

    2015-11-01

    This study reports the surgical and clinical outcomes of spinal tumors managed with total en bloc spondylectomy. The authors searched their prospectively maintained database for patients undergoing total en bloc spondylectomy between 2001 and 2013. Ten patients (9 men, 1 woman; average age, 50.7 years; range, 42-68 years) were identified. The authors obtained demographic information, surgical outcomes (estimated blood loss, complications), and clinical outcomes (recurrence, survival). All patients had pain and were classified as American Spinal Injury Association grade E. The lesions were located in the thoracic (8 patients) and lumbar (2 patients) spine. Anterior column reconstruction was performed with strut allograft (7 patients), mesh cage (2 patients), and polymethyl methacrylate (1 patient). An average of 2.3 (range, 2-4) of 6 portions of the vertebrae were involved, according to the Kostuik classification. Mean estimated blood loss, operative time, and hospital stay were 3.5 L, 500 minutes, and 7.8 days, respectively. Perioperative complications included pleural tear (2 patients) and aortic tear, vena cava tear, retained sponge, pulmonary embolism, urinary tract infection, pneumothorax, anterior column support failure, and prominent instrumentation requiring removal (1 patient each). Postoperatively, all patients remained classified as American Spinal Injury Association grade E. Two patients had recurrence at distant spinal segments, and 1 had a new lesion in the thigh. Five patients had died (mean, 34.5 months after surgery), and 5 were alive a mean of 19.6 months after surgery (range, 6-48 months). Total en bloc spondylectomy is challenging, but in appropriately selected patients, it can be used to treat primary and metastatic spinal lesions.

  9. Efficacy of liposome-encapsulated indomethacin in response against metastatic 3LL and B16F1 tumor cells.

    PubMed

    Aliño, S F; Unda, F J; Iruarrizaga, A; Alfaro, J; Hilario, E; Pérez-Yarza, G; Bobadilla, M; Lejarreta, M

    1992-06-01

    The ability of large liposomes to be taken up by tissue phagocytic cells, e.g., macrophages, has made it possible to increase the efficacy of several drugs as immunomodulating agents. In the present work, we have evaluated the effect of indomethacin, a prostaglandin synthesis inhibitor, both free and encapsulated in liposomes, on the spontaneous metastatic potential of 3LL and B16F1 tumor cells. Liposomes containing either carboxyfluorescein, indomethacin, or carboxyfluorescein plus indomethacin, were made in order to evaluate their in vitro plasma stability and in vivo clearance from the blood. The liposomes showed a high stability after 6 hours of plasma incubation and they were rapidly cleared in vivo. Liposomes encapsulating propidium iodide, a fluorescent DNA binding dye, were mainly taken up in vivo by hepatic and spleen macrophages 1 hour after intravenous injection, but not by lung macrophages. When C57BL/6 mice were intravenously inoculated with 10(5) 3LL or B16F1 tumor cells previously incubated with indomethacin (10(-7) M) for 48 hours, the number of experimental lung metastatic foci was increased with respect to their respective control groups. Also, in 3LL or B16F1 tumor-bearing mice, treatment with indomethacin (0.5 mg/kg weight/day) for 10 days enhanced the number of lung metastases, but not significantly. However, when mice received indomethacin encapsulated in liposomes, the number of metastases was significantly reduced. In addition, encapsulated indomethacin (0.5 mg/kg weight/day) inhibits prostaglandin E2 production by peritoneal and spleen macrophages, whereas no significant inhibitory effect was observed with control-liposomes or equivalent doses of free indomethacin. We conclude that intravenous administration of liposome-encapsulated indomethacin has an antimetastatic effect on tumor-bearing mice. Use of indomethacin in liposomes may avoid the stimulation of metastases observed when the drug is administered alone.

  10. Stereotactic body radiotherapy for small lung tumors in the University of Tokyo Hospital.

    PubMed

    Yamashita, Hideomi; Takahashi, Wataru; Haga, Akihiro; Kida, Satoshi; Saotome, Naoya; Nakagawa, Keiichi

    2014-01-01

    Our work on stereotactic body radiation therapy (SBRT) for primary and metastatic lung tumors will be described. The eligibility criteria for SBRT, our previous SBRT method, the definition of target volume, heterogeneity correction, the position adjustment using four-dimensional cone-beam computed tomography (4D CBCT) immediately before SBRT, volumetric modulated arc therapy (VMAT) method for SBRT, verifying of tumor position within internal target volume (ITV) using in-treatment 4D-CBCT during VMAT-SBRT, shortening of treatment time using flattening-filter-free (FFF) techniques, delivery of 4D dose calculation for lung-VMAT patients using in-treatment CBCT and LINAC log data with agility multileaf collimator, and SBRT method for centrally located lung tumors in our institution will be shown. In our institution, these efforts have been made with the goal of raising the local control rate and decreasing adverse effects after SBRT.

  11. A case of metastatic bladder cancer in both lungs treated with korean medicine therapy alone.

    PubMed

    Lee, Dong-Hyun; Kim, Sung-Su; Seong, Shin; Woo, Chang-Ryoul; Han, Jae-Bok

    2014-05-01

    This case report is aimed to investigate the effects of Korean medicine therapy (KMT) including oral herbal medicine and herb nebulizer therapy in treating metastatic bladder cancer in the lungs. A 74-year-old man was diagnosed with metastatic bladder cancer in both lungs in August 2013. He refused any chemotherapy and was admitted to our hospital in a much progressed state on January 11, 2014. Since then, he was treated with KMT until May 17, 2014. The main oral herbal medicines were Hyunamdan made of heat-processed ginseng, Hangamdan S made of Cordyceps militaris, Panax ginseng radix, Commiphora myrrha, calculus bovis, margarita, Boswellia carteri, Panax notoginseng radix and Cremastra appendiculata tuber, and nebulizer therapy with Soram nebulizer solution made of wild ginseng and Cordyceps sinensis distillate. Their effect was evaluated considering the change of the main symptoms and using serial chest X-ray. The size and number of multiple metastatic nodules in both lungs were markedly decreased and the symptoms had disappeared. These results suggest that KMT can be an effective method to treat metastatic bladder cancer in the lungs. PMID:25232323

  12. A Case of Metastatic Bladder Cancer in Both Lungs Treated with Korean Medicine Therapy Alone

    PubMed Central

    Lee, Dong-Hyun; Kim, Sung-Su; Seong, Shin; Woo, Chang-Ryoul; Han, Jae-Bok

    2014-01-01

    Abstract This case report is aimed to investigate the effects of Korean medicine therapy (KMT) including oral herbal medicine and herb nebulizer therapy in treating metastatic bladder cancer in the lungs. A 74-year-old man was diagnosed with metastatic bladder cancer in both lungs in August 2013. He refused any chemotherapy and was admitted to our hospital in a much progressed state on January 11, 2014. Since then, he was treated with KMT until May 17, 2014. The main oral herbal medicines were Hyunamdan made of heat-processed ginseng, Hangamdan S made of Cordyceps militaris, Panax ginseng radix, Commiphora myrrha, calculus bovis, margarita, Boswellia carteri, Panax notoginseng radix and Cremastra appendiculata tuber, and nebulizer therapy with Soram nebulizer solution made of wild ginseng and Cordyceps sinensis distillate. Their effect was evaluated considering the change of the main symptoms and using serial chest X-ray. The size and number of multiple metastatic nodules in both lungs were markedly decreased and the symptoms had disappeared. These results suggest that KMT can be an effective method to treat metastatic bladder cancer in the lungs. PMID:25232323

  13. A case of metastatic bladder cancer in both lungs treated with korean medicine therapy alone.

    PubMed

    Lee, Dong-Hyun; Kim, Sung-Su; Seong, Shin; Woo, Chang-Ryoul; Han, Jae-Bok

    2014-05-01

    This case report is aimed to investigate the effects of Korean medicine therapy (KMT) including oral herbal medicine and herb nebulizer therapy in treating metastatic bladder cancer in the lungs. A 74-year-old man was diagnosed with metastatic bladder cancer in both lungs in August 2013. He refused any chemotherapy and was admitted to our hospital in a much progressed state on January 11, 2014. Since then, he was treated with KMT until May 17, 2014. The main oral herbal medicines were Hyunamdan made of heat-processed ginseng, Hangamdan S made of Cordyceps militaris, Panax ginseng radix, Commiphora myrrha, calculus bovis, margarita, Boswellia carteri, Panax notoginseng radix and Cremastra appendiculata tuber, and nebulizer therapy with Soram nebulizer solution made of wild ginseng and Cordyceps sinensis distillate. Their effect was evaluated considering the change of the main symptoms and using serial chest X-ray. The size and number of multiple metastatic nodules in both lungs were markedly decreased and the symptoms had disappeared. These results suggest that KMT can be an effective method to treat metastatic bladder cancer in the lungs.

  14. Differential Effects of Drugs Targeting Cancer Stem Cell (CSC) and Non-CSC Populations on Lung Primary Tumors and Metastasis

    PubMed Central

    Larzabal, Leyre; El-Nikhely, Nefertiti; Redrado, Miriam; Seeger, Werner; Savai, Rajkumar; Calvo, Alfonso

    2013-01-01

    Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/− populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05), whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change) when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis. PMID

  15. Differential effects of drugs targeting cancer stem cell (CSC) and non-CSC populations on lung primary tumors and metastasis.

    PubMed

    Larzabal, Leyre; El-Nikhely, Nefertiti; Redrado, Miriam; Seeger, Werner; Savai, Rajkumar; Calvo, Alfonso

    2013-01-01

    Cancer stem cells (CSCs) are thought to be responsible for tumor initiation and recurrence after chemotherapy. Targeting CSCs and non-CSCs with specific compounds may be an effective approach to reduce lung cancer growth and metastasis. The aim of this study was to investigate the effect of salinomycin, a selective inhibitor of CSCs, with or without combination with paclitaxel, in a metastatic model. To evaluate the effect of these drugs in metastasis and tumor microenvironment we took advantage of the immunocompetent and highly metastatic LLC mouse model. Aldefluor assays were used to analyze the ALDH+/- populations in murine LLC and human H460 and H1299 lung cancer cells. Salinomycin reduced the proportion of ALDH+ CSCs in LLC cells, whereas paclitaxel increased such population. The same effect was observed for the H460 and H1299 cell lines. Salinomycin reduced the tumorsphere formation capacity of LLC by more than 7-fold, but paclitaxel showed no effect. In in vivo experiments, paclitaxel reduced primary tumor volume but increased the number of metastatic nodules (p<0.05), whereas salinomycin had no effect on primary tumors but reduced lung metastasis (p<0.05). Combination of both drugs did not improve the effect of single therapies. ALDH1A1, SOX2, CXCR4 and SDF-1 mRNA levels were higher in metastatic lesions than in primary tumors, and were significantly elevated in both locations by paclitaxel treatment. On the contrary, such levels were reduced (or in some cases did not change) when mice were administered with salinomycin. The number of F4/80+ and CD11b+ cells was also reduced upon administration of both drugs, but particularly in metastasis. These results show that salinomycin targets ALDH+ lung CSCs, which has important therapeutic effects in vivo by reducing metastatic lesions. In contrast, paclitaxel (although reducing primary tumor growth) promotes the selection of ALDH+ cells that likely modify the lung microenvironment to foster metastasis. PMID

  16. Imaging changes following stereotactic radiosurgery for metastatic intracranial tumors: differentiating pseudoprogression from tumor progression and its effect on clinical practice

    PubMed Central

    Kleinberg, Lawrence; Rigamonti, Daniele

    2014-01-01

    Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions. PMID:24233257

  17. [Two Surgical Techniques for Metastatic Brain Tumors:Minimum Resection and Removal with Safety Margin].

    PubMed

    Nakasu, Yoko; Mitsuya, Koichi; Hayashi, Nakamasa; Ito, Ichiro

    2016-03-01

    Successful resection of cerebral metastases is based on good basic neurosurgical techniques, in conjunction with technologies for tumor localization. A clear understanding about the border zone pathology of metastatic lesions leads to two different techniques for safe and effective tumor removal. There is no capsule or pseudocapsule around the metastatic brain tumors. The border zone is widely heterogeneous, especially in lesions after stereotactic irradiation. Resection can be performed in a circumferential and en bloc fashion with sufficient safety margin of the normal brain in non-eloquent area. However, enucleation should be done without surrounding brain damage in and near eloquent areas.

  18. Tumor progression: analysis of the instability of the metastatic phenotype, sensitivity to radiation and chemotherapy

    SciTech Connect

    Welch, D.R.

    1984-01-01

    The major complications for tumor therapy are 1) tumor spread (metastasis); 2) the mixed nature of tumors (heterogeneity); and 3) the capacity of tumors to evolve (progress). To study these tumor characteristics, the rat 13762NF mammary adenocarcinoma was cloned and studied for metastatic properties and sensitivities to therapy (chemotherapy, radiation and hyperthermia). The cell clones were heterogeneous and no correlation between metastatic potential and therapeutic sensitivities was observed. Further, these phenotypes were unstable during pasage in vitro; yet, the changes were clone dependent and reproducible using different cryoprotected cell stocks. To understand the phenotypic instability, subclones were isolated from low and high passage cell clones. The results demonstrated that 1) tumor cells are heterogeneous for multiple phenotypes; 2) tumor cells are unstable for multiple phenotypes; 3) the magnitude, direction and time of occurrence of phenotypic drift is clone dependent; 4) the sensitivity of cell clones to ionizing radiation (..gamma.. or heat) and chemotherapy agents is independent of their metastatic potential; 5) shifts in metastatic potential and sensitivity to therapy may occur simultaneously but are not linked; and 6) tumor cells independently diverge to form several subpopulations with unique phenotypic profiles.

  19. Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog

    PubMed Central

    Withers, Sita S.; Lawson, Corinne M.; Burton, Andrew G.; Rebhun, Robert B.; Steffey, Michele A.

    2016-01-01

    We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID:26933269

  20. Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

    PubMed

    Gurumurthi, Ravichandran; Thirumalai, Raja; Easow, Jose M; Mohan, Subhashini

    2014-07-01

    Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

  1. Combination Chemotherapy in Treating Patients With Recurrent, Refractory, or Metastatic Solid Tumors or Lymphomas

    ClinicalTrials.gov

    2012-03-21

    Colorectal Cancer; Esophageal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Liver Cancer; Lung Cancer; Lymphoma; Pancreatic Cancer; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

  2. Optical Detection and Virotherapy of Live Metastatic Tumor Cells in Body Fluids with Vaccinia Strains

    PubMed Central

    Minev, Boris R.; Zimmermann, Martina; Aguilar, Richard J.; Zhang, Qian; Sturm, Julia B.; Fend, Falko; Yu, Yong A.; Cappello, Joseph; Lauer, Ulrich M.; Szalay, Aladar A.

    2013-01-01

    Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. Here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (VACV). In contrast to the FDA-approved CellSearch system, VACV detects circulating tumor cells (CTCs) in a cancer biomarker-independent manner, thus, free of any bias related to the use of antibodies, and can be potentially a universal system for detection of live CTCs of any tumor type, not limited to CTCs of epithelial origin. Furthermore, we demonstrate for the first time that VACV was effective in preventing and reducing circulating tumor cells in mice bearing human tumor xenografts. Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer. Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease. PMID:24019862

  3. Extratumoral Heme Oxygenase-1 (HO-1) Expressing Macrophages Likely Promote Primary and Metastatic Prostate Tumor Growth

    PubMed Central

    Adamo, Hanibal; Thysell, Elin; Jernberg, Emma; Stattin, Pär; Widmark, Anders; Wikström, Pernilla; Bergh, Anders

    2016-01-01

    Aggressive tumors induce tumor-supporting changes in the benign parts of the prostate. One factor that has increased expression outside prostate tumors is hemoxygenase-1 (HO-1). To investigate HO-1 expression in more detail, we analyzed samples of tumor tissue and peritumoral normal prostate tissue from rats carrying cancers with different metastatic capacity, and human prostate cancer tissue samples from primary tumors and bone metastases. In rat prostate tumor samples, immunohistochemistry and quantitative RT-PCR showed that the main site of HO-1 synthesis was HO-1+ macrophages that accumulated in the tumor-bearing organ, and at the tumor-invasive front. Small metastatic tumors were considerably more effective in attracting HO-1+ macrophages than larger non-metastatic ones. In clinical samples, accumulation of HO-1+ macrophages was seen at the tumor invasive front, almost exclusively in high-grade tumors, and it correlated with the presence of bone metastases. HO-1+ macrophages, located at the tumor invasive front, were more abundant in bone metastases than in primary tumors. HO-1 expression in bone metastases was variable, and positively correlated with the expression of macrophage markers but negatively correlated with androgen receptor expression, suggesting that elevated HO-1 could be a marker for a subgroup of bone metastases. Together with another recent observation showing that selective knockout of HO-1 in macrophages reduced prostate tumor growth and metastatic capacity in animals, the results of this study suggest that extratumoral HO-1+ macrophages may have an important role in prostate cancer. PMID:27280718

  4. Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer.

    PubMed

    Herman, Joseph M; Hoffman, John P; Thayer, Sarah P; Wolff, Robert A

    2015-05-01

    New combinations of cytotoxic chemotherapy have been proven to increase response rates and survival times compared with single-agent gemcitabine for patients with metastatic pancreatic cancer. These responses have been dramatic for a subset of patients, therefore raising questions about the management of limited metastatic disease with surgery or other ablative methods. Similarly, for patients having a complete radiographic response to chemotherapy in the metastatic compartment, whether to consider local therapy in the form of radiation or surgery for the primary tumor is now an appropriate question. Therefore, collaboration among experts in surgery, medical oncology, and radiation oncology has led to the development of guiding principles for local therapies to the primary intact pancreatic tumor for patients with limited metastatic disease and those who have had a significant response after systemic therapy.

  5. pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen

    SciTech Connect

    Matsumoto, Yasuyuki; Zhang, Qing; Akita, Kaoru; Nakada, Hiroshi; Hamamura, Kazunori; Tokuda, Noriyo; Tsuchida, Akiko; Matsubara, Takeshi; Hori, Tomoko; Okajima, Tetsuya; Furukawa, Keiko; Urano, Takeshi; Furukawa, Koichi

    2012-03-02

    Highlights: Black-Right-Pointing-Pointer ppGalNAc-T13 was up-regulated in high metastatic sublines of Lewis lung cancer. Black-Right-Pointing-Pointer ppGalNAc-T13 expression enhanced cell invasion activity in low metastatic sublines. Black-Right-Pointing-Pointer Trimeric Tn antigen was induced in the transfectant cells of ppGalNAc-T13 cDNA. Black-Right-Pointing-Pointer A major protein carrying trimeric Tn structure was identified as Syndecan-1. Black-Right-Pointing-Pointer Silencing of ppGalNAc-T13 resulted in the reduction of invasion and of metastasis.. -- Abstract: In order to analyze the mechanisms for cancer metastasis, high metastatic sublines (H7-A, H7-Lu, H7-O, C4-sc, and C4-ly) were obtained by repeated injection of mouse Lewis lung cancer sublines H7 and C4 into C57BL/6 mice. These sublines exhibited increased proliferation and invasion activity in vitro. Ganglioside profiles exhibited lower expression of GM1 in high metastatic sublines than the parent lines. Then, we established GM1-Si-1 and GM1-Si-2 by stable silencing of GM1 synthase in H7 cells. These GM1-knockdown clones exhibited increased proliferation and invasion. Then, we explored genes that markedly altered in the expression levels by DNA microarray in the combination of C4 vs. C4-ly or H7 vs. H7 (GM1-Si). Consequently, pp-GalNAc-T13 gene was identified as up-regulated genes in the high metastatic sublines. Stable transfection of pp-GalNAc-T13 cDNA into C4 (T13-TF) resulted in increased invasion and motility. Then, immunoblotting and flow cytometry using various antibodies and lectins were performed. Only anti-trimeric Tn antibody (mAb MLS128), showed increased expression levels of trimeric Tn antigen in T13-TF clones. Moreover, immunoprecipitation/immunoblotting was performed by mAb MLS128, leading to the identification of an 80 kDa band carrying trimeric Tn antigen, i.e. Syndecan-1. Stable silencing of endogenous pp-GalNAc-T13 in C4-sc (T13-KD) revealed that primary tumors generated by

  6. Fibrous lung tumor: a peculiar case.

    PubMed

    Barrettara, Barbara; Napoli, Gaetano; Lacitignola, Angelo; Sardelli, Paolo

    2013-08-01

    Solitary fibrous tumor (SFT) of the pleura and the lung is an uncommon spindle cell neoplasm arising from the visceral pleura in the majority of the cases. However there are some extrapleural sites including the lung. Current considerations were raised by a peculiar recent case: an 81-year-old female, no smoker, presented with undefined left thoracic pain. Radiographic findings of a large solid lung mass (10 cm × 9 cm). Computed tomography (CT) confirmed the thoracic mass showing characteristics of a well defined mass with capsule, the position of the mass in proximity of the postero-basal and lateral-basal wall. No secondary lesions were found. Through a left inferior lobectomy and ilo-mediastinal lymph node sampling, the entire mass was resected. Histopathological examination revealed a SFT. In conclusion STF is a rare lesion and this case showed a peculiar extremely large lesion never described before in literature. PMID:23991334

  7. Fibrous lung tumor: a peculiar case.

    PubMed

    Barrettara, Barbara; Napoli, Gaetano; Lacitignola, Angelo; Sardelli, Paolo

    2013-08-01

    Solitary fibrous tumor (SFT) of the pleura and the lung is an uncommon spindle cell neoplasm arising from the visceral pleura in the majority of the cases. However there are some extrapleural sites including the lung. Current considerations were raised by a peculiar recent case: an 81-year-old female, no smoker, presented with undefined left thoracic pain. Radiographic findings of a large solid lung mass (10 cm × 9 cm). Computed tomography (CT) confirmed the thoracic mass showing characteristics of a well defined mass with capsule, the position of the mass in proximity of the postero-basal and lateral-basal wall. No secondary lesions were found. Through a left inferior lobectomy and ilo-mediastinal lymph node sampling, the entire mass was resected. Histopathological examination revealed a SFT. In conclusion STF is a rare lesion and this case showed a peculiar extremely large lesion never described before in literature.

  8. Enhancement of lung tumor formation in mice

    SciTech Connect

    Witschi, H.P.

    1984-01-01

    There is now a great deal of data available to show that butylated hydroxytoluene (BHT) enhances the development of lung tumors in mice. In many ways BHT functions like a promoting agent. Interestingly, it also has tumor enhancing or promoting properties in organs other than mouse lung such as rat liver, rat bladder, possibly rat GI tract and in in vitro systems. The development of lung tumors by BHT may be influenced by comparatively low exposure regimens; the minimum dose found so far to be effective are 6 intraperitoneal injections of 50 mg/kg or a diet containing 500 ppM of BHT for 2 weeks. While these findings seem to require that the continued use of BHT as a food additive needs to be reevaluated it should be mentioned that other considerations have lead to the conclusion that BHT probably has a large margin of safety. This makes it important to establish the mechanism of action of BHT which remains unknown. 41 references, 1 figure, 3 tables.

  9. Once-Weekly, High-Dose Stereotactic Body Radiotherapy for Lung Cancer: 6-Year Analysis of 60 Early-Stage, 42 Locally Advanced, and 7 Metastatic Lung Cancers

    SciTech Connect

    Salazar, Omar M. Sandhu, Taljit S.; Lattin, Paul B.; Chang, Jung H.; Lee, Choon K.; Groshko, Gayle A.; Lattin, Cheryl J.

    2008-11-01

    Purpose: To explore once-weekly stereotactic body radiotherapy (SBRT) in nonoperable patients with localized, locally advanced, or metastatic lung cancer. Methods and Materials: A total of 102 primary (89 untreated plus 13 recurrent) and 7 metastatic tumors were studied. The median follow-up was 38 months, the average patient age was 75 years. Of the 109 tumors studied, 60 were Stage I (45 IA and 15 IB), 9 were Stage II, 30 were Stage III, 3 were Stage IV, and 7 were metastases. SBRT only was given in 73% (40 Gy in four fractions to the planning target volume to a total dose of 53 Gy to the isocenter for a biologically effective dose of 120 Gy{sub 10}). SBRT was given as a boost in 27% (22.5 Gy in three fractions once weekly for a dose of 32 Gy at the isocenter) after 45 Gy in 25 fractions to the primary plus the mediastinum. The total biologically effective dose was 120 Gy{sub 10}. Respiration gating was used in 46%. Results: The overall response rate was 75%; 33% had a complete response. The overall response rate was 89% for Stage IA patients (40% had a complete response). The local control rate was 82%; it was 100% and 93% for Stage IA and IB patients, respectively. The failure rate was 37%, with 17% within the planning target volume. No Grade 3-4 acute toxicities developed in any patient; 12% and 7% of patients developed Grade 1 and 2 toxicities, respectively. Late toxicity, all Grade 2, developed in 3% of patients. The 5-year cause-specific survival rate for Stage I was 70% and was 74% and 64% for Stage IA and IB patients, respectively. The 3-year Stage III cause-specific survival rate was 30%. The patients with metastatic lung cancer had a 57% response rate, a 27% complete response rate, an 86% local control rate, a median survival time of 19 months, and 23% 3-year survival rate. Conclusions: SBRT is noninvasive, convenient, fast, and economically attractive; it achieves results similar to surgery for early or metastatic lung cancer patients who are older

  10. Veliparib, Capecitabine, and Temozolomide in Patients With Advanced, Metastatic, and Recurrent Neuroendocrine Tumor

    ClinicalTrials.gov

    2016-07-10

    Functional Pancreatic Neuroendocrine Tumor; Malignant Somatostatinoma; Merkel Cell Carcinoma; Metastatic Adrenal Gland Pheochromocytoma; Metastatic Carcinoid Tumor; Multiple Endocrine Neoplasia Type 1; Multiple Endocrine Neoplasia Type 2A; Multiple Endocrine Neoplasia Type 2B; Neuroendocrine Neoplasm; Non-Functional Pancreatic Neuroendocrine Tumor; Pancreatic Glucagonoma; Pancreatic Insulinoma; Recurrent Adrenal Cortex Carcinoma; Recurrent Adrenal Gland Pheochromocytoma; Recurrent Merkel Cell Carcinoma; Somatostatin-Producing Neuroendocrine Tumor; Stage III Adrenal Cortex Carcinoma; Stage III Thyroid Gland Medullary Carcinoma; Stage IIIA Merkel Cell Carcinoma; Stage IIIB Merkel Cell Carcinoma; Stage IV Adrenal Cortex Carcinoma; Stage IV Merkel Cell Carcinoma; Stage IVA Thyroid Gland Medullary Carcinoma; Stage IVB Thyroid Gland Medullary Carcinoma; Stage IVC Thyroid Gland Medullary Carcinoma; Thymic Carcinoid Tumor; VIP-Producing Neuroendocrine Tumor; Well Differentiated Adrenal Cortex Carcinoma; Zollinger Ellison Syndrome

  11. Synergistic anti-tumor effects of zoledronic acid and radiotherapy against metastatic hepatocellular carcinoma.

    PubMed

    Morii, Kazuhiko; Aoyama, Yuhki; Nakamura, Shinichiro; Okushin, Hiroaki

    2015-01-01

    A 72-year-old man with advanced hepatocellular carcinoma and decompensated hepatitis C virus-related cirrhosis suffered from a metastatic femoral fracture. After undergoing radiotherapy, he was only treated with supportive care, except for the administration of zoledronic acid (ZA). Thereafter, the initially elevated serum α-fetoprotein and des-gamma carboxyprothrombin levels declined to within the normal ranges. Hepatic and metastatic adrenal tumors, distant from the radiation field, exhibited a surprising regression. ZA is known to inhibit the activity of osteoclasts, bone-residential macrophages, and has been reported to have a direct anti-tumor effect. ZA may adjust the immunological milieu in tumor microenvironments by inhibiting the tumor-associated macrophages. Because radiotherapy can enhance the presentation of tumor-associated antigens, ZA and radiotherapy may exert synergistic anti-tumor effects. PMID:26466697

  12. KRAS Mutations in Primary Colorectal Cancer Tumors and Related Metastases: A Potential Role in Prediction of Lung Metastasis

    PubMed Central

    Cejas, Paloma; López-Gómez, Miriam; Aguayo, Cristina; Madero, Rosario; de Castro Carpeño, Javier; Belda-Iniesta, Cristóbal; Barriuso, Jorge; Moreno García, Víctor; Larrauri, Javier; López, Rocío; Casado, Enrique; Gonzalez-Barón, Manuel; Feliu, Jaime

    2009-01-01

    Background KRAS mutations in colorectal cancer primary tumors predict resistance to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody therapy in patients with metastatic colorectal cancer, and thus represent a true indicator of EGFR pathway activation status. Methodology/Principal Findings KRAS mutations were retrospectively studied using polymerase chain reactions and subsequent sequencing of codons 12 and 13 (exon 2) in 110 patients with metastatic colorectal tumors. These studies were performed using tissue samples from both the primary tumor and their related metastases (93 liver, 84%; 17 lung, 16%). All patients received adjuvant 5-Fluorouracil-based polychemotherapy after resection of metastases. None received anti-EGFR therapy. Mutations in KRAS were observed in 37 (34%) of primary tumors and in 40 (36%) of related metastases, yielding a 94% level of concordance (kappa index 0.86). Patients with primary tumors possessing KRAS mutations had a shorter disease-free survival period after metastasis resection (12.0 vs 18.0 months; P = 0.035) than those who did not. A higher percentage of KRAS mutations was detected in primary tumors of patiens with lung metastases than in patients with liver metastases (59% vs 32%; p = 0.054). To further evaluate this finding we analyzed 120 additional patients with unresectable metastatic colorectal cancer who previously had their primary tumors evaluated for KRAS mutational status for clinical purposes. Separately, the analysis of these 120 patients showed a tendency towards a higher degree of KRAS mutations in primary tumors of patients with lung metastases, although it did not reach statistical significance. Taken together the group of 230 patients showed that KRAS was mutated significantly more often in the primary tumors of patients with lung metastases (57% vs 35%; P = 0.006). Conclusions/Significance Our results suggest a role for KRAS mutations in the propensity of primary colorectal tumors to

  13. Pulmonary Codelivery of Doxorubicin and siRNA by pH-Sensitive Nanoparticles for Therapy of Metastatic Lung Cancer.

    PubMed

    Xu, Caina; Wang, Ping; Zhang, Jingpeng; Tian, Huayu; Park, Kinam; Chen, Xuesi

    2015-09-01

    A pulmonary codelivery system that can simultaneously deliver doxorubicin (DOX) and Bcl2 siRNA to the lungs provides a promising local treatment strategy for lung cancers. In this study, DOX is conjugated onto polyethylenimine (PEI) by using cis-aconitic anhydride (CA, a pH-sensitive linker) to obtain PEI-CA-DOX conjugates. The PEI-CA-DOX/siRNA complex nanoparticles are formed spontaneously via electrostatic interaction between cationic PEI-CA-DOX and anionic siRNA. The drug release experiment shows that DOX releases faster at acidic pH than at pH 7.4. Moreover, PEI-CA-DOX/Bcl2 siRNA complex nanoparticles show higher cytotoxicity and apoptosis induction in B16F10 cells than those treated with either DOX or Bcl2 siRNA alone. When the codelivery systems are directly sprayed into the lungs of B16F10 melanoma-bearing mice, the PEI-CA-DOX/Bcl2 siRNA complex nanoparticles exhibit enhanced antitumor efficacy compared with the single delivery of DOX or Bcl2 siRNA. Compared with systemic delivery, most drug and siRNA show a long-term retention in the lungs via pulmonary delivery, and a considerable number of the drug and siRNA accumulate in tumor tissues of lungs, but rarely in normal lung tissues. The PEI-CA-DOX/Bcl2 siRNA complex nanoparticles are promising for the treatment of metastatic lung cancer by pulmonary delivery with low side effects on the normal tissues.

  14. Identification of Molecular Determinants of Primary and Metastatic Tumor Re-Initiation in Breast Cancer

    PubMed Central

    Ross, Jason B.; Huh, Doowon; Noble, Lisa B.; Tavazoie, Sohail F.

    2015-01-01

    Through in vivo selection of multiple ER-negative human breast cancer populations for enhanced tumor-forming capacity, we have derived sub-populations that generate tumors more efficiently than their parental populations at low cell numbers. Tumorigenic-enriched (TE) sub-populations displayed increased expression of LAMA4, FOXQ1 and NAP1L3—genes that are also expressed at greater levels by independently derived metastatic sub-populations. These genes promote metastatic efficiency. FOXQ1 promotes LAMA4 expression, while LAMA4 enhances clonal expansion upon substratum-detachment in vitro, tumor re-initiation in multiple organs, and disseminated metastatic cell proliferation and colonization. LAMA4’s promotion of cancer cell proliferation and tumor re-initiation requires β1-integrin. Increased LAMA4 expression marks the transition of human pre-malignant breast lesions to malignant carcinomas, while tumoral LAMA4 over-expression predicts reduced relapse-free survival in ER-negative patients. Our findings reveal common features that govern primary and metastatic tumor re-initiation and identify a key molecular determinant of these processes. PMID:25866923

  15. pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen.

    PubMed

    Matsumoto, Yasuyuki; Zhang, Qing; Akita, Kaoru; Nakada, Hiroshi; Hamamura, Kazunori; Tokuda, Noriyo; Tsuchida, Akiko; Matsubara, Takeshi; Hori, Tomoko; Okajima, Tetsuya; Furukawa, Keiko; Urano, Takeshi; Furukawa, Koichi

    2012-03-01

    In order to analyze the mechanisms for cancer metastasis, high metastatic sublines (H7-A, H7-Lu, H7-O, C4-sc, and C4-ly) were obtained by repeated injection of mouse Lewis lung cancer sublines H7 and C4 into C57BL/6 mice. These sublines exhibited increased proliferation and invasion activity in vitro. Ganglioside profiles exhibited lower expression of GM1 in high metastatic sublines than the parent lines. Then, we established GM1-Si-1 and GM1-Si-2 by stable silencing of GM1 synthase in H7 cells. These GM1-knockdown clones exhibited increased proliferation and invasion. Then, we explored genes that markedly altered in the expression levels by DNA microarray in the combination of C4 vs. C4-ly or H7 vs. H7 (GM1-Si). Consequently, pp-GalNAc-T13 gene was identified as up-regulated genes in the high metastatic sublines. Stable transfection of pp-GalNAc-T13 cDNA into C4 (T13-TF) resulted in increased invasion and motility. Then, immunoblotting and flow cytometry using various antibodies and lectins were performed. Only anti-trimeric Tn antibody (mAb MLS128), showed increased expression levels of trimeric Tn antigen in T13-TF clones. Moreover, immunoprecipitation/immunoblotting was performed by mAb MLS128, leading to the identification of an 80 kDa band carrying trimeric Tn antigen, i.e. Syndecan-1. Stable silencing of endogenous pp-GalNAc-T13 in C4-sc (T13-KD) revealed that primary tumors generated by subcutaneous injection of T13-KD clones showed lower coalescence to fascia and peritoneum, and significantly reduced lung metastasis than control clones. These data suggested that high expression of pp-GalNAc-T13 gene generated trimeric Tn antigen on Syndecan-1, leading to the enhanced metastasis.

  16. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

    PubMed

    Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

    2016-08-27

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

  17. Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

    PubMed

    Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

    2016-01-01

    Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis. PMID:27618887

  18. Macrophage depletion reduces postsurgical tumor recurrence and metastatic growth in a spontaneous murine model of melanoma

    PubMed Central

    Tham, Muly; Khoo, Karen; Yeo, Kim Pin; Kato, Masashi; Prevost-Blondel, Amelle; Angeli, Veronique; Abastado, Jean-Pierre

    2015-01-01

    Surgical resection of tumors is often followed by regrowth at the primary site and metastases may emerge rapidly following removal of the primary tumor. Macrophages are important drivers of tumor growth, and here we investigated their involvement in postoperative relapse as well as explore macrophage depletion as an adjuvant to surgical resection. RETAAD mice develop spontaneous metastatic melanoma that begins in the eye. Removal of the eyes as early as 1 week of age did not prevent the development of metastases; rather, surgery led to increased proliferation of tumor cells locally and in distant metastases. Surgery-induced increase in tumor cell proliferation correlated with increased macrophage density within the tumor. Moreover, macrophages stimulate tumor sphere formation from tumor cells of post-surgical but not control mice. Macrophage depletion with a diet containing the CSF-1R specific kinase inhibitor Ki20227 following surgery significantly reduced postoperative tumor recurrence and abrogated enhanced metastatic outgrowth. Our results confirm that tumor cells disseminate early, and show that macrophages contribute both to post-surgical tumor relapse and growth of metastases, likely through stimulating a population of tumor-initiating cells. Thus macrophage depletion warrants exploration as an adjuvant to surgical resection. PMID:25762633

  19. Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing.

    PubMed

    Boursault, Lucile; Haddad, Véronique; Vergier, Béatrice; Cappellen, David; Verdon, Severine; Bellocq, Jean-Pierre; Jouary, Thomas; Merlio, Jean-Philippe

    2013-01-01

    BRAF inhibitors have demonstrated improvement of overall survival in patients with metastatic melanoma and BRAF(V600) mutations. In order to evaluate BRAF tumor heterogeneity between primary and metastatic site, we have evaluated the performance of immunohistochemistry (IHC) with an anti-BRAF(V600E) antibody in both localization by comparison with high resolution melting analysis followed by Sanger sequencing in a parallel blinded study. A total of 230 samples distributed as primary melanoma (n = 88) and different types of metastatic samples (n = 142) were studied in 99 patients with advanced or metastatic melanoma (stage III or IV). The prevalence of each BRAF mutation was c.1799T>A, BRAF(V600E) (45.2%), c.1799_1800TG>AA, BRAF(V600E2) (3.0%), c.1798_1799GT>AA, BRAF(V600K) (3.0%), c.1801 A>G, BRAF(K601E) (1.3%), c.1789_1790CT>TC, BRAF(L597S) (0.4%), c.1780G>A, BRAF(D594N) (0.9%) respectively. IHC was positive in 109/112 samples harboring BRAF(V600E/E2) mutations and negative in other cases. The cytoplasmic staining was either strongly positive in tumor cells of BRAF(V600E) mutated cases. It appeared strong brown, different from the vesicular grey cytoplasmic pigmentation of melanophages. Concordance between the two techniques was 96.4%. Sensitivity of IHC for detecting the BRAF(V600E/E2) mutations was 97.3%, while specificity was 100%. Both our IHC and molecular study demonstrated homogeneity between primary and metastatic sites for BRAF status in melanoma. This study also provides evidence that IHC may be a cost-effective first-line method for BRAF(V600E) detection. Thereafter, molecular techniques should be used in negative, ambiguous or non-contributive cases.

  20. Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis.

    PubMed

    Vermeer, Daniel W; Coppock, Joseph D; Zeng, Erliang; Lee, Kimberly M; Spanos, William C; Onken, Michael D; Uppaluri, Ravindra; Lee, John H; Vermeer, Paola D

    2016-04-26

    Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60-80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis. PMID:27013584

  1. Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

    PubMed Central

    Vermeer, Daniel W.; Coppock, Joseph D.; Zeng, Erliang; Lee, Kimberly M.; Spanos, William C.; Onken, Michael D.; Uppaluri, Ravindra; Lee, John H.; Vermeer, Paola D.

    2016-01-01

    Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis. PMID:27013584

  2. 'Inflammatory breast cancer' due to metastatic adenocarcinoma of lung.

    PubMed

    Ninan, Jacob; Naik, Vinay; George, Gemy Maria

    2016-01-01

    A 67-year-old woman with a history of lung adenocarcinoma presented with 3 weeks of redness, pain, swelling and skin changes in her right breast. Her vital signs and physical examination were within physiological limits except for the right breast. She had extensive red streaks radiating from the right nipple with peau d'orange appearance of her overlying skin. Her breast was tender on examination and did not have any associated cervical or axillary lymphadenopathy. Her mammography revealed thickening of the skin, increased parenchymal markings and shrinkage the breast. Multiple skin biopsies demonstrated moderately differentiated lung adenocarcinoma with lymphovascular invasion. The patient made an informed decision to undergo radiotherapy following discussion with her oncologist and breast surgeon. She succumbed to her illness 2 months after the diagnosis of metastasis to her breast. PMID:27587745

  3. Gene expression patterns associated with the metastatic phenotype in rodent and human tumors.

    PubMed

    Nestl, A; Von Stein, O D; Zatloukal, K; Thies, W G; Herrlich, P; Hofmann, M; Sleeman, J P

    2001-02-15

    Using subtractive technology, we have generated metastasis-associated gene expression profiles for rat mammary and pancreatic adenocarcinomas. Several genes whose expression is thought to be related to tumor progression such as c-Met, urokinase-type plasminogen activator receptor, ezrin, HMG-1, oncomodulin, cathepsin, and caveolin were thereby isolated. Half of the metastasis-associated clones showed no significant homology to genes with known function. Notably, several of the metastasis-associated clones were also expressed in metastatic lines but not in nonmetastatic lines of other tumor models. Furthermore, in situ hybridization using selected clones documents the relevance of these results for human cancer because strong expression in tumor cells including metastases was detected in human colorectal cancer samples and, to a lesser extent, in mammary cancer samples. These data support the concept that tumors express a "metastatic program" of genes. PMID:11245467

  4. High lung-metastatic variant of human osteosarcoma cells, selected by passage of lung metastasis in nude mice, is associated with increased expression of α(v)β(3) integrin.

    PubMed

    Tome, Yasunori; Kimura, Hiroaki; Maehara, Hiroki; Sugimoto, Naotoshi; Bouvet, Michael; Tsuchiya, Hiroyuki; Kanaya, Fuminori; Hoffman, Robert M

    2013-09-01

    Altered expression of αvβ3 integrin is associated with tumor progression and metastasis in several types of cancer, including metastatic osteosarcoma. In this study, we demonstrate that in vivo passaging of lung metastasis in nude mice can generate an aggressive variant of human osteosarcoma cells. Experimental metastases were established by injecting 143B human osteosarcoma cells, expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm, in the tail vein of nude mice. Lung metastases were harvested under fluorescence microscopy from nude mice to establish cell lines which were then injected via the tail vein of additional nude mice. This procedure was repeated for four passages in order to isolate highly metastatic variant sublines. When the parental and metastatic variants were transplanted orthotopically into the tibia of nude mice, the 143B-LM4 variant had the highest metastatic rate, approximately 18-fold higher than the parent (p<0.01). αvβ3 integrin expression was increased approximately 5.6-fold in 143B-LM4 compared to parental cells (p<0.05). Thus, serial passage of lung metastases created a highly metastatic variant of human osteosarcoma cells which had increased expression of αvβ3 integrin, suggesting that αvβ3 integrin plays an essential role in osteosarcoma metastasis. With this highly metastatic variant overexpressing αvβ3 integrin, it will now be possible to further investigate the mechanism by which αvβ3 integrin facilitates metastasis.

  5. A metastatic glomus jugulare tumor. A temporal bone report

    SciTech Connect

    El Fiky, F.M.; Paparella, M.M.

    1984-01-01

    The clinicopathologic findings in the temporal bone of a patient with a highly malignant metastasizing glomus jugulare tumor are reported. The patient exhibited all the symptoms of primary malignant tumors of the ear, including facial paralysis, otorrhea, pain, hearing loss, tinnitus, dizziness, and vertigo. He was treated with cobalt irradiation followed by radium implant in the ear canal for a residual tumor; then a left-sided radical mastoidectomy was performed.

  6. Polymethylmethacrylate-augmented screw fixation for stabilization in metastatic spinal tumors. Technical note.

    PubMed

    Jang, Jee Soo; Lee, Sang Ho; Rhee, Chang Hun; Lee, Seung Hoon

    2002-01-01

    Screw fixation augmented with polymethylmethacrylate (PMMA) or some other biocompatible bone cement has been used in patients with osteoporosis requiring spinal fusion. No clinical studies have been conducted on PMMA-augmented screw fixation for stabilization of the vertebral column in patients with metastatic spinal tumors. The purpose of this study was to determine whether screw fixation augmented with PMMA might be suitable in patients treated for multilevel metastatic spinal tumors. Ten patients with metastatic spinal tumors involving multiple vertebral levels underwent stabilization procedures in which PMMA was used to augment screw fixation after decompression of the spinal cord. Within 15 days, partial or complete relief from pain was obtained in all patients postoperatively. Two of four patients in whom neurological deficits caused them to be nonambulatory before surgery were able to ambulate postoperatively. Neither collapse of the injected vertebral bodies nor failure of the screw fixation was observed during the mean follow-up period of 6.7 months. Screw fixation augmented with PMMA may offer stronger stabilization and facilitate the instrumentation across short segments in the treatment of multilevel metastatic spinal tumors. PMID:11795702

  7. A rare cause in etiology of left atrial mass: metastatic testicular germ cell tumor

    PubMed Central

    Huseyin, Serhat; Okyay, Ahmet; Hacıbekiroğlu, İlhan; Tastekin, Ebru; Yılmaztepe, Mustafa; Taylan, Gökay; Canbaz, Suat; Çiçin, İrfan

    2016-01-01

    Although intracardiac metastasis of germ cell tumors is rare, it can be localized in the right or left heart by disseminating spread and give their cardiac symptoms depending on the location of metastatic mass. We present a 38-year-old male patient with a preliminary diagnosis of testicular tumor who was followed by the medical oncology clinic with cerebrovascular event and heart failure symptoms. PMID:27212979

  8. Visualization of immediate immune responses to pioneer metastatic cells in the lung

    PubMed Central

    Headley, Mark B.; Bins, Adriaan; Nip, Alyssa; Roberts, Edward W.; Looney, Mark R.; Gerard, Audrey; Krummel, Matthew F.

    2016-01-01

    Lung metastasis is the lethal determinant in many cancers1,2 and a number of lines of evidence point to monocytes and macrophages having key roles in its development3–5. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice6 for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed ‘waves’ of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells3. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer antimetastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding. PMID:26982733

  9. Total enbloc spondylectomy for metastatic high grade spinal tumors: Early results

    PubMed Central

    Patil, Sanganagouda S; Nene, Abhay M

    2016-01-01

    Background: High grade metastatic spinal tumors are most common and are invasive. These patients can succumb to disease progression if not treated timely. Although considered as invasive and morbid, total enbloc spondylectomy (TES) in selected cases has better survival rates. The authors describe the results of TES for high grade metastatic spinal tumors. Materials and Methods: Five patients (four females and one male) underwent TES for solitary metastatic vertebral lesion between November 2012 and January 2014. These patients presented to us with spinal instability, unrelenting severe spinal pain and/or with severe progressive radiculopathy. Average age was 46.2 years (range 39–62 years). After complete investigations, computed tomography scan, magnetic resonance imaging scan and positron emission tomography (PET) scan, it was confirmed that these patients had high grade solitary vertebral metastatic tumor. Results: Average duration of followup was 18 months (range 16–20 months). The average preoperative visual analog scale score of 9.4 (range 9–10) improved to 2 (range 1–4) at last followup. Average blood loss was 1440 mL (range 1000–2000 mL). Average duration of surgery was 198 min (range 180–240 min). Significant pain relief was noticed in each patient in the immediate postoperative period and during followups. These patients attained complete functional activities of daily living with in a month. The imaging showed implants in situ, no recurrence of tumor, and no activity on PET scan at the final followup. Conclusion: The present series shows favorable short term results of TES for solitary, metastatic, high grade vertebral body tumors by a team approach. PMID:27512215

  10. Effect of bevacizumab combined with boron neutron capture therapy on local tumor response and lung metastasis

    PubMed Central

    MASUNAGA, SHIN-ICHIRO; SAKURAI, YOSHINORI; TANO, KEIZO; TANAKA, HIROKI; SUZUKI, MINORU; KONDO, NATSUKO; NARABAYASHI, MASARU; WATANABE, TSUBASA; NAKAGAWA, YOSUKE; MARUHASHI, AKIRA; ONO, KOJI

    2014-01-01

    The aim of the present study was to evaluate the effect of bevacizumab on local tumor response and lung metastatic potential during boron neutron capture therapy (BNCT) and in particular, the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously administered bromodeoxyuridine (BrdU) to label all proliferating (P) tumor cells. The tumors were irradiated with thermal neutron beams following the administration of a 10B-carrier [L-para-boronophenylalanine-10B (BPA) or sodium mercaptoundecahydrododecaborate-10B (BSH)], with or without the administration of bevacizumab. This was further combined with an acute hypoxia-releasing agent (nicotinamide) or mild temperature hyperthermia (MTH, 40°C for 60 min). Immediately following the irradiation, cells from certain tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q cells and the total (P+Q) cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days following irradiation, lung metastases were enumerated. Three days following bevacizumab administration, the sensitivity of the total tumor cell population following BPA-BNCT had increased more than that following BSH-BNCT. The combination with MTH, but not with nicotinamide, further enhanced total tumor cell population sensitivity. Regardless of the presence of a 10B-carrier, MTH enhanced the sensitivity of the Q cell population. Regardless of irradiation, the administration of bevacizumab, as well as nicotinamide treatment, demonstrated certain potential in reducing the number of lung metastases especially in BPA-BNCT compared with BSH-BNCT. Thus, the current study revealed that BNCT combined with bevacizumab has the potential to sensitize total tumor cells and cause a reduction in the number of lung metastases to a similar level as nicotinamide. PMID:24944637

  11. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs.

    PubMed

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D

    2015-05-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies.

  12. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs

    PubMed Central

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D.

    2015-01-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies. PMID:26266007

  13. Large Malignant Phyllodes Tumor of the Breast with Metastases to the Lungs.

    PubMed

    Augustyn, Alexander; Sahoo, Sunati; Wooldridge, Rachel D

    2015-05-01

    Phyllodes tumors of the breast account for less than 0.5% of breast cancers and present most commonly in women 45 to 49 years old. The importance in managing fibroepithelial lesions lies in distinguishing fibroadenomas, which are benign, from phyllodes tumors, which can be malignant and require complete surgical excision. We report the case of a 56-year-old female who presented with a rapidly enlarging mass in her right breast 18 cm in maximum dimension that completely effaced the breast and distorted the nipple. The patient underwent a successful total mastectomy after core biopsy revealed a diagnosis of phyllodes tumor. Surgical resection is the primary treatment modality; neoadjuvant and adjuvant therapies remain controversial. Here, we report the case of a large malignant phyllodes tumor metastatic to the lungs, review the literature, and discuss diagnostic modalities and adjunct nonsurgical therapies. PMID:26266007

  14. In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide.

    PubMed

    Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A; Luker, Kathryn E; Chen, Daiqin; Cauble, Meagan A; Banaszak Holl, Mark M; Luker, Gary D; Ross, Brian D; Liu, Zhuang; Hong, Hao

    2016-10-01

    Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers

  15. In vivo targeting of metastatic breast cancer via tumor vasculature-specific nano-graphene oxide.

    PubMed

    Yang, Dongzhi; Feng, Liangzhu; Dougherty, Casey A; Luker, Kathryn E; Chen, Daiqin; Cauble, Meagan A; Banaszak Holl, Mark M; Luker, Gary D; Ross, Brian D; Liu, Zhuang; Hong, Hao

    2016-10-01

    Angiogenesis, i.e. the formation of neovasculatures, is a critical process during cancer initiation, progression, and metastasis. Targeting of angiogenic markers on the tumor vasculature can result in more efficient delivery of nanomaterials into tumor since no extravasation is required. Herein we demonstrated efficient targeting of breast cancer metastasis in an experimental murine model with nano-graphene oxide (GO), which was conjugated to a monoclonal antibody (mAb) against follicle-stimulating hormone receptor (FSHR). FSHR has been confirmed to be a highly selective tumor vasculature marker, which is abundant in both primary and metastatic tumors. These functionalized GO nano-conjugates had diameters of ∼120 nm based on atomic force microscopy (AFM), TEM, and dynamic laser scattering (DLS) measurement. (64)Cu was incorporated as a radiolabel which enabled the visualization of these GO conjugates by positron emission tomography (PET) imaging. Breast cancer lung metastasis model was established by intravenous injection of click beetle green luciferase-transfected MDA-MB-231 (denoted as cbgLuc-MDA-MB-231) breast cancer cells into female nude mice and the tumor growth was monitored by bioluminescence imaging (BLI). Systematic in vitro and in vivo studies have been performed to investigate the stability, targeting efficacy and specificity, and tissue distribution of GO conjugates. Flow cytometry and fluorescence microscopy examination confirmed the targeting specificity of FSHR-mAb attached GO conjugates against cellular FSHR. More potent and persistent uptake of (64)Cu-NOTA-GO-FSHR-mAb in cbgLuc-MDA-MB-231 nodules inside the lung was witnessed when compared with that of non-targeted GO conjugates ((64)Cu-NOTA-GO). Histology evaluation also confirmed the vasculature accumulation of GO-FSHR-mAb conjugates in tumor at early time points while they were non-specifically captured in liver and spleen. In addition, these GO conjugates can serve as good drug carriers

  16. Anti-metastatic effects of antrodan, the Antrodia cinnamomea mycelia glycoprotein, in lung carcinoma cells.

    PubMed

    Fa, Kuan-Ning; Yang, Chih-Min; Chen, Pei-Chun; Lee, Yin-Ying; Chyau, Charng-Cherng; Hu, Miao-Lin

    2015-03-01

    This study investigated the anti-metastatic effects of antrodan, the glycoprotein from Antrodia cinnamomea (AC) mycelia, through direct actions and indirect immunomodulatory effects in Lewis lung carcinoma (LLC). Antrodan was isolated from AC mycelia by alkali extraction, acid precipitation, and purification using sepharose CL-6B column chromatography. In the direct anti-metastatic action, antrodan (30-70 μg/mL) was found to significantly inhibit invasion and migration of LLC cells, and these effects involved up-regulation of tissue inhibitor of matrix metalloproteinase (TIMP)-1, TIMP-2, and nm23-H1 protein expression leading to decreased activities and protein expression of MMP-2 and MMP-9. For testing the indirect immunomodulatory effect, antrodan was incubated for 3d with mononuclear cells (MNCs) isolated from human peripheral blood to obtain the condition medium (CM). Antrodan significantly increased interleukin (IL)-12 and IL-1β levels, but decreased TNF-α, IL-6 and IL-8 levels in the MMC-CM, which also significantly inhibited invasion, migration, and the activities and protein expression of MMP-2 and MMP-9, but significantly increased protein expression of TIMP-1, TIMP-2, and nm23-H1 in LLC cells. The indirect immunomodulatory effect of antrodan was stronger than the direct anti-metastatic effect at the same concentrations (50 and 60 μg/mL). Overall, the results suggest the anti-metastatic potential of antrodan in LLC cells.

  17. Metastatic testicular tumor presenting as a scrotal hydrocele: An initial manifestation of pancreatic adenocarcinoma

    PubMed Central

    KIM, YEON WOOK; KIM, JIN WON; KIM, JEE-HYUN; LEE, JUNGSIL; LEE, EUIJAE; KIM, MOON YOUNG; YANG, HYUN KYUNG; CHANG, HYUN

    2014-01-01

    Metastatic pancreatic adenocarcinoma involving the testis is a rare condition with a poor prognosis. The current study describes the case of a 69-year-old male who presented with a painful swelling of the left scrotum. Scrotal ultrasonography revealed hydroceles in the scrotal sacs, with the left one being larger in size. The patient underwent left hydrocelectomy and was eventually diagnosed with metastatic adenocarcinoma. Abdominal computed tomography, which was performed to detect the primary cancer, showed a pancreatic tail carcinoma with liver and multiple lymph node metastases, and peritoneal carcinomatosis. The patient received gemcitabine-based chemotherapy but resulted in progressive disease. This case shows that in a patient in whom a primary testicular tumor is unusual due to their age, a testicular mass or hydrocele should be a suspect for possible metastatic disease. PMID:24932235

  18. Selective photothermal laser-tissue interaction with augmentation of immunoadjuvants in treatment of DMBA-4 metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-09-01

    Induced anti-tumor immunity can be the most effective and long-term cure for cancers, particularly for metastatic tumors. Laser immunotherapy has been developed to induce such immunological responses in rats bearing DMBA-4 metastatic mammary tumors. It involves an intratumoral administration of a laser-absorbing dye (indocyanine green) and a specially formulated immunoadjuvant (glycated chitosan), followed by an irradiation of a near-infrared laser (805-nm diode laser). To understand the immunity induced in this tumor model, immunization using freeze-thaw cell lysates against the DMBA-4 tumors was performed, followed by the tumor challenge twenty-one days later. Also performed is the surgical removal of the primary tumors of the rats before the observation of metastatic tumors. The immunization only delayed the emergence of the primary and metastases in the rats but did not provide immunity against the tumor challenge. After surgical removal of the primary tumors, the tumors re-emerged at the primary sites and the metastases developed at multiple remote sites. In contrast, laser immunotherapy cured rats experienced tumor regression and eradication. Our research has provided strong support for the working mechanism of laser immunotherapy. The experimental results showed that selective photothermal laser-tissue interaction with a complementary use of immunoadjuvant could be a potential therapy for treatment of metastatic tumors by inducing a tumor-specific, long-lasting immunity.

  19. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    NASA Astrophysics Data System (ADS)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  20. Molecular Testing for Treatment of Metastatic Non-Small Cell Lung Cancer: How to Implement Evidence-Based Recommendations

    PubMed Central

    Chioda, Marc D.; Herndon, Dana; Longshore, John W.; Mohamed, Mohamed; Ou, Sai-Hong Ignatius; Reynolds, Craig; Singh, Jaspal; Wistuba, Ignacio I.; Bunn, Paul A.; Hirsch, Fred R.

    2015-01-01

    The recent discovery of relevant biomarkers has reshaped our approach to therapy selection for patients with non-small cell lung cancer. The unprecedented outcomes demonstrated with tyrosine kinase inhibitors in molecularly defined cohorts of patients has underscored the importance of genetic profiling in this disease. Despite published guidelines on biomarker testing, successful tumor genotyping faces significant hurdles at both academic and community-based practices. Oncologists are now faced with interpreting large-scale genomic data from multiple tumor types, possibly making it difficult to stay current with practice standards in lung cancer. In addition, physicians’ lack of time, resources, and face-to-face opportunities can interfere with the multidisciplinary approach that is essential to delivery of care. Finally, several challenges exist in optimizing the amount and quality of tissue for molecular testing. Recognizing the importance of biomarker testing, a series of advisory boards were recently convened to address these hurdles and clarify best practices. We reviewed these challenges and established recommendations to help optimize tissue acquisition, processing, and testing within the framework of a multidisciplinary approach. Implications for Practice: Although several professional societies have incorporated biomarker testing recommendations into clinical practice guidelines for the diagnosis and management of non-small cell lung cancer (NSCLC), health care providers still face considerable challenges when establishing and implementing these standards. Developing and instituting protocols to ensure that all appropriate patients are tested for molecular biomarkers requires communication among the various specialists involved in the care of patients with NSCLC. This report provides insights into key challenges and recommendations for molecular testing of patients with metastatic NSCLC, summarized from a multidisciplinary team of experts spanning

  1. Dynamic modeling of lung tumor motion during respiration

    NASA Astrophysics Data System (ADS)

    Kyriakou, E.; McKenzie, D. R.

    2011-05-01

    A dynamic finite element model of the lung that incorporates a simplified geometry with realistic lung material properties has been developed. Observations of lung motion from respiratory-gated computed tomography were used to provide a database against which the predictions of the model are assessed. Data from six patients presenting with lung tumors were processed to give sagittal sections of the lung containing the tumor as a function of the breathing phase. Statistical shape modeling was used to outline the diaphragm, the tumor volume and the thoracic wall at each breathing phase. The motion of the tumor in the superior-inferior direction was plotted against the diaphragm displacement. The finite element model employed a simplified geometry in which the lung material fills a rectangular volume enabling two-dimensional coordinates to be used. The diaphragm is represented as a piston, driving the motion. Plots of lung displacement against diaphragm displacement form hysteresis loops that are a sensitive indicator of the characteristics of the motion. The key parameters of lung material that determine the motion are the density and elastic properties of lung material and the airway permeability. The model predictions of the hysteresis behavior agreed well with observation only when lung material is modeled as viscoelastic. The key material parameters are suggested for use as prognostic indicators of the progression of disease and of changes arising from the response of the lung to radiation treatment.

  2. Ablation techniques for primary and metastatic liver tumors

    PubMed Central

    Ryan, Michael J; Willatt, Jonathon; Majdalany, Bill S; Kielar, Ania Z; Chong, Suzanne; Ruma, Julie A; Pandya, Amit

    2016-01-01

    Ablative treatment methods have emerged as safe and effective therapies for patients with primary and secondary liver tumors who are not surgical candidates at the time of diagnosis. This article reviews the current literature and describes the techniques, complications and results for radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation. PMID:26839642

  3. Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

    SciTech Connect

    Kim, Yoo-Shin; Lee, Tae Hoon; O'Neill, Brian E.

    2015-08-14

    Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

  4. Human Lung Cancer Cells Grown on Acellular Rat Lung Matrix Create Perfusable Tumor Nodules

    PubMed Central

    Mishra, Dhruva K.; Thrall, Michael J.; Baird, Brandi N.; Ott, Harald C.; Blackmon, Shanda H.; Kurie, Jonathan M.; Kim, Min P.

    2015-01-01

    Background Extracellular matrix allows lung cancer to form its shape and grow. Recent studies on organ reengineering for orthotopic transplantation have provided a new avenue for isolating purified native matrix to use for growing cells. Whether human lung cancer cells grown in a decellularized rat lung matrix would create perfusable human lung cancer nodules was tested. Methods Rat lungs were harvested and native cells were removed using sodium dodecyl sulfate and Triton X-100 in a decellularization chamber to create a decellularized rat lung matrix. Human A549, H460, or H1299 lung cancer cells were placed into the decellularized rat lung matrix and grown in a customized bioreactor with perfusion of oxygenated media for 7 to 14 days. Results Decellularized rat lung matrix showed preservation of matrix architecture devoid of all rat cells. All three human lung cancer cell lines grown in the bioreactor developed tumor nodules with intact vasculature. Moreover, the lung cancer cells developed a pattern of growth similar to the original human lung cancer. Conclusions Overall, this study shows that human lung cancer cells form perfusable tumor nodules in a customized bioreactor on a decellularized rat lung matrix created by a customized decellularization chamber. The lung cancer cells grown in the matrix had features similar to the original human lung cancer. This ex vivo model can be used potentially to gain a deeper understanding of the biologic processes involved in human lung cancer. PMID:22385822

  5. Biomechanics of vertebral level, geometry, and transcortical tumors in the metastatic spine.

    PubMed

    Tschirhart, Craig E; Finkelstein, Joel A; Whyne, Cari M

    2007-01-01

    Metastatic involvement can disrupt the mechanical integrity of the spine, rendering vertebrae susceptible to burst fracture and neurologic damage. Fracture risk assessment for patients with spinal metastases is important in considering prophylactic treatment options. Stability of thoracic vertebrae affected by metastatic disease has been shown to be dependent on tumor size and bone density, but additional structural and geometric factors may also play a role in fracture risk assessment. The objective of this study was to use parametric finite element modeling to determine the effects of vertebral level, geometry, and metastatic compromise to the cortical shell on the risk of burst fracture in the thoracic spine. Analysis of vertebral level and geometry was assessed by investigation of seven scenarios ranging in geometry from T2-T4 to T10-T12. The effects of cortical shell compromised were assessed by comparison of four transcortical scenarios to a fully contained central vertebral body tumor scenario. Results demonstrated that upper thoracic vertebrae are at greater risk of burst fracture and that kyphotic motion segments are at decreased risk of burst fracture. Vertebrae with transcortical lesions are up to 30% less likely to lead to burst fracture initiation. The findings of this study are important for improving the understanding of burst fracture mechanics in metastatically involved vertebrae and guiding future modeling efforts.

  6. Imaging characteristic analysis of metastatic spine lesions from breast, prostate, lung, and renal cell carcinomas for surgical planning: Osteolytic versus osteoblastic

    PubMed Central

    Reddington, Justin A.; Mendez, Gustavo A.; Ching, Alex; Kubicky, Charlotte Dai; Klimo, Paul; Ragel, Brian T.

    2016-01-01

    Background: Surgeons treating metastatic spine disease can use computed tomography (CT) imaging to determine whether lesions are osteolytic, osteoblastic, or mixed. This enables treatment that considers the structural integrity of the vertebral body (VB), which is impaired with lytic lesions but not blastic lesions. The authors analyzed CT imaging characteristics of spine metastasis from breast, lung, prostate, and renal cell carcinomas (RCCs) to determine the metastasis patterns of each of these common tumors. Methods: The authors identified patients with metastatic spine disease treated during a 3-year period. Variables studied included age, sex, and cancer type. Lesions from breast, lung, prostate, and RCC primary lesions were selected for imaging analysis. Results: Sixty-six patients were identified: 17 had breast metastasis, 14 prostate, 18 lung, and 17 RCC. Breast cancer metastasis involved 33% of VBs with 56%, 20%, and 24% osteolytic, osteoblastic, and mixed, respectively. Prostate cancer metastasis involved 35% of VBs with 14%, 62%, and 24% osteolytic, osteoblastic, and mixed, respectively. Lung cancer metastasis involved 13% of VBs with 64%, 33%, and 3% osteolytic, osteoblastic, and mixed, respectively. RCC metastasis involved 11% of VBs with 91%, 7%, and 2% osteolytic, osteoblastic, and mixed lesions, respectively. Conclusions: To improve surgical planning, we advocate the use of CT prior to surgery to evaluate whether spine metastases are osteolytic or osteoblastic. In cases of osteolytic lesions, the concern is of segmental instability requiring reconstruction and the risk for screw pull out should instrumentation be considered. In cases of osteoblastic lesions, surgeons should consider debulking dense bone. PMID:27274410

  7. Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors.

    PubMed

    van Rijt, Sabine H; Bölükbas, Deniz A; Argyo, Christian; Datz, Stefan; Lindner, Michael; Eickelberg, Oliver; Königshoff, Melanie; Bein, Thomas; Meiners, Silke

    2015-03-24

    Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors.

  8. Protease-mediated release of chemotherapeutics from mesoporous silica nanoparticles to ex vivo human and mouse lung tumors.

    PubMed

    van Rijt, Sabine H; Bölükbas, Deniz A; Argyo, Christian; Datz, Stefan; Lindner, Michael; Eickelberg, Oliver; Königshoff, Melanie; Bein, Thomas; Meiners, Silke

    2015-03-24

    Nanoparticles allow for controlled and targeted drug delivery to diseased tissues and therefore bypass systemic side effects. Spatiotemporal control of drug release can be achieved by nanocarriers that respond to elevated levels of disease-specific enzymes. For example, matrix metalloproteinase 9 (MMP9) is overexpressed in tumors, is known to enhance the metastatic potency of malignant cells, and has been associated with poor prognosis of lung cancer. Here, we report the synthesis of mesoporous silica nanoparticles (MSNs) tightly capped by avidin molecules via MMP9 sequence-specific linkers to allow for site-selective drug delivery in high-expressing MMP9 tumor areas. We provide proof-of-concept evidence for successful MMP9-triggered drug release from MSNs in human tumor cells and in mouse and human lung tumors using the novel technology of ex vivo 3D lung tissue cultures. This technique allows for translational testing of drug delivery strategies in diseased mouse and human tissue. Using this method we show MMP9-mediated release of cisplatin, which induced apoptotic cell death only in lung tumor regions of Kras mutant mice, without causing toxicity in tumor-free areas or in healthy mice. The MMP9-responsive nanoparticles also allowed for effective combinatorial drug delivery of cisplatin and proteasome inhibitor bortezomib, which had a synergistic effect on the (therapeutic) efficiency. Importantly, we demonstrate the feasibility of MMP9-controlled drug release in human lung tumors. PMID:25703655

  9. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  10. Non-Prostate-Specific Membrane Antigen-Avid Metastatic Lung Nodule From Primary Prostatic Adenocarcinoma.

    PubMed

    Shetty, Deepa; Loh, Han; Bui, Chuong; Mansberg, Robert; Hadjashrafi, Amirazin; Do, Viet

    2016-10-01

    Ga-prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate recurrent prostatic malignancy due to its high specificity. A 56-year-old man with previous history of treated prostate cancer 4 years earlier presented with rising prostate-specific antigen level and underwent Ga-PSMA PET/CT, which demonstrated an enlarging pulmonary nodule without PSMA avidity. The pulmonary nodule, however, showed moderate uptake on a corresponding FDG PET/CT study, suspicious of primary lung malignancy. Cytological and histopathological examination of the pulmonary nodule confirmed a metastatic deposit from ductal prostatic adenocarcinoma, an uncommon variant of prostatic malignancy.

  11. Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

    ClinicalTrials.gov

    2016-10-18

    Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

  12. Function of immunoadjuvants in laser immunotherapy for treatment of metastatic breast tumors in rats

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; Liu, Hong; Wolf, Roman F.; Lucroy, Michael D.; Nordquist, Robert E.

    2002-06-01

    Tumor cell destruction usually induces host immune responses, such as local inflammation and increased activities of macrophages and neutrophils. Use of immunoadjuvant can usually enhance such immune activities. Laser immunotherapy is designed to use the combination of laser photothermal and immunological interactions to induce long-term antitumor immunity with the help of immunoadjuvant. It uses a selective hyperthermia for acute tumor destruction through an intratumor administration of indocyanine green and a noninvasive irradiation by an 805-nm laser. The concurrent in situ administration of immunoadjuvant helped achieve the desired effect: tumor eradication and antitumor immunity. The current study further explores the function of immunoadjuvants in laser immunotherapy by testing four different adjuvants: glycated chitosan, complete Freund's adjuvant, incomplete Freund's adjuvant, and c-parvum. Each adjuvant provided long-term tumor cure in the treatment of a metastatic mammary tumor model in rats. However, glycated chitosan and complete Freund's adjuvant were most effective with 25% and 18% long- term cure rates, respectively. Different concentrations of glycated chitosan were also used in treatment of rats bearing metastatic breast tumors.

  13. Metastatic extra-abdominal presentation of gastrointestinal stromal tumors in a young Hispanic male: a case presentation and literature review.

    PubMed

    Di Marco, Anna; Paulo-Malave, Liza; Alayon-Laguer, Diogenes; Baez, Luis; Conde, Daniel; William, Caceres

    2012-01-01

    This article presents the medical history and management of a 44-year-old Hispanic male with metastatic extra-abdominal gastrointestinal stromal tumor including a literature review on this rare clinical presentation.

  14. GPI/AMF inhibition blocks the development of the metastatic phenotype of mature multi-cellular tumor spheroids.

    PubMed

    Gallardo-Pérez, Juan Carlos; Rivero-Segura, Nadia Alejandra; Marín-Hernández, Alvaro; Moreno-Sánchez, Rafael; Rodríguez-Enríquez, Sara

    2014-06-01

    Epithelial-mesenchymal transition (EMT) and cellular invasiveness are two pivotal processes for the development of metastatic tumor phenotypes. The metastatic profile of non-metastatic MCF-7 cells growing as multi-cellular tumor microspheroids (MCTSs) was analyzed by determining the contents of the EMT, invasive and migratory proteins, as well as their migration and invasiveness potential and capacity to secrete active cytokines such as the glucose phosphate isomerase/AMF (GPI/AMF). As for the control, the same analysis was also performed in MCF-7 and MDA-MB-231 (highly metastatic, MDA) monolayer cells, and in stage IIIB and IV human metastatic breast biopsies. The proliferative cell layers (PRL) of mature MCF-7 MCTSs, MDA monolayer cells and metastatic biopsies exhibited increased cellular contents (2-15 times) of EMT (β-catenin, SNAIL), migratory (vimentin, cytokeratin, and fibronectin) and invasive (MMP-1, VEGF) proteins versus MCF-7 monolayer cells, quiescent cell layers of mature MCF-7 MCTS and non-metastatic breast biopsies. The increase in metastatic proteins correlated with substantially elevated cellular abilities for migration (18-times) and invasiveness (13-times) and with the higher level (6-times) of the cytokine GPI/AMF in the extracellular medium of PRL, as compared to MCF-7 monolayer cells. Interestingly, the addition of the GPI/AMF inhibitors erythrose-4-phosphate or 6-phosphogluconate at micromolar doses significantly decreased its extracellular activity (>80%), with a concomitant diminution in the metastatic protein content and migratory tumor cell capacity, and with no inhibitory effect on tumor lactate production or toxicity on 3T3 mouse fibroblasts. The present findings provide new insights into the discovery of metabolic inhibitors to be used as complementary therapy against metastatic and aggressive tumors.

  15. In vivo selection for spine-derived highly metastatic lung cancer cells is associated with increased migration, inflammation and decreased adhesion

    PubMed Central

    Deng, Huayun; Zhang, Jishen; Li, Shichang; Wei, Haifeng; Yang, Cheng; Xu, Leqin; Jin, Rongrong; Li, Zhenxi; Zhou, Wang; Ding, JianDong; Chu, Jianjun; Jia, Lianshun; Jia, Qi; Tan, Chengjun; Liu, Mingyao; Xiao, Jianru

    2015-01-01

    We developed a murine spine metastasis model by screening five metastatic non-small cell lung cancer cell lines (PC-9, A549, NCI-H1299, NCI-H460, H2030). A549 cells displayed the highest tendency towards spine metastases. After three rounds of selection in vivo, we isolated a clone named A549L6, which induced spine metastasis in 80% of injected mice. The parameters of the A549L6 cell spinal metastatic mouse models were consistent with clinical spine metastasis features. All the spinal metastatic mice developed symptoms of nerve compression after 40 days. A549L6 cells had increased migration, invasiveness and decreased adhesion compared to the original A549L0 cells. In contrast, there was no significant differences in cell proliferation, apoptosis and sensitivity to chemotherapeutic agents such as cisplatin. Comparative transcriptomic analysis and Real-time PCR analysis showed that expression of signaling molecules regulating several tumor properties including migration (MYL9), metastasis (CEACAM6, VEGFC, CX3CL1, CST1, CCL5, S100A9, IGF1, NOTCH3), adhesion (FN1, CEACAM1) and inflammation (TRAF2, NFκB2 and RelB) were altered in A549L6 cells. We suggest that migration, adhesion and inflammation related genes contribute to spine metastatic capacity. PMID:26090868

  16. In vivo selection for spine-derived highly metastatic lung cancer cells is associated with increased migration, inflammation and decreased adhesion.

    PubMed

    Cai, Xiaopan; Luo, Jian; Yang, Xinghai; Deng, Huayun; Zhang, Jishen; Li, Shichang; Wei, Haifeng; Yang, Cheng; Xu, Leqin; Jin, Rongrong; Li, Zhenxi; Zhou, Wang; Ding, JianDong; Chu, Jianjun; Jia, Lianshun; Jia, Qi; Tan, Chengjun; Liu, Mingyao; Xiao, Jianru

    2015-09-01

    We developed a murine spine metastasis model by screening five metastatic non-small cell lung cancer cell lines (PC-9, A549, NCI-H1299, NCI-H460, H2030). A549 cells displayed the highest tendency towards spine metastases. After three rounds of selection in vivo, we isolated a clone named A549L6, which induced spine metastasis in 80% of injected mice. The parameters of the A549L6 cell spinal metastatic mouse models were consistent with clinical spine metastasis features. All the spinal metastatic mice developed symptoms of nerve compression after 40 days. A549L6 cells had increased migration, invasiveness and decreased adhesion compared to the original A549L0 cells. In contrast, there was no significant differences in cell proliferation, apoptosis and sensitivity to chemotherapeutic agents such as cisplatin. Comparative transcriptomic analysis and real-time PCR analysis showed that expression of signaling molecules regulating several tumor properties including migration (MYL9), metastasis (CEACAM6, VEGFC, CX3CL1, CST1, CCL5, S100A9, IGF1, NOTCH3), adhesion (FN1, CEACAM1) and inflammation (TRAF2, NFκB2 and RelB) were altered in A549L6 cells. We suggest that migration, adhesion and inflammation related genes contribute to spine metastatic capacity. PMID:26090868

  17. Estimation of lung tissue incompressibility variation throughout respiration for tumor targeting in lung radiotherapy

    NASA Astrophysics Data System (ADS)

    Shirzadi, Zahra; Samani, Abbas

    2013-03-01

    A novel technique is proposed to characterize lung tissue incompressibility variation during respiration. Lung tissue incompressibility variation stems from significant air content variation in the tissue throughout respiration. Estimating lung tissue incompressibility and its variation is critical for computer assisted tumor motion tracking. Continuous tumor motion during respiration is a major challenge in lung cancer treatment by external beam radiotherapy. If not accounted for, this motion leads to areas of radiation over dosage for the lung normal tissues. Since no effective imaging modality is available for real-time lung tumor tracking, computer based modeling which has the capability for accurate tissue deformation estimation can be a good alternative. Lung tissue deformation estimation can be made using the lung Finite Element (FE) model where its accuracy depends on input tissue biomechanical properties including incompressibility parameter. In this research, an optimization algorithm is proposed to estimate the incompressibility parameter function in terms of respiration cycle time. In this algorithm, the incompressibility parameter and lung pressure values are varied systematically until optimal values, which result in maximum similarity between acquired and simulated 4D CT images of the lung, are achieved for each respiration time point. The simulated images are constructed using a reference image in conjunction with the deformation field obtained from the lung's FE model in each respiration time increment. We demonstrated that utilizing the calculated function along with respiratory system FE modeling leads to accurate tumor targeting, hence potentially improving lung radiotherapy outcome.

  18. Assessment of Tumor Radioresponsiveness and Metastatic Potential by Dynamic Contrast-Enhanced Magnetic Resonance Imaging

    SciTech Connect

    Ovrebo, Kirsti Marie; Gulliksrud, Kristine; Mathiesen, Berit; Rofstad, Einar K.

    2011-09-01

    Purpose: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. Methods and Materials: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, and parametric images of K{sup trans} (the volume transfer constant of Gd-DTPA) and v{sub e} (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. Results: Tumors with hypoxic cells showed significantly lower K{sup trans} values than tumors without significant hypoxia (p < 0.0001, n = 30), and K{sup trans} decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p < 0.0001, n = 20). Tumors in metastasis-positive mice had significantly lower K{sup trans} values than tumors in metastasis-negative mice (p < 0.0001, n = 50). Significant correlations between v{sub e} and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. Conclusions: R-18 tumors with low K{sup trans} values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological

  19. Biological Therapy in Treating Patients With Metastatic Cancer

    ClinicalTrials.gov

    2013-02-21

    Breast Cancer; Colorectal Cancer; Extrahepatic Bile Duct Cancer; Gallbladder Cancer; Gastric Cancer; Head and Neck Cancer; Liver Cancer; Lung Cancer; Metastatic Cancer; Ovarian Cancer; Pancreatic Cancer; Testicular Germ Cell Tumor

  20. Retroperitoneal metastatic germ cell tumor presenting as a psoas abscess: a diagnostic pitfall.

    PubMed

    Dieker, Carrie A; De Las Casas, Luis E; Davis, Brian R

    2013-07-01

    Most testicular neoplasms are germ cell tumors, the vast majority of which represent seminomas. Most seminomas present localized to the testis, whereas nonseminomatous germ cell tumors more often present with lymph node metastases. Psoas abscesses generally arise from a contiguous intra-abdominal or pelvic infectious process, an adjacent focus of osteomyelitis or septic emboli from distant infectious foci. In this study, the case of a 24-year-old man who presented with a right psoas mass presumptively diagnosed as an abscess secondary to fever and leukocytosis is presented. The patient had a history of right testicular seminoma, and normal serum levels of alpha-fetoprotein and human chorionic gonadotropin. Surgical exploration and biopsy demonstrated seminoma metastasis. This case represents an extremely unusual clinical presentation of metastatic germ cell tumor presenting as a psoas abscess. This unique case represents an unusual presentation of a recurrent germ cell tumor mimicking a psoas abscess. Awareness of possible metastatic testicular germ cell neoplasm as a psoas abscess could prevent diagnosis delay before retroperitoneal tumor debulking. PMID:23360792

  1. Inhibition of growth, induction of apoptosis and alteration of gene expression by tea polyphenols in the highly metastatic human lung cancer cell line NCI-H460.

    PubMed

    Ganguly, Chaiti; Saha, Prosenjit; Panda, Chinmay Kr; Das, Sukta

    2005-01-01

    Lung cancer is a complex group of diseases but each lesion is thought to originate from a single mutated progenitor cell. It is evident that multiple genetic changes are involved in the generation of each specific type of lung cancer. Due to the high complexity of these processes and rapid metastasis, treatment of advanced lung cancer, particularly of NSCLCs, is far from satisfactory. Thus, there is a need for innovative strategies for modulation of adverse alteration in protooncogene or tumor suppressor genes so that lung carcinogenesis can be suppressed or delayed. To this end, we have evaluated the effects of tea compounds (theaflavins, epicatechin-gallate and epigallo-catechin-gallate) on proliferation and apoptosis and associated gene expression in a highly metastatic human lung cancer cell line NCI-H460. Significant reduction of cell proliferation, detected in situ by BrdU incorporation, and induction of apoptosis, assessed by the by the TUNEL method, were noted following treatments. Expression of p53, Bcl-2, c-Myc and H-Ras, was localized by immunocytochemistry and analysed by Western blotting. Tea compounds upregulated expression of p53, downregulated expression of Bcl-2 but there was no significant influence on H-ras and c-Myc expressions. It is suggested that tea compounds can influence genetic alteration to disfavour, growth and survival of lung cancer cells. PMID:16235994

  2. Percutaneous Cryoablation of Metastatic Renal Cell Carcinoma for Local Tumor Control: Feasibility, Outcomes, and Estimated Cost-effectiveness for Palliation

    PubMed Central

    Bang, Hyun J.; Littrup, Peter J.; Goodrich, Dylan J.; Currier, Brandt P.; Aoun, Hussein D.; Heilbrun, Lance K.; Vaishampayan, Ulka; Adam, Barbara; Goodman, Allen C.

    2013-01-01

    Purpose To assess complications, local tumor recurrences, overall survival (OS), and estimates of cost-effectiveness for multisite cryoablation (MCA) of oligometastatic renal cell carcinoma (RCC). Materials and Methods A total of 60 computed tomography- and/or ultrasound-guided percutaneous MCA procedures were performed on 72 tumors in 27 patients (three women and 24 men). Average patient age was 63 years. Tumor location was grouped according to common metastatic sites. Established surgical selection criteria graded patient status. Median OS was determined by Kaplan–Meier method and defined life-years gained (LYGs). Estimates of MCA costs per LYG were compared with established values for systemic therapies. Results Total number of tumors and cryoablation procedures for each anatomic site are as follows: nephrectomy bed, 11 and 11; adrenal gland, nine and eight; paraaortic, seven and six; lung, 14 and 13; bone, 13 and 13; superficial, 12 and nine; intraperitoneal, five and three; and liver, one and one. A mean of 2.2 procedures per patient were performed, with a median clinical follow-up of 16 months. Major complication and local recurrence rates were 2% (one of 60) and 3% (two of 72), respectively. No patients were graded as having good surgical risk, but median OS was 2.69 years, with an estimated 5-year survival rate of 27%. Cryoablation remained cost-effective with or without the presence of systemic therapies according to historical cost comparisons, with an adjunctive cost-effectiveness ratio of $28,312–$59,554 per LYG. Conclusions MCA was associated with very low morbidity and local tumor recurrence rates for all anatomic sites, with apparent increased OS. Even as an adjunct to systemic therapies, MCA appeared cost-effective for palliation of oligometastatic RCC. PMID:22538119

  3. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens

    PubMed Central

    Baine, Marina K.; Turcu, Gabriela; Zito, Christopher R.; Adeniran, Adebowale J.; Camp, Robert L.; Chen, Lieping

    2015-01-01

    Renal cell carcinoma (RCC) is one of the most chemo- and radio-resistant malignancies, with poor associated patient survival if the disease metastasizes. With recent advances in immunotherapy, particularly with PD-1/PD-L1 blockade, outcomes are improving, but a substantial subset of patients does not respond to the new agents. Identifying such patients and improving the therapeutic ratio has been a challenge, although much effort has been made to study PD-1/PD-L1 status in pre-treatment tumor. However, tumor infiltrating lymphocyte (TIL) content might also be predictive of response, and our goal was to characterize TIL content and PD-L1 expression in RCC tumors from various anatomic sites. Utilizing a quantitative immunofluorescence technique, TIL subsets were examined in matched primary and metastatic specimens. In metastatic specimens, we found an association between low CD8+ to Foxp3+ T-cell ratios and high levels of PD-L1. High PD-L1-expressing metastases were also found to be associated with tumors that were high in both CD4+ and Foxp3+ T-cell content. Taken together these results provide the basis for combining agents that target the PD-1/PD-L1 pathway with agonist of immune activation, particularly in treating RCC metastases with unfavorable tumor characteristics and microenvironment. In addition, CD8+ TIL density and CD8:Foxp3 T-cell ratio were higher in primary than metastatic specimens, supporting the need to assess distant sites for predictive biomarkers when treating disseminated disease. PMID:26317902

  4. Fluoroscopic tumor tracking for image-guided lung cancer radiotherapy

    NASA Astrophysics Data System (ADS)

    Lin, Tong; Cerviño, Laura I.; Tang, Xiaoli; Vasconcelos, Nuno; Jiang, Steve B.

    2009-02-01

    Accurate lung tumor tracking in real time is a keystone to image-guided radiotherapy of lung cancers. Existing lung tumor tracking approaches can be roughly grouped into three categories: (1) deriving tumor position from external surrogates; (2) tracking implanted fiducial markers fluoroscopically or electromagnetically; (3) fluoroscopically tracking lung tumor without implanted fiducial markers. The first approach suffers from insufficient accuracy, while the second may not be widely accepted due to the risk of pneumothorax. Previous studies in fluoroscopic markerless tracking are mainly based on template matching methods, which may fail when the tumor boundary is unclear in fluoroscopic images. In this paper we propose a novel markerless tumor tracking algorithm, which employs the correlation between the tumor position and surrogate anatomic features in the image. The positions of the surrogate features are not directly tracked; instead, we use principal component analysis of regions of interest containing them to obtain parametric representations of their motion patterns. Then, the tumor position can be predicted from the parametric representations of surrogates through regression. Four regression methods were tested in this study: linear and two-degree polynomial regression, artificial neural network (ANN) and support vector machine (SVM). The experimental results based on fluoroscopic sequences of ten lung cancer patients demonstrate a mean tracking error of 2.1 pixels and a maximum error at a 95% confidence level of 4.6 pixels (pixel size is about 0.5 mm) for the proposed tracking algorithm.

  5. Imaging of primary and regionally metastatic lung cancer with Tc-99m SESTAMIBI

    SciTech Connect

    Akansel, G.; Liu, Y.; Uygur, G.A.

    1994-05-01

    The significance of pulmonary, hilar, and mediastinal uptake of Tc-99m SESTAMIBI in patients undergoing myocardial perfusion imaging was retrospectively investigated. SPECT myocardial perfusion images for 34 adult patients (ages: 52-to-82 years) with known lung cancer undergoing preoperative assessment of cardiac status and 29 {open_quotes}control{close_quotes} patients with normal chest radiographs and no history of lung cancer were reviewed. For the 29 patients without lung cancer there was no abnormal pulmonary, hilar, or mediastinal uptake of Tc-99m SESTAMIBI. For the 34 patients with histologically proven lung cancer, Tc-99m SESTAMIBI uptake was detected in 27 of 34 primary pulmonary lesions (79% sensitivity), 2 of 4 surgically proven hilar metastases, and 1 of 4 mediastinal metastases. The smallest lesion detected was 1.0 cm in diameter and the largest lesion not detected was 5.5 cm in diameter. For squamous cell carcinoma, 20 of 22 primary lesions were detected (91% sensitivity). Tc-99m SESTAMIBI detected 5 of 34 primary pulmonary lesions, 2 of 4 hilar metasteses, and 1 of 4 mediastinal metastases not identified by conventional chest radiographs. CT was superior to Tc-99m SESTAMIBI for detection of primary pulmonary lesions and was similar to Tc-99m SESTAMIBI in the limited number of cases with hilar and mediastinal metastatic involvement. We conclude that abnormal pulmonary, hilar, or mediastinal uptake of Tc-99m SESTAMIBI may be a clinically significant finding which should be correlated with chest radiography or CT.

  6. Vorinostat in Combination With Paclitaxel and Carboplatin in Treating Patients With Metastatic or Recurrent Solid Tumors and HIV Infection

    ClinicalTrials.gov

    2016-10-11

    HIV Infection; Recurrent Anal Cancer; Recurrent Breast Cancer; Recurrent Esophageal Cancer; Recurrent Gastric Cancer; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Anal Cancer; Stage IV Breast Cancer; Stage IV Esophageal Cancer; Stage IV Gastric Cancer; Stage IV Non-small Cell Lung Cancer; Stage IV Ovarian Epithelial Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific

  7. Photothermal and immunological reactions against metastatic tumors using laser photosensitizer immunoadjuvant

    NASA Astrophysics Data System (ADS)

    Chen, Wei R.; El-Samad, Ahmad; Nordquist, Robert E.

    1999-06-01

    Photothermal tissue interaction is the most common phenomenon when laser energy is deposited in tissue. Because of the sensitivity of cancer cells to temperature increase, photothermal reaction can be an effective mechanism of direct cancer destruction using lasers. Tumor-specific immune response is crucial in achieving systemic and long-term cures for cancers, particularly for metastatic cancers. Can photothermal interaction induce sufficient immunological reaction when the local destruction of tumor cells occurs? To achieve selective photothermal destruction, indocyanine green as a photosensitizer was directly injected into rat mammary tumors, followed by irradiation of 805 nm laser light. Although extensive photothermal tumor killing was achieved and tumor growth was slowed down immediately following the treatment, photothermal reaction alone was shown not sufficient in controlling the treated primary tumors and their metastases. When an immunoadjuvant was used with the indocyanine green, however, the same laser treatment not only could eventually eradicate the treated primary tumors but also eradicate the untreated metastases at remote sites. The tumor eradication went through a growth-regression process over a period of six to nine weeks post-treatment, indicating an induced immune response. The Western Blot analysis using the serum from a laser-immunotherapy cured rat showed that the tumor-specific antibody induced by the treatment had a long- lasting effect. Our experimental data indicated that photothermal interaction alone was not sufficient to slow and eventually reverse tumor growth. However, it can reduce the tumor burden and at the same time release tumor antigens to be recognized by the host immune system. Therefore, in conjunction with specific immunological stimulation using in situ immunoadjuvants, the selective thermal injury to tumors plays an important and a direct role in this laser immunotherapy.

  8. Mutational analysis of single circulating tumor cells by next generation sequencing in metastatic breast cancer

    PubMed Central

    Galardi, Francesca; Pestrin, Marta; Gabellini, Stefano; Simi, Lisa; Mancini, Irene; Vannucchi, Alessandro Maria; Pazzagli, Mario; Di Leo, Angelo; Pinzani, Pamela

    2016-01-01

    Circulating Tumor Cells (CTCs) represent a “liquid biopsy” of the tumor potentially allowing real-time monitoring of cancer biology and therapies in individual patients. The purpose of the study was to explore the applicability of a protocol for the molecular characterization of single CTCs by Next Generation Sequencing (NGS) in order to investigate cell heterogeneity and provide a tool for a personalized medicine approach. CTCs were enriched and enumerated by CellSearch in blood from four metastatic breast cancer patients and singularly isolated by DEPArray. Upon whole genome amplification 3–5 single CTCs per patient were analyzed by NGS for 50 cancer-related genes. We found 51 sequence variants in 25 genes. We observed inter- and intra-patient heterogeneity in the mutational status of CTCs. The highest number of somatic deleterious mutations was found in the gene TP53, whose mutation is associated with adverse prognosis in breast cancer. The discordance between the mutational status of the primary tumor and CTCs observed in 3 patients suggests that, in advanced stages of cancer, CTC characteristics are more closely linked to the dynamic modifications of the disease status. In one patient the mutational profiles of CTCs before and during treatment shared only few sequence variants. This study supports the applicability of a non-invasive approach based on the liquid biopsy in metastatic breast cancer patients which, in perspective, should allow investigating the clonal evolution of the tumor for the development of new therapeutic strategies in precision medicine. PMID:27034166

  9. Reassessing the need for primary tumor surgery in unresectable metastatic colorectal cancer: overview and perspective.

    PubMed

    Poultsides, George A; Paty, Phillip B

    2011-01-01

    In the absence of symptoms, primary tumor resection in patients who present with unresectable metastatic colorectal cancer is of uncertain benefit. Prophylactic surgery has been traditionally considered in this setting in order to prevent subsequent complications of perforation, obstruction, or bleeding later during the treatment course, which may require urgent surgery associated with higher mortality. However, recent data have called into question the efficacy of this upfront surgical strategy. We provide a brief overview of how current combinations of systemic chemotherapy including fluorouracil, oxaliplatin, irinotecan, and targeted biologic agents have allowed improved local (in addition to distant) tumor control, significantly decreasing the incidence of late primary-related complications requiring surgery from roughly 20% in the era of single-agent fluoropyrimidine chemotherapy to almost 7% in the era of modern triple-drug chemotherapy. In addition, we attempt to highlight those factors most associated with subsequent primary tumor-related complications in an effort to identify the subset of patients with synchronous metastatic colorectal cancer who might benefit from a surgery-first approach. Finally, we discuss modern nonsurgical options available for palliation of the primary colorectal tumor and review the outcome of patients for which emergent surgery is eventually required to address primary-related symptoms. PMID:21789154

  10. Five-year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs

    PubMed Central

    Lin, Jessica J.; Cardarella, Stephanie; Lydon, Christine A.; Dahlberg, Suzanne E.; Jackman, David M.; Jänne, Pasi A.; Johnson, Bruce E.

    2016-01-01

    Introduction Activating mutations in the epidermal growth factor receptor (EGFR) predict for prolonged progression-free survival in patients with advanced non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy. Long-term survival outcomes, however, remain undefined. The objective of this study was to determine the 5-year survival in these patients, and identify clinical factors associated with overall survival (OS). Methods Patients with EGFR-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009 were included. OS was analyzed. Results Among 137 patients, median PFS and OS were 12.1 months (95% CI, 10.2-13.5 months) and 30.9 months (95% CI, 28.2-35.7 months), respectively. Twenty patients (14.6%) were 5-year survivors. In multivariate analysis, exon 19 deletions (hazard ratio [HR], 0.63; 95% CI, 0.44-0.91; P = 0.01), absence of extrathoracic (HR 0.62; 95% CI, 0.41-0.93; P = 0.02) or brain metastasis (HR 0.48; 95% CI, 0.30-0.77, P = 0.002), and not a current smoker (HR 0.23; 95% CI, 0.09-0.59; P = 0.002) were associated with prolonged OS. Age, gender, stage at diagnosis, liver or bone or adrenal metastasis, specific TKI, and line of TKI therapy were not associated with OS. Conclusions Our data suggest that the prevalence of 5-year survival among EGFR-mutant metastatic lung adenocarcinoma patients treated with erlotinib or gefitinib is 14.6%. Exon 19 deletions and absence of extrathoracic or brain metastasis are associated with prolonged survival. Based on our findings, clinicians can gain an enhanced estimation of long-term outcomes in this population. PMID:26724471

  11. Interfractional Variations of Tumor Centroid Position and Tumor Regression during Stereotactic Body Radiotherapy for Lung Tumor

    PubMed Central

    Sun, Yanan; Lu, Yufei; Cheng, Siguo; Guo, Wei; Ye, Ke; Zhao, Huiyun; Zheng, Xiaoli; Li, Dingjie; Wang, Shujuan; Yang, Chengliang; Ge, Hong

    2014-01-01

    Purpose. To determine interfractional changes of lung tumor centroid position and tumor regression during stereotactic body radiation therapy (SBRT). Methods and Materials. 34 patients were treated by SBRT in 4-5 fractions to a median dose of 50 Gy. The CT scans acquired for verification were registered with simulation CT scans. The gross target volume (GTV) was contoured on all verification CT scans and compared to the initial GTV in treatment plan system. Results. The mean (±standard deviation, SD) three-dimension vector shift was 5.2 ± 3.1 mm. The mean (±SD) interfractional variations of tumor centroid position were −0.7 ± 4.5 mm in anterior-posterior (AP) direction, 0.2 ± 3.1 mm in superior-inferior (SI) direction, and 0.4 ± 2.4 mm in right-left (RL) direction. Large interfractional variations (≥5 mm) were observed in 5 fractions (3.3%) in RL direction, 16 fractions (10.5%) in SI direction, and 36 fractions (23.5%) in AP direction. Tumor volume did not decrease significantly during lung SBRT. Conclusions. Small but insignificant tumor volume regression was observed during lung SBRT. While the mean interfractional variations of tumor centroid position were minimal in three directions, variations more than 5 mm account for approximately a third of all, indicating additional margin for PTV, especially in AP direction. PMID:25548770

  12. Integrated Multimodal Imaging of Dynamic Bone-Tumor Alterations Associated with Metastatic Prostate Cancer

    PubMed Central

    Chenevert, Thomas L.; Jacobson, Jon A.; Boes, Jennifer L.; Galbán, Stefanie; Rehemtulla, Alnawaz; Johnson, Timothy D.; Pienta, Kenneth J.; Galbán, Craig J.; Meyer, Charles R.; Schakel, Timothy; Nicolay, Klaas; Alva, Ajjai S.; Hussain, Maha; Ross, Brian D.

    2015-01-01

    Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM) of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05). These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease. Trial Registration ClinicalTrials.gov NCT02064283 PMID:25859981

  13. Hepatic Arterial Chemoembolization Using Drug-Eluting Beads in Gastrointestinal Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Gaur, Shantanu K.; Friese, Jeremy L.; Sadow, Cheryl A.; Ayyagari, Rajasekhara; Binkert, Christoph A.; Schenker, Matthew P.; Kulke, Matthew; Baum, Richard

    2011-06-15

    Purpose: This study was designed to evaluate short (<3 months) and intermediate-term (>3 months) follow-up in patients with metastatic neuroendocrine tumor to the liver who underwent hepatic arterial chemoembolization with drug-eluting beads at a single institution. Methods: Institutional review board approval was obtained for this retrospective review. All patients who were treated with 100-300 or 300-500 {mu}m drug-eluting LC Beads (Biocompatibles, UK) preloaded with doxorubicin (range, 50-100 mg) for GI neuroendocrine tumor metastatic to the liver from June 2004 to June 2009 were included. CT and MRI were evaluated for progression using Response Evaluation Criteria In Solid Tumors (RECIST) or European Association for the Study of the Liver (EASL) criteria. Short-term (<3 months) and intermediate-term (>3 months) imaging response was determined and Kaplan-Meier survival curves were plotted. Results: Thirty-eight drug-eluting bead chemoembolization procedures were performed on 32 hepatic lobes, comprising 21 treatment cycles in 18 patients. All procedures were technically successful with two major complications (biliary injuries). At short-term follow-up (<3 months), 22 of 38 (58%) procedures and 10 of 21 (48%) treatment cycles produced an objective response (OR) with the remainder having stable disease (SD). At intermediate-term follow-up (mean, 445 days; range, 163-1247), 17 of 26 (65%) procedures and 8 of 14 (57%) treatment cycles produced an OR. Probability of progressing was approximately 52% at 1 year with a median time to progression of 419 days. Conclusions: Drug-eluting bead chemoembolization is a reasonable alternative to hepatic arterial embolization and chemoembolization for the treatment of metastatic neuroendocrine tumor to the liver.

  14. Inhibition of lung tumor growth and augmentation of radiosensitivity by decreasing peroxiredoxin I expression

    SciTech Connect

    Chen, M.-F.; Keng, Peter C.; Shau Hungyi; Wu, C.-T.; Hu, Y.-C.; Liao, S.-K.; Chen, W.-C. . E-mail: miaofen@adm.cgmh.org.tw

    2006-02-01

    Purpose: In this study, we examined the role of peroxiredoxin I (Prx I) in lung cancer cell growth in vitro and in vivo and its influence on these tumor cells' sensitivity to radiotherapy. Methods and materials: We established stable transfectants of A549 (p53+) and H1299 (p53-) lung carcinoma cell lines with Prx I antisense to downregulate their Prx I protein. We then examined their in vitro biologic changes and used nude mice xenografts of these cell lines to compare tumor invasion, spontaneous metastatic capacity, and sensitivity to radiotherapy. Results: The Prx I antisense transfectants of both cell lines showed a significant reduction in Prx I protein production. Prx I antisense transfectants grew more slowly than did the wild type. As xenografts in mice, A549 Prx I antisense transfectants showed a threefold delay in the generation of palpable tumors. The incidence of spontaneous metastasis of Prx I antisense transfectants was significantly less than that of the wild-type cells. Furthermore, irradiation of Prx I antisense transfectants caused more than twice the growth delay compared with the wild type. Conclusion: The results of these studies suggest that inactivation of Prx I may be a promising approach to improve the treatment outcome of patients with lung cancer.

  15. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients.

    PubMed

    Ni, Xiaohui; Zhuo, Minglei; Su, Zhe; Duan, Jianchun; Gao, Yan; Wang, Zhijie; Zong, Chenghang; Bai, Hua; Chapman, Alec R; Zhao, Jun; Xu, Liya; An, Tongtong; Ma, Qi; Wang, Yuyan; Wu, Meina; Sun, Yu; Wang, Shuhang; Li, Zhenxiang; Yang, Xiaodan; Yong, Jun; Su, Xiao-Dong; Lu, Youyong; Bai, Fan; Xie, X Sunney; Wang, Jie

    2013-12-24

    Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.

  16. Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients

    PubMed Central

    Ni, Xiaohui; Zhuo, Minglei; Su, Zhe; Duan, Jianchun; Gao, Yan; Wang, Zhijie; Zong, Chenghang; Bai, Hua; Chapman, Alec R.; Zhao, Jun; Xu, Liya; An, Tongtong; Ma, Qi; Wang, Yuyan; Wu, Meina; Sun, Yu; Wang, Shuhang; Li, Zhenxiang; Yang, Xiaodan; Yong, Jun; Su, Xiao-Dong; Lu, Youyong; Bai, Fan; Xie, X. Sunney; Wang, Jie

    2013-01-01

    Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics. PMID:24324171

  17. A case of S-100 negative melanoma: A diagnostic pitfall in the workup of a poorly differentiated metastatic tumor of unknown origin

    PubMed Central

    Biernacka, Anna; Linos, Konstantinos D.; DeLong, Peter A.; Suriawinata, Arief A.; Padmanabhan, Vijayalakshmi; Liu, Xiaoying

    2016-01-01

    When confronted with a metastatic poorly differentiated tumor of unknown origin, the initial workup includes the standard panel of immunostains to rule out carcinoma, sarcoma, lymphoma, and the greatest mimicker in pathology – malignant melanoma. Although not specific, the S-100 protein is expressed in over 95% of malignant melanomas. Herein, we present a case of multiorgan metastatic malignancy with a dominant hilar and mediastinal mass in a current smoker; clinically, highly suggestive of widespread primary lung cancer. This case was eventually classified as malignant melanoma, despite a significant diagnostic challenge due to lack of prior history, unusual cytomorphology, and S-100 protein negativity. A battery of immunostains was performed and the addition of other melanocytic-associated markers confirmed the melanocytic lineage of the neoplasm. This case highlights the pitfalls in the differential diagnosis of a metastatic tumor of unknown origin by fine needle aspiration cytology due to the significant morphologic overlap of poorly differentiated malignancies. We emphasize that, albeit rare, malignant melanomas can be completely negative for S-100 protein and the use of additional melanocytic-associated markers in the differential workup maybe critical in arriving promptly at a proper diagnosis. We also briefly discuss other currently available immunohistochemical markers that can assist in the identification of the S-100 negative melanoma. PMID:27729935

  18. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    PubMed Central

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+ Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL. PMID:26137413

  19. Hypercalcemia from metastatic pancreatic neuroendocrine tumor secreting 1,25-dihydroxyvitamin D

    PubMed Central

    Zhu, Viola; de las Morenas, Antonio; Janicek, Milos

    2014-01-01

    Malignant hypercalcemia occurs in about 20-30% of patients with cancer, both solid tumors and hematologic malignancies. The secretion of parathyroid hormone-related protein (PTH-rP) is the most common cause and has been shown to be the etiology of hypercalcemia associated with neuroendocrine tumors. Here we report the case of a patient with metastatic pancreatic neuroendocrine tumor who developed hypercalcemia more than 4 years after the initial diagnosis as a result of secretion of 1,25-dihydroxyvitamin D, a mechanism only commonly seen in lymphomas. The successful control of the patient’s disease with capecitabine and temozolomide led to the alleviation of this paraneoplastic syndrome. PMID:25083313

  20. Interstitial laser irradiation of metastatic mammary tumors in combination with intratumoral injection of immunoadjuvant

    NASA Astrophysics Data System (ADS)

    Joshi, Chet; Jose, Jessnie; Figueroa, Daniel; Goddard, Jessica; Li, Xiaosong; Liu, Hong; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2012-03-01

    Laser immunotherapy (LIT) was developed to treat metastatic cancers using a combination of laser irradiation and immunological stimulation. The original design of LIT employs a non-invasive, selective laser photothermal interaction, using an in situ light-absorbing dye. However, this non-invasive treatment mode faces challenges in treating deep, large tumors. Furthermore, it has difficulties in the cases of highly pigmented skin overlying target tumors. To overcome these limitations, interstitial laser immunotherapy (ILIT) was proposed. In ILIT, a cylindrical, side-fire fiber diffuser is placed inside the target tumor to induce thermal damage. To enhance the interstitial irradiation induced photothermal interaction, an immunological modifier, glycated chitosan (GC), is injected into the tumor after the laser treatment. In this study, a cylindrical diffuser with an active length of 1 cm was used to treat tumors of 1 to 1.5 cm in size. Different laser powers (1 to 3 watts) and different irradiation durations (10 to 30 minutes) were used to test the thermal effects of ILIT. Different doses of the GC (1.0%, 0.1 to 0.6 ml per rat) were used to determine the immunological effects of ILIT. Our results show that the animal survival depends on both laser dose and GC dose. A dose of 0.2 ml per tumor appeared to result in the highest survival rate under interstitial laser irradiation with 2.5 watts and 20 minutes. While the results in this study are not conclusive, they indicate that interstitial laser irradiation can be combined with immunotherapy to treat metastatic cancers. Furthermore, our results suggest that an optimal combination of laser dose and GC dose could be obtained for future clinical protocols using interstitial laser immunotherapy.

  1. Liposomal delivery of dexamethasone attenuates prostate cancer bone metastatic tumor growth In Vivo

    PubMed Central

    Buijs, Jeroen T.; van der Horst, Geertje; Cheung, Henry; van der Mark, Maaike; van Bloois, Louis; Rizzo, Larissa Y.; Lammers, Twan; Pelger, Rob C.; Storm, Gert; van der Pluijm, Gabri; Metselaar, Josbert M.

    2015-01-01

    Background The inflammatory tumor microenvironment, and more specifically the tumor‐associated macrophages, plays an essential role in the development and progression of prostate cancer towards metastatic bone disease. Tumors are often characterized by a leaky vasculature, which ‐ combined with the prolonged circulation kinetics of liposomes ‐ leads to efficient tumor localization of these drug carriers, via the so‐called enhanced permeability and retention (EPR) ‐effect. In this study, we evaluated the utility of targeted, liposomal drug delivery of the glucocorticoid dexamethasone in a model of prostate cancer bone metastases. Methods Tumor‐bearing Balb‐c nu/nu mice were treated intravenously with 0.2–1.0–5.0 mg/kg/week free‐ and liposomal DEX for 3–4 weeks and tumor growth was monitored by bioluminescent imaging. Results Intravenously administered liposomes localize efficiently to bone metastases in vivo and treatment of established bone metastases with (liposomal) dexamethasone resulted in a significant inhibition of tumor growth up to 26 days after initiation of treatment. Furthermore, 1.0 mg/kg liposomal dexamethasone significantly outperformed 1.0 mg/kg free dexamethasone, and was found to be well‐tolerated at clinically‐relevant dosages that display potent anti‐tumor efficacy. Conclusions Liposomal delivery of the glucocorticoid dexamethasone inhibits the growth of malignant bone lesions. We believe that liposomal encapsulation of dexamethasone offers a promising new treatment option for advanced, metastatic prostate cancer which supports further clinical evaluation. Prostate 75: 815–824, 2015. © 2015 The Authors. The Prostate, published by Wiley Periodicals, Inc. PMID:25663076

  2. Molecular features in arsenic-induced lung tumors

    PubMed Central

    2013-01-01

    Arsenic is a well-known human carcinogen, which potentially affects ~160 million people worldwide via exposure to unsafe levels in drinking water. Lungs are one of the main target organs for arsenic-related carcinogenesis. These tumors exhibit particular features, such as squamous cell-type specificity and high incidence among never smokers. Arsenic-induced malignant transformation is mainly related to the biotransformation process intended for the metabolic clearing of the carcinogen, which results in specific genetic and epigenetic alterations that ultimately affect key pathways in lung carcinogenesis. Based on this, lung tumors induced by arsenic exposure could be considered an additional subtype of lung cancer, especially in the case of never-smokers, where arsenic is a known etiological agent. In this article, we review the current knowledge on the various mechanisms of arsenic carcinogenicity and the specific roles of this metalloid in signaling pathways leading to lung cancer. PMID:23510327

  3. Metastatic islet cell tumor with ACTH, gastrin, and glucagon secretion. Clinical and pathologic studies with multiple therapies.

    PubMed

    Lokich, J; Bothe, A; O'Hara, C; Federman, M

    1987-06-15

    A patient with metastatic islet cell carcinoma demonstrated multiple clinical syndromes simultaneously with secretion of ACTH, gastrin, glucagon, and serotonin. Hepatic arterial embolization resulted in an initial decrease in all secretory products, which was sustained for glucagon and serotonin. Recrudescence of the Cushings and Zollinger-Ellison syndrome was managed by surgical extirpation of the primary tumor and regional metastases as well as bilateral adrenalectomy. Electron microscopy and immunocytochemistry of the primary tumor and the metastatic lesions revealed the presence of multiple types of granules within single cells and, different patterns of secretory profiles in different tumor sites.

  4. [Magnetic resonance imaging of non-organic bulky masses of the retroperitoneal space. Part 2. Primary and metastatic tumors].

    PubMed

    Dombrovskiĭ, V I

    2003-01-01

    Based on MRI findings in 15 patients with primary non-organic tumors and 9 patients with metastatic neoplasms of the retroperitoneal space, the paper describes the MRI-semiotics of these diseases and proposes methodological approaches to their identification in its second part. By comparing the data of MRI and autopsies, the author defines the values of the sensitivity, specificity, and accuracy of the technique in detecting primary and metastatic non-organic tumors of the retroperitoneal space. The author emphasizes the advantages and disadvantages of MRI, shows how difficult to make a differential diagnosis of benign and malignant types of primary non-organic tumors by means of this method.

  5. CGH analysis of secondary genetic changes in Ewing tumors: correlation with metastatic disease in a series of 43 cases.

    PubMed

    Brisset, S; Schleiermacher, G; Peter, M; Mairal, A; Oberlin, O; Delattre, O; Aurias, A

    2001-10-01

    The occurrence of secondary chromosome changes is frequent in Ewing tumors, in particular trisomies for chromosomes 8 and 12, and unbalanced (1;16) translocations leading to gains of 1q and losses of 16q. The prognostic value of these secondary aberrations has not been statistically demonstrated. We report here a CGH analysis of a series of 43 primary tumors corresponding to 21 localized and 22 metastatic tumors. For five of them, a sufficient amount of DNA for the CGH analysis was available from the frozen samples. For 19 samples, a preliminary step of DOP-PCR amplification of the DNA was necessary. For the last 19 tumors, DNA was obtained after DOP-PCR amplification of small amount of DNA contaminating the RNA. As a whole, the main chromosome imbalances previously described, such as trisomies for 1q, 8, and 12, were observed. It is noteworthy that the mean number of imbalances was more frequent in localized versus metastatic tumors. Gain of 1q was more frequent in metastatic than in localized tumors. Nevertheless, these two results do not reach statistical significance. Conversely, a statistically significant excess of copy number of chromosome 2 was observed in non-metastatic tumors, suggesting that this imbalance, which has never been previously reported, could be associated with more favorable tumor behavior. PMID:11672775

  6. Tumor Acquisition for Biomarker Research in Lung Cancer

    PubMed Central

    Stevenson, Marvaretta; Christensen, Jared; Shoemaker, Debra; Foster, Traci; Barry, William T.; Tong, Betty C.; Wahidi, Momen; Shofer, Scott; Datto, Michael; Ginsburg, Geoffrey; Crawford, Jeffrey; D’Amico, Thomas; Ready, Neal

    2015-01-01

    The biopsy collection data from two lung cancer trials that required fresh tumor samples be obtained for microarray analysis were reviewed. In the trial for advanced disease, microarray data were obtained on 50 patient samples, giving an overall success rate of 60.2%. The majority of the specimens were obtained through CT-guided lung biopsies (N=30). In the trial for early-stage patients, 28 tissue specimens were collected from excess tumor after surgical resection with a success rate of 85.7%. This tissue procurement program documents the feasibility in obtaining fresh tumor specimens prospectively that could be used for molecular testing. PMID:24810245

  7. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer.

    PubMed

    Lohr, Jens G; Adalsteinsson, Viktor A; Cibulskis, Kristian; Choudhury, Atish D; Rosenberg, Mara; Cruz-Gordillo, Peter; Francis, Joshua M; Zhang, Cheng-Zhong; Shalek, Alex K; Satija, Rahul; Trombetta, John J; Lu, Diana; Tallapragada, Naren; Tahirova, Narmin; Kim, Sora; Blumenstiel, Brendan; Sougnez, Carrie; Lowe, Alarice; Wong, Bang; Auclair, Daniel; Van Allen, Eliezer M; Nakabayashi, Mari; Lis, Rosina T; Lee, Gwo-Shu M; Li, Tiantian; Chabot, Matthew S; Ly, Amy; Taplin, Mary-Ellen; Clancy, Thomas E; Loda, Massimo; Regev, Aviv; Meyerson, Matthew; Hahn, William C; Kantoff, Philip W; Golub, Todd R; Getz, Gad; Boehm, Jesse S; Love, J Christopher

    2014-05-01

    Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

  8. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances

    PubMed Central

    Ito, Tetsuhide; Igarashi, Hisato

    2013-01-01

    Neuroendocrine tumors (NETs) [carcinoids, pancreatic neuroendocrine tumors (pNETs)] are becoming an increasing clinical problem because not only are they increasing in frequency, but they can frequently present with advanced disease that requires diagnostic and treatment approaches different from those used in the neoplasms that most physicians are used to seeing and treating. In the past few years there have been numerous advances in all aspects of NETs including: an understanding of their unique pathogenesis; specific classification systems developed which have prognostic value; novel methods of tumor localization developed; and novel treatment approaches described. In patients with advanced metastatic disease these include the use of newer chemotherapeutic approaches, an increased understanding of the role of surgery and cytoreductive methods, the development of methods for targeted delivery of cytotoxic agents, and the development of targeted medical therapies (everolimus, sunitinib) based on an increased understanding of the disease biology. Although pNETs and gastrointestinal NETs share many features, recent studies show they differ in pathogenesis and in many aspects of diagnosis and treatment, including their responsiveness to different therapies. Because of limited space, this review will be limited to the advances made in the management and treatment of patients with advanced metastatic pNETs over the past 5 years. PMID:22886480

  9. Treatment of non-resectable and metastatic gastrointestinal stromal tumors: experience with the use of tyrosine kinase inhibitors in a third level hospital in Mexico

    PubMed Central

    Pimentel Renteria, Alberto; Pluma Jiménez, Miguel; Pérez Martínez, Mario; Martínez Martínez, Gloria; Rivera Rivera, Samuel; Grajales Álvarez, Rocío; Bautista Aragón, Yolanda; Quintana Quintana, Miguel; Alejandro Silva, Juan

    2016-01-01

    Background Stromal tumors of the digestive tract are uncommon malignant diseases, are subclassified as leiomyosarcomas and Gastrointestinal Stromal Tumors (GIST) depending on the molecular expression of tyrosine kinase receptor KIT (CD117). GISTs represent 1% of malignant tumors affecting this anatomical site. Localized tumours diseases are reasonably well controlled by surgical resection and several criteria define the need for adjuvant therapy. In the case of metastatic disease a poor prognosis has been reported with systemic treatment based on chemotherapy. Recently, significant advances have been shown since tyrosine kinase inhibitors (TKIs) were introduced, with median overall survival close to 5 years. Unfortunately in Mexico, even though the therapy has been long used there are no published data of the experience in the treatment of these tumors. Methods We used an electronic data base to obtain clinical, radiological and histological data of patients diagnosed with GIST and treated in the oncological center of the Mexican Institute of Social Security, patients were subclassified by stage, symptoms at diagnosis as well as the initial and subsequent systemic treatment. Finally we made an analysis for progression free survival and overall survival identifying prognostic factors. Results We obtained information of 71 patients with metastatic, non-resectable or recurrent GIST, treated with a TKI, we observed a predominant relation for women (60.4%) with median age of 58 years. Stage at diagnosis was predominantly metastatic (46.5%), most frequently affected sites were lung, liver and retroperitoneum. Median progression free survival was 30.6 months and overall survival was 81.3 months. All patients were initially treated with imatinib at a dose of 400 mg per day. Treatment was well-tolerated in most cases. Conclusions Metastatic GIST evaluated in our center shows a different affection in gender and age, and our population shows a different response to TKIs

  10. Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer.

    PubMed

    Cooper, Maryann R; Binkowski, Chelsea; Hartung, Jessica; Towle, Jennifer

    2016-01-01

    The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.

  11. Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer

    PubMed Central

    Cooper, Maryann R; Binkowski, Chelsea; Hartung, Jessica; Towle, Jennifer

    2016-01-01

    The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC. PMID:27110124

  12. [Management of complications after residual tumor resection for metastatic testicular cancer].

    PubMed

    Lusch, A; Zaum, M; Winter, C; Albers, P

    2014-07-01

    Residual tumor resection (RTR) in patients with metastatic testicular cancer plays a pivotal role in a multimodal treatment. It can be performed unilaterally or as an extended bilateral RTR. Additional surgical procedures might be necessary, such as nephrectomy, splenectomy, partial colectomy, or vascular interventions with possible caval resection, cavotomy, or aortic resection with aortic grafting. Consequently, several complications can be seen in the intra- and postoperative course, most common of which are superficial wound infections, intestinal paralysis, lymphocele, and chylous ascites. We sought to describe complication management and how to prevent complications before they arise. PMID:25023235

  13. Microvessel count predicts metastatic disease and survival in non-small cell lung cancer.

    PubMed

    Fontanini, G; Bigini, D; Vignati, S; Basolo, F; Mussi, A; Lucchi, M; Chine, S; Angeletti, C A; Harris, A L; Bevilacqua, G

    1995-09-01

    The growth of newly formed vessels, or neoangiogenesis, represents an important step in both physiological and pathological situations: in particular, tumour growth and metastasis require angiogenesis. Microvessel count (MC), which represents a measure of tumour angiogenesis, has been associated with metastatic spread in cutaneous, mammary, prostatic, head and neck, and early-stage lung cancer. In this study, the role of tumour angiogenesis as a prognostic indicator was examined in 253 primary non-small lung cancer (NSCLC) patients. Microvessels were counted by highlighting endothelial cells with anti-Factor VIII monoclonal antibody (Mab) in methacarn-fixed tumour samples. In univariat analysis, MC (P< 0.000001), sex (P=0.0036), histotype (P < 0.014), tumour status (P <0.007), and vessel invasion (P < 0.019) were significantly related to hilar and/or mediastinal nodal involvement. However, in the stepwise logistic regression analysis, MC (P<0.000003) retained the most important influence on nodal metastasis. The overall survival analysis calculated by the Kaplan-Meier method revealed that tumours with high MC ( > 25 vessels/field) were significantly associated with increased death risk (log-rank test P = 0.00067; Cox's test P = 0.00046; Gehan's Wilcoxon test P = 0.00108). In 94 patients, the development of metastatic disease during follow-up was significantly related to MC. Indeed, patients who developed metastasis during follow-up showed a higher MC, either as a dichotomous (P = 0.01) or as a continuous (P = 0.003) variable, than patients who had developed no metastasis at the time of the analysis. Moreover, in the stepwise logistic regression analysis, MC retained the most important influence on distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Tumor cell-driven extracellular matrix remodeling drives haptotaxis during metastatic progression

    PubMed Central

    Oudin, Madeleine J.; Jonas, Oliver; Kosciuk, Tatsiana; Broye, Liliane C.; Guido, Bruna C.; Wyckoff, Jeff; Riquelme, Daisy; Lamar, John M.; Asokan, Sreeja B.; Whittaker, Charlie; Ma, Duanduan; Langer, Robert; Cima, Michael J.; Wisinski, Kari B.; Hynes, Richard O.; Lauffenburger, Douglas A.; Keely, Patricia J.; Bear, James E.; Gertler, Frank B.

    2016-01-01

    Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration. PMID:26811325

  15. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors

    PubMed Central

    Cives, M; Kunz, P L; Morse, B; Coppola, D; Schell, M J; Campos, T; Nguyen, P T; Nandoskar, P; Khandelwal, V; Strosberg, J R

    2015-01-01

    Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response. PMID:25376618

  16. TLR8 Agonist VTX-2337 and Cyclophosphamide in Treating Patients With Metastatic, Persistent, Recurrent, or Progressive Solid Tumors

    ClinicalTrials.gov

    2016-06-15

    Colorectal Adenocarcinoma; Metastatic Pancreatic Adenocarcinoma; Recurrent Breast Carcinoma; Recurrent Colorectal Carcinoma; Recurrent Melanoma of the Skin; Recurrent Non-Small Cell Lung Carcinoma; Recurrent Pancreatic Carcinoma; Recurrent Renal Cell Carcinoma; Solid Neoplasm; Stage IV Breast Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Renal Cell Cancer; Stage IV Skin Melanoma; Stage IVA Colorectal Cancer; Stage IVA Pancreatic Cancer; Stage IVB Colorectal Cancer; Stage IVB Pancreatic Cancer

  17. Research results on biomagnetic imaging of the lung tumors

    NASA Astrophysics Data System (ADS)

    Sillerud, Laurel O.; Popa, Sorin G.; Coutsias, Evangelos A.; Sheltraw, Daniel; Kuethe, Dean; Adolphi, Natalie

    2005-04-01

    Recent results on the development and implementation of a novel technology for lung tumor detection and imaging is presented. This technology offers high-sensitivity imaging of magnetic nanoparticles to provide specific diagnostic images of early lung tumors and potential distant metastases. Recent developments in giant magnetostrictive (GMS) or magnetic shape memory (MSM) materials have led to the possibility of developing small, low-cost, room-temperature, portable, high-sensitivity, fiber-optic sensors capable of robustly detecting magnetic nanoparticles, without direct contact with the skin. Magnetic nanoparticles are conjugated with antibodies, which target them to lung tumors. A prototype fiber-optic biomagnetic sensor, based on giant magnetostrictive or magnetic shape memory materials, with the requisite sensitivity to image the magnetic signals generated by antibody-labeled magnetic nanoparticles in lung tumors has been built and calibrated. The uniqueness of the biomagnetic sensor lies in the fact that it offers high sensitivity at room temperature, and is not a SQUID-based system. The results obtained during the process of choosing the right magnetostrictive materials are presented. Then, for the construction of an accurate image of the lung tumor, the optimum spatial distribution of one-channel sensors and nanoparticle polarization has been analyzed.

  18. Tumor lysis syndrome in metastatic breast cancer after a single dose of paclitaxel.

    PubMed

    Vaidya, Gaurang Nandkishor; Acevedo, Russell

    2015-02-01

    Tumor lysis syndrome (TLS) is an oncologic emergency characterized by spillage of intracellular material into the blood caused by disruption of massive load of tumor cells. It is more commonly reported in hematological cancers and can have fatal consequences due to renal and multi-organ failure and arrhythmias due to electrolyte imbalance. We describe a case with metastatic breast cancer who presented with TLS after a single dose of paclitaxel, second such case in literature. The development of a risk stratification score to assess the need for hospitalization or close observation of these patients and the documentation of appropriate preventive strategies could help prevent such fatal occurrences. TLS should be included in the differential when cancer patients on treatment present with acute decompensation. PMID:25178848

  19. Preemptive tumor profiling for biomarker-stratified early clinical drug development in metastatic breast cancer patients.

    PubMed

    Welt, Anja; Tewes, Mitra; Aktas, Bahriye; O Hoffmann, Oliver; Wiesweg, Marcel; Ting, Saskia; Reis, Henning; Worm, Karl; Richly, Heike; Hense, Jörg; Palmer, Michael R; Lee, Benjamin H; Wendling, Johanna; Kossow, Josef; Scheulen, Max E; Lehnerdt, Cathrin; Kohl, Marzena; Derks, Cordula; Skottky, Silke; Haus, Ulrike; Schmid, Kurt W; Kimmig, Rainer; Schuler, Martin; Kasper, Stefan

    2013-11-01

    Biomarker-stratified cancer pharmacotherapy was pioneered in the care of breast cancer patients. The utility of agents modulating hormone receptors, synthesis of steroid hormones, or HER2-targeting agents has been greatly enhanced by the detection of predictive biomarkers in diagnostic tumor samples. Based on deeper understanding of breast cancer biology multiple drug candidates have been developed to modulate additional molecular targets which may associate with specific biomarker profiles. Accordingly, exploratory biomarkers are increasingly incorporated in early clinical trials, thus demanding a new process of patient selection. Here, we describe the implementation of preemptive, multiplexed biomarker profiling linked to standard diagnostic algorithms for metastatic breast cancer patients treated at the West German Cancer Center. Profiling for experimental biomarkers was prospectively offered to patients with metastatic breast cancer who met generic clinical trial inclusion criteria. Formalin-fixed, paraffin-embedded tumor samples were retrieved and studied for potentially “actionable” biomarkers related to active clinical trials by immunohistochemistry, amplicon sequencing, and in situ hybridization. The clinical course of those “profiled” patients was closely monitored to offer trial participation whenever applicable. Here, we report results from the first 131 patients enrolled in this program. PIK3CA mutations (23 %) and amplifications (2 %), loss of PTEN expression (13 %), and FGFR1 amplifications (8 %) were detected next to established biomarkers such as estrogen (67 %) and progesterone receptor expression (52 %), and HER2 overexpression or amplification (23 %). So far 16 “profiled” patients (12 %) have been enrolled in biomarker-stratified early clinical trials. Preemptive profiling of investigational biomarkers can be integrated into the diagnostic algorithm of a large Comprehensive Cancer Center. Extensive administrative efforts are required

  20. A Proteogenomic Approach to Understanding MYC Function in Metastatic Medulloblastoma Tumors

    PubMed Central

    Staal, Jerome A.; Pei, Yanxin; Rood, Brian R.

    2016-01-01

    Brain tumors are the leading cause of cancer-related deaths in children, and medulloblastoma is the most prevalent malignant childhood/pediatric brain tumor. Providing effective treatment for these cancers, with minimal damage to the still-developing brain, remains one of the greatest challenges faced by clinicians. Understanding the diverse events driving tumor formation, maintenance, progression, and recurrence is necessary for identifying novel targeted therapeutics and improving survival of patients with this disease. Genomic copy number alteration data, together with clinical studies, identifies c-MYC amplification as an important risk factor associated with the most aggressive forms of medulloblastoma with marked metastatic potential. Yet despite this, very little is known regarding the impact of such genomic abnormalities upon the functional biology of the tumor cell. We discuss here how recent advances in quantitative proteomic techniques are now providing new insights into the functional biology of these aggressive tumors, as illustrated by the use of proteomics to bridge the gap between the genotype and phenotype in the case of c-MYC-amplified/associated medulloblastoma. These integrated proteogenomic approaches now provide a new platform for understanding cancer biology by providing a functional context to frame genomic abnormalities. PMID:27775567

  1. Advances in Personalized Targeted Treatment of Metastatic Melanoma and Non-Invasive Tumor Monitoring

    PubMed Central

    Klinac, Dragana; Gray, Elin S.; Millward, Michael; Ziman, Mel

    2013-01-01

    Despite extensive scientific progress in the melanoma field, treatment of advanced stage melanoma with chemotherapeutics and biotherapeutics has rarely provided response rates higher than 20%. In the past decade, targeted inhibitors have been developed for metastatic melanoma, leading to the advent of more personalized therapies of genetically characterized tumors. Here we review current melanoma treatments and emerging targeted molecular therapies. In particular we discuss the mutant BRAF inhibitors Vemurafenib and Dabrafenib, which markedly inhibit tumor growth and advance patients’ overall survival. However this response is almost inevitably followed by complete tumor relapse due to drug resistance hampering the encouraging initial responses. Several mechanisms of resistance within and outside the MAPK pathway have now been uncovered and have paved the way for clinical trials of combination therapies to try and overcome tumor relapse. It is apparent that personalized treatment management will be required in this new era of targeted treatment. Circulating tumor cells (CTCs) provide an easily accessible means of monitoring patient relapse and several new approaches are available for the molecular characterization of CTCs. Thus CTCs provide a monitoring tool to evaluate treatment efficacy and early detection of drug resistance in real time. We detail here how advances in the molecular analysis of CTCs may provide insight into new avenues of approaching therapeutic options that would benefit personalized melanoma management. PMID:23515890

  2. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

    PubMed Central

    Anderberg, Charlotte; Cunha, Sara I.; Zhai, Zhenhua; Cortez, Eliane; Pardali, Evangelia; Johnson, Jill R.; Franco, Marcela; Páez-Ribes, Marta; Cordiner, Ross; Fuxe, Jonas; Johansson, Bengt R.; Goumans, Marie-José; Casanovas, Oriol; ten Dijke, Peter; Arthur, Helen M.

    2013-01-01

    Therapy-induced resistance remains a significant hurdle to achieve long-lasting responses and cures in cancer patients. We investigated the long-term consequences of genetically impaired angiogenesis by engineering multiple tumor models deprived of endoglin, a co-receptor for TGF-β in endothelial cells actively engaged in angiogenesis. Tumors from endoglin-deficient mice adapted to the weakened angiogenic response, and refractoriness to diminished endoglin signaling was accompanied by increased metastatic capability. Mechanistic studies in multiple mouse models of cancer revealed that deficiency for endoglin resulted in a tumor vasculature that displayed hallmarks of endothelial-to-mesenchymal transition, a process of previously unknown significance in cancer biology, but shown by us to be associated with a reduced capacity of the vasculature to avert tumor cell intra- and extravasation. Nevertheless, tumors deprived of endoglin exhibited a delayed onset of resistance to anti-VEGF (vascular endothelial growth factor) agents, illustrating the therapeutic utility of combinatorial targeting of multiple angiogenic pathways for the treatment of cancer. PMID:23401487

  3. Inhibition Effect of a Custom Peptide on Lung Tumors

    PubMed Central

    Huang, Chih-Yu; Huang, Hsuan-Yu; Forrest, Michael D.; Pan, Yun-Ru; Wu, Wei-Jen; Chen, Hueih-Min

    2014-01-01

    Cecropin B is a natural antimicrobial peptide and CB1a is a custom, engineered modification of it. In vitro, CB1a can kill lung cancer cells at concentrations that do not kill normal lung cells. Furthermore, in vitro, CB1a can disrupt cancer cells from adhering together to form tumor-like spheroids. Mice were xenografted with human lung cancer cells; CB1a could significantly inhibit the growth of tumors in this in vivo model. Docetaxel is a drug in present clinical use against lung cancers; it can have serious side effects because its toxicity is not sufficiently limited to cancer cells. In our studies in mice: CB1a is more toxic to cancer cells than docetaxel, but dramatically less toxic to healthy cells. PMID:25310698

  4. Primary Tumor Location as a Prognostic Factor in Metastatic Colorectal Cancer

    PubMed Central

    Loupakis, Fotios; Yang, Dongyun; Yau, Linda; Feng, Shibao; Cremolini, Chiara; Zhang, Wu; Maus, Martin K. H.; Antoniotti, Carlotta; Langer, Christiane; Scherer, Stefan J.; Müller, Thomas; Hurwitz, Herbert I.; Saltz, Leonard; Falcone, Alfredo

    2015-01-01

    Background: We sought to clarify the prognostic impact of primary tumor location in metastatic colorectal cancer (mCRC). Methods: We evaluated the association between tumor location and survival parameters in patients with previously untreated mCRC receiving first-line chemotherapy ± bevacizumab in three independent cohorts: a prospective pharmacogenetic study (PROVETTA) and two randomized phase III trials, AVF2107g and NO16966. Cancers proximal or distal of the splenic flexure were classified as right-sided or left-sided, respectively. The primary end point was overall survival (OS). Data were analyzed with Cox proportional hazards and logistic regression models. All statistical tests were two-sided. Results: Among evaluable patients in the PROVETTA (n = 200), AVF2107g (n = 559), and NO16966 (n = 1268) studies, 72.0%, 63.1%, and 73.7% had left-sided tumors, respectively. In PROVETTA, patients with left-sided tumors had superior OS (left-sided vs right-sided: hazard ratio [HR] = .44, 95% confidence interval [CI] = .28 to .70, P < .001) and progression-free survival (HR = .52, 95% CI = .36 to .75, P < .001) outcomes. Multivariable analyses confirmed right-sided location as a negative prognostic variable, independent of mucinous histology and BRAF mutational status. Data from the AVF2107g (HR for OS = .55, 95% CI = .43 to .70) and NO16966 trials (HR for OS = .71, 95% CI = .62 to .82 both P < .001) also showed favorable outcomes in patients with left-sided tumors. In both randomized studies, the efficacy of bevacizumab was independent of tumor location. Conclusions: These data demonstrate that primary tumor location is an important prognostic factor in previously untreated mCRC. Given the consistency across an exploratory set and two confirmatory phase III studies, side of tumor origin should be considered for stratification in randomized trials. PMID:25713148

  5. Acute Abdominal Pain after Intercourse: Adrenal Hemorrhage as the First Sign of Metastatic Lung Cancer

    PubMed Central

    Packer, Clifford D.

    2014-01-01

    Although the adrenal glands are a common site of cancer metastases, they are often asymptomatic and discovered incidentally on CT scan or autopsy. Spontaneous adrenal hemorrhage associated with metastatic lung cancer is an exceedingly rare phenomenon, and diagnosis can be difficult due to its nonspecific symptoms and ability to mimic other intra-abdominal pathologies. We report a case of a 65-year-old man with a history of right upper lobectomy seven months earlier for stage IB non-small cell lung cancer who presented with acute abdominal pain after intercourse. CT scan revealed a new right adrenal mass with surrounding hemorrhage, and subsequent FDG-PET scan confirmed new metabolic adrenal metastases. The patient's presentation of abdominal pain and adrenal hemorrhage immediately after sexual intercourse suggests that exertion, straining, or increased intra-abdominal pressure might be risk factors for precipitation of hemorrhage in patients with adrenal metastases. Management includes pain control and supportive treatment in mild cases, with arterial embolization or adrenalectomy being reserved for cases of severe hemorrhage. PMID:25126096

  6. Early tumor cavitation with regorafenib in metastatic colorectal cancer: A case report

    PubMed Central

    KAWASAKI, KENTA; HAMAMOTO, YASUO; ADACHI, MASAYUKI; KANAI, TAKANORI; TAKAISHI, HIROMASA

    2016-01-01

    Tumoral cavity formation is a characteristic phenomenon reported in anti-angiogenic therapy in lung lesions. A 57-year-old male with multiple pulmonary metastases from colorectal cancer treated with an oral tyrosine kinase inhibitor, regorafenib, exhibited a characteristic cavity formation after the first two cycles. The decrease in the size of tumors was calculated as 38%, and there were associated decreases in the serum concentrations of the tumor markers carcinoembryonic antigen and CA19-9. After eight cycles of treatment, the cavity gradually disappeared through filling-in. This unique morphological response is not only reported in lung cancer but also in liver metastasis in colorectal cancer. However, the association between morphological changes including cavity formation and clinical benefit remains controversial. Pulmonary hemorrhage and pneumothorax are well-known consequences of cavitation, as reported with the other anti-angiogenic inhibitors. Early tumor cavitation in lung metastasis may demonstrate the predictive potential of regorafenib in colorectal cancer, although it is necessary to be mindful of toxicity. PMID:26870193

  7. Benefit-Risk Summary of Crizotinib for the Treatment of Patients With ROS1 Alteration-Positive, Metastatic Non-Small Cell Lung Cancer

    PubMed Central

    Blumenthal, Gideon M.; Luo, Lola; He, Kun; Fran, Ingrid; Lemery, Steven; Pazdur, Richard

    2016-01-01

    On March 11, 2016, after an expedited 5-month review, the U.S. Food and Drug Administration expanded the crizotinib metastatic non-small cell lung cancer (mNSCLC) indication to include the treatment of patients whose tumors harbor a ROS1 rearrangement. The approval was based on a clinically meaningful, durable objective response rate (ORR) in a multicenter, single-arm clinical trial (ROS1 cohort of Trial PROFILE 1001) in patients with ROS1-positive mNSCLC. The trial enrolled 50 patients (age range: 25–77 years) whose tumors were prospectively determined to have a ROS1 gene rearrangement by break-apart fluorescence in situ hybridization (96%) or reverse transcriptase polymerase chain reaction (4%) clinical trial assays. Crizotinib demonstrated an ORR of 66% (95% confidence interval [CI]: 51%–79%) with a median duration of response of 18.3 months by independent radiology review and 72% (95% CI: 58%–84%) by investigator review. Patients received crizotinib 250 mg twice daily and had a median duration of exposure of 34.4 months. The toxicity profile in ROS1-positive patients was generally consistent with the randomized safety data in the U.S. Product Insert from two ALK-positive mNSCLC trials. The most common (≥25%) adverse reactions and laboratory test abnormalities included vision disorders, elevation of alanine transaminase and aspartate transaminase levels, nausea, hypophosphatemia, diarrhea, edema, vomiting, constipation, neutropenia, and fatigue. There were no treatment-related deaths. A favorable benefit-to-risk evaluation led to the traditional approval of crizotinib for this new supplemental indication. Implications for Practice: Given the results from the ROS1 cohort of the clinical trial PROFILE 1001, crizotinib represents a new treatment option and the first approved therapy for patients with metastatic non-small cell lung cancer whose tumors are ROS1 positive. Crizotinib demonstrated efficacy irrespective of prior treatment status. PMID:27328934

  8. Multi-course PDT of malignant tumors: the influence on primary tumor, metastatic spreading and homeostasis of cancer patients

    NASA Astrophysics Data System (ADS)

    Sokolov, Victor V.; Chissov, Valery I.; Yakubovskaya, Raisa I.; Filonenko, E. V.; Sukhin, Garry M.; Nemtsova, E. R.; Belous, T. A.; Zharkova, Natalia N.

    1996-12-01

    The first clinical trials of photodynamic therapy (PDT) of cancer with two photosensitizers, PHOTOHEME and PHOTOSENS, were started in P.A. Hertzen Research Oncological Institute (Moscow, Russia) in 1992 and 1994. Up to now, 208 patients with primary, recurrent and metastatic malignant tumors (469) of skin (34 patients/185 tumors), breast cancer (24/101), head and neck (30/31), trachea and bronchus (31/42), esophagus (35/35), stomach (31/32), rectum (4/4), vagina and uterine cervix (7/8) and bladder (12/31) have been treated by PDT. One-hundred-thirty patients were injected with PHOTOHEME, 64 patients were injected with PHOTOSENS, 14 patients were injected with PHOTOHEME and PHOTOSENS. Totally, 302 courses of treatment were performed: 155 patients had one course and 53 patients were subjected to two to nine PDT sources with intervals from 1 to 18 months. A therapeutic effect of a one-course and multi- course PDT of malignant tumors (respiratory, digestive and urogenital systems) was evaluated clinically, histologically, roentgenologically, sonographically and endoscopically. The biochemical, hematological and immunological investigations were performed for all the patients in dynamics. Results of our study showed that a multi-course PDT method seems to be perspective in treatment of malignant tumors of basic localizations.

  9. Sublingual Vaccination Induces Mucosal and Systemic Adaptive Immunity for Protection against Lung Tumor Challenge

    PubMed Central

    Singh, Shailbala; Yang, Guojun; Schluns, Kimberly S.; Anthony, Scott M.; Sastry, K. Jagannadha

    2014-01-01

    Sublingual route offers a safer and more practical approach for delivering vaccines relative to other systemic and mucosal immunization strategies. Here we present evidence demonstrating protection against ovalbumin expressing B16 (B16-OVA) metastatic melanoma lung tumor formation by sublingual vaccination with the model tumor antigen OVA plus synthetic glycolipid alpha-galactosylceramide (aGalCer) for harnessing the adjuvant potential of natural killer T (NKT) cells, which effectively bridge innate and adaptive arms of the immune system. The protective efficacy of immunization with OVA plus aGalCer was antigen-specific as immunized mice challenged with parental B16 tumors lacking OVA expression were not protected. Multiple sublingual immunizations in the presence, but not in the absence of aGalCer, resulted in repeated activation of NKT cells in the draining lymph nodes, spleens, and lungs of immunized animals concurrent with progressively increasing OVA-specific CD8+ T cell responses as well as serum IgG and vaginal IgA levels. Furthermore, sublingual administration of the antigen only in the presence of the aGalCer adjuvant effectively boosted the OVA-specific immune responses. These results support potential clinical utility of sublingual route of vaccination with aGalCer-for prevention of pulmonary metastases. PMID:24599269

  10. The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.

    PubMed

    Liekens, Sandra; Noppen, Sam; Gijsbers, Sofie; Sienaert, Rebecca; Ronca, Roberto; Tobia, Chiara; Presta, Marco

    2015-03-10

    The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy. PMID:25609197

  11. Dimethylarginine dimethylaminohydrolase 2 promotes tumor angiogenesis in lung adenocarcinoma.

    PubMed

    Shiozawa, Toshihiro; Iyama, Shinji; Toshima, Shotaro; Sakata, Akiko; Usui, Shingo; Minami, Yuko; Sato, Yukio; Hizawa, Nobuyuki; Noguchi, Masayuki

    2016-02-01

    Although embryonal proteins have been used as tumor marker, most are not useful for detection of early malignancy. In the present study, we developed mouse monoclonal antibodies against fetal lung of miniature swine, and screened them to find an embryonal protein that is produced at the early stage of malignancy, focusing on lung adenocarcinoma. We found an antibody clone that specifically stained stroma of lung adenocarcinoma. LC-MS/MS identified the protein recognized by this clone as dimethylarginine dimethylaminohydrolase 2 (DDAH2), an enzyme known for antiatherosclerotic activity. DDAH2 was found to be expressed in fibroblasts of stroma of malignancies, with higher expression in minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma than in adenocarcinoma in situ (AIS). Moreover, tumors with high stromal expression of DDAH2 had a poorer prognosis than those without. In vitro analysis showed that DDAH2 increases expression of endothelial nitric oxide synthase (eNOS), inducing proliferation and capillary-like tube formation of vascular endothelial cells. In resected human tissues, eNOS also showed higher expression in invasive adenocarcinoma than in AIS and normal lung, similarly to DDAH2. Our data indicate that expression of DDAH2 is associated with invasiveness of lung adenocarcinoma via tumor angiogenesis. DDAH2 expression might be a prognostic factor in lung adenocarcinoma.

  12. Pulmonary Artery Pseudoaneurysm Related to Radiofrequency Ablation of Lung Tumor

    SciTech Connect

    Sakurai, Jun Mimura, Hidefumi; Gobara, Hideo; Hiraki, Takao; Kanazawa, Susumu

    2010-04-15

    We describe a case of pulmonary artery (PA) pseudoaneurysm related to radiofrequency ablation (RFA) of lung tumor. We performed RFA for a pulmonary epithelioid hemangioendothelioma directly adjacent to a branch of the PA. Seventeen days later, the patient complained of hemoptysis. A chest CT image revealed PA pseudoaneurysm. Transcatheter coil embolization was performed 59 days after RFA. Although PA pseudoaneurysm is rare, with an incidence of 0.2% (1/538 sessions) at our institution, it should be recognized as a risk when treating lung tumors adjacent to a branch of the PA.

  13. Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer.

    PubMed

    Luporini, G; Barni, S; Marchi, E; Daffonchio, L

    1998-07-01

    Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.i.d.) were evaluated in comparison with dihydrocodeine drops (10 mg t.i.d.; 7 days). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurring during the clinical trial, including presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with either levodropropizine and dihydrocodeine, the antitussive effect and its time-profile being similar for both drugs. Also, according to the investigator's evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n=6) and dihydrocodeine (n=4) group. However, the percentage of patients experiencing somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favourable benefit/risk profile when compared to dihydrocodeine.

  14. Efficacy and safety of levodropropizine and dihydrocodeine on nonproductive cough in primary and metastatic lung cancer.

    PubMed

    Luporini, G; Barni, S; Marchi, E; Daffonchio, L

    1998-07-01

    Nonproductive cough is a frequent and distressing symptom in patients with lung cancer, and it is not even relieved by palliative chemotherapy. A double-blind, randomized clinical trial regarding the treatment of nonproductive cough was performed in 140 adults with primary lung cancer or metastatic cancer of the lungs. The therapeutic efficacy and the tolerability of a 7-day treatment with levodropropizine drops (75 mg t.i.d.) were evaluated in comparison with dihydrocodeine drops (10 mg t.i.d.; 7 days). Efficacy was assessed on the basis of cough severity scores, number of night awakenings due to cough, and overall estimate of antitussive efficacy. Tolerability was evaluated by laboratory results, vital signs and any adverse event occurring during the clinical trial, including presence or absence of somnolence. Subjective cough severity was significantly reduced during treatment with either levodropropizine and dihydrocodeine, the antitussive effect and its time-profile being similar for both drugs. Also, according to the investigator's evaluation, both levodropropizine and dihydrocodeine produced a significant decrease in cough severity. Concurrently with the relief of cough, the number of night awakenings was decreased significantly by both drugs, with no difference between the two treatments. No change in laboratory test values was considered clinically relevant, and vital signs were not clinically affected. The number of patients reporting adverse events was similar in the levodropropizine (n=6) and dihydrocodeine (n=4) group. However, the percentage of patients experiencing somnolence in the group receiving levodropropizine (8%) was significantly lower as compared with that of the dihydrocodeine group (22%). These results confirm the antitussive effectiveness of levodropropizine and suggest a more favourable benefit/risk profile when compared to dihydrocodeine. PMID:9701421

  15. Influence of patient's physiologic factors and immobilization choice with stereotactic body radiotherapy for upper lung tumors.

    PubMed

    Sio, Terence T; Jensen, Andrew R; Miller, Robert C; Fong de los Santos, Luis E; Hallemeier, Christopher L; Foster, Nathan R; Park, Sean S; Bauer, Heather J; Chang, Kenneth; Garces, Yolanda I; Olivier, Kenneth R

    2014-09-08

    The purpose of the present study was to compare the impact of pulmonary function, body habitus, and stereotactic body radiation therapy (SBRT) immobilization on setup and reproducibility for upper lung tumor. From 2008 through 2011, our institution's prospective SBRT database was searched for patients with upper lung tumors. Two SBRT immobilization strategies were used: full-length BodyFIX and thermoplastic S-frame. At simulation, free-breathing, four-dimensional computed tomography was performed. For each treatment, patients were set up to isocenter with in-room lasers and skin tattoos. Shifts from initial and subsequent couch positions with cone-beam computed tomography (CBCT) were analyzed. Accounting for setup uncertainties, institutional tolerance of CBCT-based shifts for treatment was 2, 2, and 4 mm in left-right, anterior-posterior, and cranial-caudal directions, respectively; shifts exceeding these limits required reimaging. Each patient's pretreatment pulmonary function test was recorded. A multistep, multivariate linear regression model was performed to elucidate intervariable dependency for three-dimensional calculated couch shift parameters. BodyFIX was applied to 76 tumors and S-frame to 17 tumors. Of these tumors, 41 were non-small cell lung cancer and 15 were metastatic from other sites. Lesions measured < 1 (15%), 1.1 to 2 (50%), 2.1 to 3 (25%), and > 3 (11%) cm. Errors from first shifts of first fractions were significantly less with S-frame than BodyFIX (p < 0.001). No difference in local control (LC) was found between S-frame and BodyFIX (p = 0.35); two-year LC rate was 94%. Multivariate modeling confirmed that the ratio of forced expiratory volume in the first second of expiration to forced vital capacity, body habitus, and the immobilization device significantly impacted couch shift errors. For upper lung tumors, initial setup was more consistent with S-frame than BodyFIX, resulting in fewer CBCT scans. Patients with obese habitus and poor lung

  16. Enhanced Quitline Intervention in Smoking Cessation for Patients With Non-Metastatic Lung Cancer

    ClinicalTrials.gov

    2015-09-28

    Limited Stage Small Cell Lung Cancer; Recurrent Small Cell Lung Cancer; Stage IA Non-small Cell Lung Cancer; Stage IB Non-small Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Tobacco Use Disorder

  17. Use of Palliative Radiotherapy Among Patients With Metastatic Non-Small-Cell Lung Cancer

    SciTech Connect

    Hayman, James A. Abrahamse, Paul H.; Lakhani, Indu; Earle, Craig C.; Katz, Steven J.

    2007-11-15

    Purpose: Radiotherapy (RT) is known to effectively palliate many symptoms of patients with metastatic non-small-cell lung cancer (NSCLC). Anecdotally, RT is believed to be commonly used in this setting, but limited population-based data are available. The objective of this study was to examine the utilization patterns of palliative RT among elderly patients with Stage IV NSCLC and, in particular, to identify factors associated with its use. Methods and Materials: A retrospective population-based cohort study was performed using linked Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify 11,084 Medicare beneficiaries aged {>=}65 years who presented with Stage IV NSCLC in the 11 SEER regions between 1991 and 1996. The primary outcome was receipt of RT. Logistic regression analysis was used to identify factors associated with receipt of RT. Results: A total of 58% of these patients received RT, with its use decreasing over time (p = 0.01). Increasing age was negatively associated with receipt of treatment (p <0.001), as was increasing comorbidities (p <0.001). Factors positively associated with the receipt of RT included income (p = 0.001), hospitalization (p <0.001), and treatment with chemotherapy (p <0.001). Although the use varied across the SEER regions (p = 0.001), gender, race/ethnicity, and distance to the nearest RT facility were not associated with treatment. Conclusions: Elderly patients with metastatic NSCLC frequently receive palliative RT, but its use varies, especially with age and receipt of chemotherapy. Additional research is needed to determine whether this variability reflects good quality care.

  18. Stereotactic body radiotherapy (SBRT) with or without surgery for primary and metastatic liver tumors

    PubMed Central

    Kirichenko, Alexander; Gayou, Olivier; Parda, David; Kudithipudi, Vijay; Tom, Kusum; Khan, Akhtar; Abrams, Peter; Szramowski, Molly; Oliva, Jose; Monga, Dulabh; Raj, Moses; Thai, Ngoc

    2015-01-01

    Objectives We report single center experience on the outcome and toxicity of SBRT alone or in combination with surgery for inoperable primary and metastatic liver tumors between 2007 and 2014. Patients and methods Patients with 1–4 hepatic lesions and tumor diameter ≤9 cm received SBRT at 46.8Gy ± 3.7 in 4–6 fractions. The primary end point was local control with at least 6 months of radiographic followup, and secondary end points were toxicity and survival. Results Eighty-seven assessable patients (114 lesions) completed liver SBRT for hepatoma (39) or isolated metastases (48) with a median followup of 20.3 months (range 1.9–64.1). Fourteen patients underwent liver transplant with SBRT as a bridging treatment or for tumor downsizing. Eight patients completed hepatic resections in combination with planned SBRT for unresectable tumors. Two-year local control was 96% for hepatoma and 93.8% for metastases; it was 100% for lesions ≤4 cm. Two-year overall survival was 82.3% (hepatoma) and 64.3% (metastases). No incidence of grade >2 treatment toxicity was observed. Conclusion In this retrospective analysis we demonstrate that liver SBRT alone or in combination with surgery is safe and effective for the treatment of isolated inoperable hepatic malignancies and provides excellent local control rates. PMID:26776856

  19. Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.

    PubMed

    Mulens-Arias, Vladimir; Rojas, José Manuel; Pérez-Yagüe, Sonia; Morales, María del Puerto; Barber, Domingo F

    2015-10-28

    Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.

  20. Differentiation of Reactive and Tumor Metastatic Lymph Nodes with Diffusion-weighted and SPIO Enhanced MRI

    PubMed Central

    Zhang, Fan; Zhu, Lei; Huang, Xinglu; Niu, Gang; Chen, Siouan

    2012-01-01

    Objectives Determination of lymphatic metastasis is of great importance for both treatment planning and patient prognosis. We aim to distinguish tumor metastatic lymph nodes (TLNs) and reactive lymph nodes (RLNs) with diffusion-weighted and superparamagnetic iron oxide (SPIO) enhanced magnetic resonance imaging (MRI). Materials and methods Ipsilateral popliteal lymph node metastasis or lymphadenitis model was established by hock injection of either luciferase-expressing 4T1 murine breast cancer cells or Complete Freund Adjuvant (CFA) in male Balb/C mice. At different time points after inoculation, bioluminescence imaging, T2-weighted, diffusion-weighted and SPIO enhanced MRI were performed. Imaging findings were confirmed by histopathological staining. Results Size enlargement was observed in both TLNs and RLNs. At day 28, TLNs showed strong bioluminescence signal and bigger size than RLNs (p < 0.01). At early stages up to day 21, both TLNs and RLNs appeared homogeneous on diffusion-weighted imaging (DWI). At day 28, TLNs showed heterogeneous apparent diffusion coefficient (ADC) map with significantly higher average ADC value of 0.41 ± 0.03 × 10−3 mm2/s than that of RLNs (0.34 ± 0.02 10−3 mm2/s, p < 0.05). On SPIO enhanced MRI, both TLNs and RLNs showed distinct T2 signal reduction at day 21 after inoculation. At day 28, TLNs demonstrated partial uptake of the iron oxide particles, which was confirmed by Prussian blue staining. Conclusions Both diffusion-weighted and SPIO enhanced MRI can distinguish tumor metastatic lymph nodes from reactive lymph nodes. However, neither method is able to detect tumor metastasis to the draining lymph nodes at early stages. PMID:22588595

  1. Effect of pedicle fixation combined with 125I seed implantation for metastatic thoracolumbar tumors

    PubMed Central

    Qian, Jiale; Bao, Zhaohua; Zou, Jun; Yang, Huilin

    2016-01-01

    Purpose The aim of this study was to investigate the clinical efficacy of pedicle fixation combined with 125I brachytherapy in treating metastatic thoracolumbar tumors. Patients and methods A retrospective analysis of the clinical data of seven metastatic thoracolumbar tumor patients who received pedicle fixation combined with radioactive 125I seed implantation brachytherapy in our department between January 2009 and December 2013 was performed. The visual analog scale (VAS) for pain and the Karnofsky performance status (KPS) score before the operation and 1, 6, and 12 months after the operation were observed and recorded. The changes in the scores at each time point were compared. Results All the patients underwent a successful operation, without any complications during their hospitalization. All the patients received postoperative follow-up, and the duration of follow-up was 15–50 months, with an average of 32.2 months. One pancreatic cancer patient died of liver failure and hypoproteinemia 28 months post surgery. The VAS scores of patients before the operation and 1, 6, and 12 months after the operation were 7.43±0.98, 2.71±0.49, 3.00±0.82, and 4.29±0.98, respectively; the KPS scores were 52.9±9.5, 84.3±5.3, 75.7±5.3, and 72.9±4.9, respectively. These results suggest that the VAS score at each time point was significantly decreased compared with that before the operation, while the KPS score was significantly increased compared with that before the operation. Both differences had statistical significance (P<0.05). Conclusion As a therapy for advanced malignant tumors with thoracolumbar metastasis, pedicle fixation combined with 125I brachytherapy can effectively relieve short-term pain and improve patient’s quality of life. PMID:27274307

  2. Host-derived MCP-1 and MIP-1α regulate protective anti-tumor immunity to localized and metastatic B16 melanoma.

    PubMed

    Nakasone, Yuko; Fujimoto, Manabu; Matsushita, Takashi; Hamaguchi, Yasuhito; Huu, Doanh Le; Yanaba, Mizuki; Sato, Shinichi; Takehara, Kazuhiko; Hasegawa, Minoru

    2012-01-01

    Leukocytic infiltration into malignant melanoma lesions is tightly regulated by chemokines. To assess the role of the CC chemokines monocyte chemotactic protein-1 (MCP-1/chemokine ligand 2) and macrophage inflammatory protein-1α (MIP-1α/chemokine ligand 3) in this process, s.c. primary and metastatic B16 F10 melanoma tumor growth levels were examined in mice lacking MCP-1 or MIP-1α. Primary s.c. B16 F10 melanoma growth was augmented by loss of MCP-1 or MIP-1α. Similarly, lung metastasis was enhanced by the deficiency of MCP-1 or MIP-1α. Enhanced tumor outgrowth was associated with decreased percentages of infiltrating CD4(+) T cells, CD8(+) T cells, and natural killer cells. In the absence of MCP-1 or MIP-1α, melanoma outgrowth was correlated with reduced local expression of interferon-γ, IL-6, tumor necrosis factor-α, and transforming growth factor-β. Among these cytokines, reduced expression levels of interferon-γ and tumor necrosis factor-α on leukocytes from the spleen were associated with the development of lung metastasis in chemokine-deficient mice. The local s.c. administration of these four cytokines significantly augmented another chemokine's expression and suppressed primary melanoma growth in mice deficient for MCP-1 or MIP-1α. The s.c. injection of MCP-1 or MIP-1α significantly inhibited the primary tumor growth in wild-type mice. These results indicate that host-derived MCP-1 and MIP-1α regulate protective anti-tumor immunity to B16 F10 melanoma by promoting lymphocyte infiltration into the tumor and subsequent cytokine production.

  3. Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens.

    PubMed

    Prickett, Todd D; Crystal, Jessica S; Cohen, Cyrille J; Pasetto, Anna; Parkhurst, Maria R; Gartner, Jared J; Yao, Xin; Wang, Rong; Gros, Alena; Li, Yong F; El-Gamil, Mona; Trebska-McGowan, Kasia; Rosenberg, Steven A; Robbins, Paul F

    2016-08-01

    Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669-78. ©2016 AACR.

  4. Alpha-carotene inhibits metastasis in Lewis lung carcinoma in vitro, and suppresses lung metastasis and tumor growth in combination with taxol in tumor xenografted C57BL/6 mice.

    PubMed

    Liu, Yi-Zhen; Yang, Chih-Min; Chen, Jen-Yin; Liao, Junn-Wang; Hu, Miao-Lin

    2015-06-01

    This study aimed to investigate the anti-metastatic activity of α-carotene (AC) in Lewis lung carcinoma (LLC) and in combination with taxol in LLC-xenografted C57BL/6 mice. Cell culture studies reveal that AC significantly inhibited invasion, migration and activities of matrix metalloproteinase (MMP)-2, -9 and urokinase plasminogen activator but increased protein expression of tissue inhibitor of MMP (TIMP)-1, -2 and plasminogen activator inhibitor (PAI)-1. These effects of AC are similar to those of β-carotene at the same concentration (2.5 μM). AC (2.5 μM) also significantly inhibited integrin β1-mediated phosphorylation of focal adhesion kinase (FAK) which then decreased the phosphorylation of MAPK family. Findings from the animal model reveal that AC treatment (5m g/kg) alone significantly decreased lung metastasis without affecting primary tumor growth, whereas taxol treatment (6 mg/kg) alone exhibited significant inhibition on both actions, as compared to tumor control group. AC treatment alone significantly decreased protein expression of integrin β1 but increased protein expression of TIMP-1 and PAI-1 without affecting protein expression of TIMP-2 and phosphorylation of FAK in lung tissues, whereas taxol treatment alone significantly increased protein expression of TIMP-1, PAI-1 and TIMP-2 but decreased protein expression of integrin β1 and phosphorylation of FAK. The combined treatment produced stronger actions on lung metastasis and lung tissues protein expression of TIMP-1, TIMP-2 and PAI-1. Overall, we demonstrate that AC effectively inhibits LLC metastasis and suppresses lung metastasis in combination with taxol in LLC-bearing mice, suggesting that AC could be used as an anti-metastatic agent or as an adjuvant for anti-cancer drugs.

  5. Identification and evaluation of metastasis-related proteins, oxysterol binding protein-like 5 and calumenin, in lung tumors.

    PubMed

    Nagano, Kazuya; Imai, Sunao; Zhao, Xiluli; Yamashita, Takuya; Yoshioka, Yasuo; Abe, Yasuhiro; Mukai, Yohei; Kamada, Haruhiko; Nakagawa, Shinsaku; Tsutsumi, Yasuo; Tsunoda, Shin-Ichi

    2015-07-01

    Metastasis is an important prognosis factor in lung cancer, therefore, it is imperative to identify target molecules and elucidate molecular mechanism of metastasis for developing new therapeutics and diagnosis methods. We searched for metastasis-related proteins by utilizing a novel antibody proteome technology developed in our laboratory that facilitated efficient screening of useful target proteins. Two-dimensional differential in-gel electrophoresis (2D-DIGE) analysis identified sixteen proteins, which were highly expressed in metastatic lung cancer cells, as protein candidates. Monoclonal single-chain variable fragments (scFvs) binding to candidates were isolated from a scFv-displaying phage library by affinity selection. Tissue microarray analysis of scFvs binding to candidates revealed that oxysterol binding protein-like 5 (OSBPL5) and calumenin (CALU) were expressed at a significantly higher levels in the lung tissues of metastasis-positive cases than that in the metastasis-negative cases (OSBPL5; p=0.0156, CALU; p=0.0055). Furthermore, 80% of OSBPL5 and CALU double-positive cases were positive for lymph node metastasis. Consistent with these observations, overexpression of OSBPL5 and CALU promoted invasiveness of lung cancer cells. Conversely, knockdown of these proteins using respective siRNAs reversed the invasiveness of the lung cancer cells. Moreover, these proteins were expressed in lung tumor tissues, but not in normal lung tissues. In conclusion, OSBPL5 and CALU are related to metastatic potential of lung cancer cells, and they could be useful targets for cancer diagnosis and also for development of drugs against metastasis.

  6. Unbiased quantitative assessment of Her-2 expression of circulating tumor cells in patients with metastatic and non-metastatic breast cancer.

    PubMed

    Ligthart, S T; Bidard, F-C; Decraene, C; Bachelot, T; Delaloge, S; Brain, E; Campone, M; Viens, P; Pierga, J-Y; Terstappen, L W M M

    2013-05-01

    Background Circulating tumor cells (CTCs) can provide the basis for a liquid biopsy and may guide the use of targeted therapies. We report on unbiased quantification of Her-2 protein expression of CTCs. Patients and methods Her-2 assessment of CTCs was carried out using the CellSearch(®) system in 103 metastatic (M1) and 88 non-metastatic (M0) breast-cancer patients. Expression of Her-2 on CTCs was determined by a manual review and an automated algorithm using Her-2- fluorescein isothiocyanate (FITC) fluorescence of leukocytes to determine the Her-2-expression threshold in each sample. Results Her-2 expression of CTCs varied greatly within and among patients compared with Her-2 expression of leukocytes. In M1 patients, a threshold of 75% of Her-2 positive CTCs in patients with ≥5 CTCs was set. Applying this threshold, 9% of M1 patients with Her-2-negative primary tumors had Her-2-positive CTC status and 29% of M1 patients with Her-2-positive primary tumors had Her-2-negative CTC status. No Her-2 discrepancy was observed between CTCs and primary tumors in M0 patients. Conclusions Our findings demonstrate that Her-2 expression is heterogeneous among CTCs within each patient. We show the feasibility of unbiased quantitative and reproducible assessment of treatment targets on CTCs, opening a path towards personalized treatment.

  7. Increased estrogen sulfation of estradiol 17beta-D-glucuronide in metastatic tumor rat livers.

    PubMed

    Sun, Huadong; Liu, Lichuan; Pang, K Sandy

    2006-11-01

    Changes in the disposition of estradiol 17beta-d-glucuronide (E(2)17G), a substrate of the organic anion-transporting polypeptide family (Oatp) and multidrug resistance-associated protein 2 (Mrp2), were examined in livers of male Wag/Rij rats that were injected with CC531 cells intraportally to induce metastatic tumors (n = 5) or with phosphate-buffered saline for sham-operated controls (n = 4). Multiple indicator dilution, single-pass liver perfusions revealed extremely high influx clearances of [(3)H]E(2)17G (>190 ml/min) in both groups. In recirculating liver perfusions, [(3)H]E(2)17G decayed monoexponentially in the reservoir perfusate, and the total (9.19 +/- 1.33 versus 8.18 +/- 0.94 ml/min) and biliary (4.94 +/- 1.07 versus 4.60 +/- 0.86 ml/min) clearances were similar in both groups (P > 0.05). The metabolic clearance of E(2)17G was higher in the tumor group (4.60 +/- 0.64 versus 3.23 +/- 0.23 ml/min, P < 0.05). E(2)3S17G, the 3-sulfate metabolite, whose identity was confirmed by mass spectrometry, appeared only in bile and not perfusate. Liver microsomal incubations of E(2)3(35)S17G and [(3)H]estrone sulfate revealed similar sulfatase activities between the tumor and sham livers, albeit the activities were much lower for E(2)3(35)S17G. Oatp1a1 and Oatp1b2 protein expression in liver membrane fragments was reduced by 42% and 38%, respectively, whereas that of cytosolic estrogen sulfotransferase (Sult1e1) was significantly increased (41%) with tumor (P < 0.05). All of the observations were captured by modeling. From modeling, we showed that reduction of the high influx clearance (546 to 283 ml/min) failed to lower the total clearance of E(2)17G, whereas up-regulation of Sult1e1 increased the E(2)17G sulfation clearance (2.56 to 3.69 ml/min) in livers with metastatic tumors. PMID:16895976

  8. Circulating tumour cells and lung microvascular tumour cell retention in patients with metastatic breast and cervical cancer.

    PubMed

    Peeters, Dieter J E; Brouwer, Anja; Van den Eynden, Gert G; Rutten, Annemie; Onstenk, Wendy; Sieuwerts, Anieta M; Van Laere, Steven J; Huget, Philippe; Pauwels, Patrick; Peeters, Marc; Vermeulen, Peter B; Dirix, Luc Y

    2015-01-28

    We have shown that in up to half of the patients with metastatic breast cancer (MBC), higher numbers of circulating tumour cells (CTCs) are present in the central venous blood (CVB) compared to the peripheral venous blood (PVB), suggesting that the lungs might retain a substantial number of CTCs. Here we report the presence of tumour cell emboli (TCE) in the microvasculature of the lungs in three out of eight patients with MBC and one patient with metastatic cervical carcinoma who had markedly elevated numbers of CTCs in the blood. All these patients suffered from symptomatic dyspnoea not easily attributable to other causes. No TCE were observed in five patients with MBC and elevated CTC counts and three patients with MBC who had low CTC counts (<5/7.5 ml). To investigate whether CTCs derived from CVB or PVB exhibit different transcriptional characteristics that might explain selective CTC retention, paired CTC samples from CVB and PVB of 12 patients with advanced breast cancer were subjected to gene expression analysis of 105 genes. No significant differences in CTC gene expression were observed. Together, these data suggest that potentially clinically relevant CTC retention in the microvasculature of the lung can occur in a subset of patients with advanced metastatic breast and cervical cancer, which seems to be transcriptionally non-selectively.

  9. Epidermal growth factor receptor expression in radiation-induced dog lung tumors by immunocytochemical localization

    SciTech Connect

    Leung, F.L.; Park, J.F.; Dagle, G.E.

    1993-06-01

    In studies to determine the role of growth factors in radiation-induced lung cancer, epidermal growth factor (EGFR) expression was examined by immunocytochemistry in 51 lung tumors from beagle dogs exposed to inhaled plutonium; 21 of 51 (41%) tumors were positive for EGFR. The traction of tumors positive for EGFR and the histological type of EGFR-positive tumors in the plutonium-exposed dogs were not different from spontaneous dog lung tumors, In which 36% were positive for EGFR. EGFR involvement in Pu-induced lung tumors appeared to be similar to that in spontaneous lung tumors. However, EGFR-positive staining was observed in only 1 of 16 tumors at the three lowest Pu exposure levels, compared to 20 of 35 tumors staining positive at the two highest Pu exposure levels. The results in dogs were in good agreement with the expression of EGFR reported in human non-small cell carcinoma of the lung, suggesting that Pu-induced lung tumors in the dog may be a suitable animal model to investigate the role of EGFR expression in lung carcinogenesis. In humans, EGFR expression in lung tumors has been primarily related to histological tumor types. In individual dogs with multiple primary lung tumors, the tumors were either all EGFR positive or EGFR negative, suggesting that EGFR expression may be related to the response of the individual dog as well as to the histological type of tumor.

  10. FOXL2 molecular status in adult granulosa cell tumors of the ovary: A study of primary and metastatic cases

    PubMed Central

    Zannoni, Gian Franco; Improta, Giuseppina; Petrillo, Marco; Pettinato, Angela; Scambia, Giovanni; Fraggetta, Filippo

    2016-01-01

    Granulosa cell tumors (GCTs) of the ovary are uncommon neoplasms, accounting for ~5% of all malignant ovarian tumors. GCTs are a relatively homogeneous group of tumors, categorized into two distinct subtypes, juvenile GCT and adult GCT (AGCT), likely arising from a limited set of molecular events usually involving the disruption of pathways that regulate granulosa cell proliferation. In the present study, the presence of forkheadbox L2 (FOXL2) c.402C>G mutation was investigated in a series of 42 samples of primary and metastatic AGCT of the ovary. The samples consisted of 37 primary and 5 metastatic ovarian AGCTs from 37 patients. FOXL2 mutational status was evaluated using a pyrosequencing approach on 2.5-µm sections of formalin-fixed paraffin-embedded tissue. FOXL2 c.402C>G mutation was found in 33/37 (89.2%) primary AGCTs and in 4/5 (80.0%) metastases, with the molecular status of the metastases recapitulating that of the primary tumors (4 mutated cases and 1 wild-type case). Overall, FOXL2 mutation is present in the majority of primary and metastatic AGCTs, and could be used as a valid tool in the diagnosis of the disease and in cases of metastatic lesions from an unknown primary origin. Moreover the concordance of FOXL2 molecular status in primary and associated metastases suggests its early appearance and genomic stability in AGCT tumorigenesis. PMID:27446412

  11. Extraosseous Benign Notochordal Cell Tumor Originating in the Lung

    PubMed Central

    Takahashi, Yusuke; Motoi, Toru; Harada, Masahiko; Fukuda, Yumiko; Hishima, Tsunekazu; Horio, Hirotoshi

    2015-01-01

    Abstract Benign notochordal cell tumors (BNCTs) are tumors originating in the axial skeleton, where chordomas occur. Although very rare, some cases of extraosseous chordoma, such as in the soft tissue and lungs, have been reported. We report a case of a primary tumor showing the notochordal characteristics of BNCTs within the axial skeleton. An asymptomatic 57-year-old woman presented with an abnormal shadow on her chest radiograph; chest computed tomography revealed a well-defined round nodule. The resected sample tissue contained a jelly-like small nodule. Histologically, it was identified as a BNCT, based on minimal nuclear atypia, extremely low mitotic activity within the tumor cells lying in a sheet-like arrangement, and focal immunopositivity for brachyury. This is the third case report of BNCT originating in the lungs; BNCTs are considered asymptomatic tumors that are identified by using highly developed chest imaging technology; however, our findings also suggest that these notochordal tumors may potentially originate from extraosseous sites that lack ideal precursor cells. Our case suggests that notochordal tumors can arise from organs that are unrelated to known notochordal development. PMID:25569657

  12. Imaging Mitochondrial Redox Potential and Its Possible Link to Tumor Metastatic Potential

    PubMed Central

    Li, Lin Z.

    2012-01-01

    Cellular redox states can regulate cell metabolism, growth, differentiation, motility, apoptosis, signaling pathways, and gene expressions etc. Growing body of literature suggest importance of redox status for cancer progression. While most studies on redox state were done on cells and tissue lysates, it is important to understand the role of redox state in tissue in vivo/ex vivo and image its heterogeneity. Redox scanning is a clinically-translatable method for imaging tissue mitochondrial redox potential with a submillimeter resolution. Redox scanning data in mouse models of human cancers demonstrate a correlation between mitochondrial redox state and tumor metastatic potential. I will discuss the significance of this correlation and possible directions for future research. PMID:22895837

  13. Is There a Role for PET/CT Parameters to Characterize Benign, Malignant, and Metastatic Parotid Tumors?

    PubMed Central

    Kendi, Ayse Tuba Karagulle; Magliocca, Kelly R.; Corey, Amanda; Galt, James R.; Switchenko, Jeffrey; Wadsworth, J. Trad; El-Deiry, Mark W.; Schuster, David M.; Saba, Nabil F.; Hudgins, Patricia A.

    2016-01-01

    OBJECTIVE Assessment of benign and malignant lesions of the parotid gland, including metastatic lesions, is challenging with current imaging methods. Fluorine-18 FDG PET/CT is a noninvasive imaging modality that provides both anatomic and metabolic information. Semiquantitative data obtained from PET/CT, also known as PET/CT parameters, are maximum, mean, or peak standardized uptake values (SUVs); metabolic tumor volume; total lesion glycolysis; standardized added metabolic activity; and normalized standardized added metabolic activity. Our aim was to determine whether FDG PET/CT parameters can differentiate benign, malignant, and metastatic parotid tumors. MATERIALS AND METHODS Thirty-four patients with parotid neoplasms underwent PET/CT before parotidectomy; maximum SUV, mean SUV, peak SUV, total lesion glycolysis, metabolic tumor volume, standardized added metabolic activity, and normalized standardized added metabolic activity were calculated on a dedicated workstation. Univariate analyses were performed. A ROC analysis was used to determine the ability of PET/CT parameters to predict pathologically proven benign, malignant, and metastatic parotid gland neoplasms. RESULTS Fourteen patients had a benign or malignant primary parotid tumor. Twenty had metastases to the parotid gland. When the specificity was set to at least 85% for each parameter to identify cut points, the corresponding sensitivities ranged from 15% to 40%. Assessment of benign versus malignant lesions of parotid tumors, as well as metastasis from squamous cell carcinoma versus other metastatic causes, revealed that none of the PET/CT parameters has enough power to differentiate among these groups. CONCLUSION PET/CT parameters, including total lesion glycolysis, metabolic tumor volume, standardized added metabolic activity, and normalized standardized added metabolic activity, are not able to differentiate benign from malignant parotid tumors, primary parotid tumors from metastasis, or metastasis

  14. Analysis of lung tumor risks in rats exposed to radon.

    PubMed

    Gilbert, E S; Cross, F T; Dagle, G E

    1996-03-01

    Using data on 3117 rats exposed by inhalation to radon, radon progeny and uranium ore dust, the hazard function (or age-specific risk) for lung tumor incidence was modeled as a function of exposure, exposure rate and other factors. The overall estimate of lifetime risk was 237 cases per 10(6) rats per WLM (237 per 10(6) WLM), reasonably comparable to estimates obtained from data for humans. The data below 1000 WLM (20-640 WLM) were consistent with linearity with positive excess risks at all levels; however, evidence of statistically significant excess risk was limited to exposures of 80 WLM or greater. Evidence for an inverse exposure-rate effect was limited primarily to cumulative exposures exceeding 1000 WLM (1280-10,240 WLM) and to comparison of results at 100 and 1000 WL. Even at these levels, the possibility that the effect might be explained by time since last exposure or by heterogeneity across experiments could not be entirely excluded. The inverse exposure-rate effect was strongest for epidermoid and adenosquamous tumors, and the only indication of such an effect at exposures below 1000 WLM was modest evidence (P=0.024) in analyses limited to these tumors. When all lung tumors, or all malignant lung tumors, were included, there was no evidence of such an effect below 1000 WLM. These data support the viewpoint that the inverse exposure-rate effect is primarily a high-dose phenomenon. PMID:8927704

  15. The NOMS Framework: Approach to the Treatment of Spinal Metastatic Tumors

    PubMed Central

    Laufer, Ilya; Rubin, David G.; Lis, Eric; Cox, Brett W.; Stubblefield, Michael D.; Yamada, Yoshiya

    2013-01-01

    Background. Spinal metastases frequently arise in patients with cancer. Modern oncology provides numerous treatment options that include effective systemic, radiation, and surgical options. We delineate and provide the evidence for the neurologic, oncologic, mechanical, and systemic (NOMS) decision framework, which is used at Memorial Sloan-Kettering Cancer Center to determine the optimal therapy for patients with spine metastases. Methods. We provide a literature review of the integral publications that serve as the basis for the NOMS framework and report the results of systematic implementation of the NOMS-guided treatment. Results. The NOMS decision framework consists of the neurologic, oncologic, mechanical, and systemic considerations and incorporates the use of conventional external beam radiation, spinal stereotactic radiosurgery, and minimally invasive and open surgical interventions. Review of radiation oncology and surgical literature that examine the outcomes of treatment of spinal metastatic tumors provides support for the NOMS decision framework. Application of the NOMS paradigm integrates multimodality therapy to optimize local tumor control, pain relief, and restoration or preservation of neurologic function and minimizes morbidity in this often systemically ill patient population. Conclusion. NOMS paradigm provides a decision framework that incorporates sentinel decision points in the treatment of spinal metastases. Consideration of the tumor sensitivity to radiation in conjunction with the extent of epidural extension allows determination of the optimal radiation treatment and the need for surgical decompression. Mechanical stability of the spine and the systemic disease considerations further help determine the need and the feasibility of surgical intervention. PMID:23709750

  16. Glucocorticoid receptor knockdown decreases the antioxidant protection of B16 melanoma cells: an endocrine system-related mechanism that compromises metastatic cell resistance to vascular endothelium-induced tumor cytotoxicity.

    PubMed

    Obrador, Elena; Valles, Soraya L; Benlloch, María; Sirerol, J Antoni; Pellicer, José A; Alcácer, Javier; Coronado, Javier Alcácer-F; Estrela, José M

    2014-01-01

    We previously reported an interorgan system in which stress-related hormones (corticosterone and noradrenaline), interleukin-6, and glutathione (GSH) coordinately regulate metastatic growth of highly aggressive B16-F10 melanoma cells. Corticosterone, at levels measured in tumor-bearing mice, also induces apoptotic cell death in metastatic cells with low GSH content. In the present study we explored the potential role of glucocorticoids in the regulation of metastatic cell death/survival during the early stages of organ invasion. Glucocorticoid receptor (GCR) knockdown decreased the expression and activity of γ-glutamylcysteine synthetase (γ-GCS), the rate-limiting step in GSH synthesis, in metastatic cells in vivo independent of the tumor location (liver, lung, or subcutaneous). The decrease in γ-GCS activity was associated with lower intracellular GSH levels. Nrf2- and p53-dependent down-regulation of γ-GCS was associated with a decrease in the activities of superoxide dismutase 1 and 2, catalase, glutathione peroxidase, and glutathione reductase, but not of the O2--generating NADPH oxidase. The GCR knockdown-induced decrease in antioxidant protection caused a drastic decrease in the survival of metastatic cells during their interaction with endothelial cells, both in vitro and in vivo; only 10% of cancer cells attached to the endothelium survived compared to 90% survival observed in the controls. This very low rate of metastatic cell survival was partially increased (up to 52%) in vivo by inoculating B16-F10 cells preloaded with GSH ester, which enters the cell and delivers free GSH. Taken together, our results indicate that glucocorticoid signaling influences the survival of metastatic cells during their interaction with the vascular endothelium.

  17. Dose Escalation for Metastatic Spinal Cord Compression in Patients With Relatively Radioresistant Tumors

    SciTech Connect

    Rades, Dirk; Freundt, Katja; Meyners, Thekla; Bajrovic, Amira; Basic, Hiba; Karstens, Johann H.; Adamietz, Irenaeus A.; Wildfang, Ingeborg; Rudat, Volker; Schild, Steven E.; Dunst, Juergen

    2011-08-01

    Purpose: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the 'standard' regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes. Methods and Materials: A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. Results: Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043). Conclusions: Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.

  18. [The first experience in interstitial brachytherapy for primary and metastatic tumors of the brain].

    PubMed

    Bentsion, D L; Gvozdev, P B; Sakovich, V P; Fialko, N V; Kolotvinov, V S; Baiankina, S N

    2006-01-01

    In 2001-2002, the authors performed a course of brachytherapy in 15 patients with inoperable primary, recurrent, and metastatic brain tumors. The histostructural distribution was as follows: low-grade astrocytoma (grade II according to the WHO classification) in 2 patients, anaplastic astrocytoma (AA) in 3, glioblastoma multiforme (GBM) in 5. Five patients had solid tumor deposits in the brain. Computer tomographic (CT) and magnetic resonance imaging (MRI) data were used to define a path for forthcoming biopsy and implantation at a "Stryker" navigation station, by taking into account the anatomy of the brain, vessels, and functionally significant areas. After having histological findings, plastic intrastats whose number had been determined by the volume of a target were implanted into a tumor by the predetermined path. Dosimetric planning was accomplished by using CT and MRI images on an "Abacus" system. The final stage involved irradiation on a "GammaMed plus" with a source of 192Ir. Irradiation was given, by hyperfractionating its dose (3-4 Gy twice daily at an interval of 4-5 hours) to the total focal dose (TFD) of 36-44 Gy. Patients with gliomas untreated with radiation also underwent external radiation in a TFD of 54-56 Gy and patients with brain metastases received total external irradiation of the brain in a TFD of 36-40 Gy. The tolerance of a course of irradiation was fair. In patients with AA and GBM, one-year survival was observed in 66 and 60%, respectively; in those having metastasis, it was in 20%. Six patients died from progressive disease. All patients with low-grade astrocytoma and one patient with anaplastic astrocytoma were alive at month 24 after treatment termination. The mean lifespan of patients with malignant gliomas and solid tumor metastasis was 11.5 and 5.8 months, respectively. Brachytherapy is a noninvasive and tolerable mode of radiotherapy that increases survival in some groups of patients with inoperable brain tumors.

  19. Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis.

    PubMed

    Karamurzin, Yevgeniy S; Kiyokawa, Takako; Parkash, Vinita; Jotwani, Anjali R; Patel, Prusha; Pike, Malcolm C; Soslow, Robert A; Park, Kay J

    2015-11-01

    Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of 3 institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (1 Li-Fraumeni, 1 Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II to IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least 1 site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 mo); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease-specific survival at 5 years was 42% for GAS versus 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon.

  20. Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.

    PubMed

    Hurley, Paula J; Hughes, Robert M; Simons, Brian W; Huang, Jessie; Miller, Rebecca M; Shinder, Brian; Haffner, Michael C; Esopi, David; Kimura, Yasunori; Jabbari, Javaneh; Ross, Ashley E; Erho, Nicholas; Vergara, Ismael A; Faraj, Sheila F; Davicioni, Elai; Netto, George J; Yegnasubramanian, Srinivasan; An, Steven S; Schaeffer, Edward M

    2015-10-15

    Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient-based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1(-/-) mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions, thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic invasion of prostate cancer. PMID:26294211

  1. Relevance of particle-induced rat lung tumors for assessing lung carcinogenic hazard and human lung cancer risk.

    PubMed Central

    Mauderly, J L

    1997-01-01

    Rats and other rodents are exposed by inhalation to identify agents that might present hazards for lung cancer in humans exposed by inhalation. In some cases, the results are used in attempts to develop quantitative estimates of human lung cancer risk. This report reviews evidence for the usefulness of the rat for evaluation of lung cancer hazards from inhaled particles. With the exception of nickel sulfate, particulate agents thought to be human lung carcinogens cause lung tumors in rats exposed by inhalation. The rat is more sensitive to carcinogenesis from nonfibrous particles than mice or Syrian hamsters, which have both produced false negatives. However, rats differ from mice and nonhuman primates in both the pattern of particle retention in the lung and alveolar epithelial hyperplastic responses to chronic particle exposure. Present evidence warrants caution in extrapolation from the lung tumor response of rats to inhaled particles to human lung cancer hazard, and there is considerable uncertainty in estimating unit risks for humans from rat data. It seems appropriate to continue using rats in inhalation carcinogenesis assays of inhaled particles, but the upper limit of exposure concentrations must be set carefully to avoid false-positive results. A positive finding in both rats and mice would give greater confidence that an agent presents a carcinogenic hazard to man, and both rats and mice should be used if the agent is a gas or vapor. There is little justification for including Syrian hamsters in assays of the intrapulmonary carcinogenicity of inhaled agents. PMID:9400748

  2. Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2016-04-18

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Metastatic Pheochromocytoma; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Recurrent Melanoma; Recurrent Neuroendocrine Carcinoma of the Skin; Recurrent Non-small Cell Lung Cancer; Recurrent Pheochromocytoma; Recurrent Renal Cell Cancer; Somatostatinoma; Stage III Neuroendocrine Carcinoma of the Skin; Stage IV Melanoma; Stage IV Non-small Cell Lung Cancer; Stage IV Renal Cell Cancer; Thyroid Gland Medullary Carcinoma; Unspecified Adult Solid Tumor, Protocol Specific

  3. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer

    PubMed Central

    Ang, Yvonne LE; Lim, Joline SJ; Soo, Ross A

    2016-01-01

    Until recently, the prognosis and treatment of patients with advanced-stage squamous cell lung cancers have been limited. An improvement in the understanding of the role of the immune system in tumor immunosurveillance has led to the development of the programmed death-1 (PD-1) immune checkpoint inhibitor nivolumab (Opdivo). Nivolumab is the first PD-1 inhibitor approved for the treatment of advanced-stage squamous cell non-small-cell lung cancer following platinum-based chemotherapy. In the key Phase III trial CHECKMATE 017, a better overall survival and progression-free survival were seen in patients treated with second-line nivolumab compared with docetaxel. Programmed death ligand-1 (PD-L1) expression did not predict for outcome. In addition, nivolumab had better safety and tolerability, and led to better patient reported outcomes. Further research on the role of PD-L1 expression as a predictive biomarker should be performed, and other biomarkers that can predict the efficacy of PD-1/PD-L1 inhibitors should also be pursued. Further studies on the combination treatment are ongoing to determine the optimal role of nivolumab as monotherapy or nivolumab with other agents in non-small-cell lung cancer. PMID:27313464

  4. Inhibition of lung tumor growth by targeting EGFR/VEGFR-Akt/NF-κB pathways with novel theanine derivatives

    PubMed Central

    Zhang, Guoying; Ye, Xinshan; Wu, Erxi; Wang, Fengfei; Wu, Fei; Tian, Huihui; Liu, Xin; Chen, Linlin; Liu, Kun; Wang, Yishan; Liu, Hanchen; Zhang, Wenhua; Guan, Yukun; Wang, Qinwen; Zhao, Xiaohang; Wan, Xiaochun

    2014-01-01

    The molecularly targeted agents, including anti-VEGF or anti-EGFR monoclonal antibody and some inhibitors of EGFR tyrosine kinase, are effective in the treatment of non-small-cell lung cancer (NSCLC) to a certain extent, but the benefit for a proportion of patients is still limited. Hence, it is necessary and urgent to develop more selective and effective molecular targeted agents against lung cancer. Here, we have synthesized novel theanine derivatives, methyl coumarin-3-carboxylyl L-theanine (TMC), ethyl coumarin-3-carboxylyl L-theanine (TEC), ethyl 6-fluorocoumarin- 3-carboxylyl L-theanine (TFC), and ethyl 6-nitrocoumarin-3-carboxylyl L-theanine (TNC), which are fluorescent small molecules, based on their parental compound theanine and studied their anticancer activities in vitro, ex vivo and in vivo models of human and mouse cancers. Our results show that the four theanine derivatives significantly inhibit the lung cancer cell migration and the growth of lung cancer and leukemia cell lines. TFC and TNC display enhanced effects with anticancer drugs cytarabine, vincristine, and methotrexate on inhibition of lung cancer cell growth and no toxicity to the normal human embryonic lung fibroblast and peripheral blood lymphocytes. TFC and TNC exhibit strong suppression of the highly metastatic Lewis lung cancer (LLC) and A549 tumor growth in tumor-bearing mice without toxicity to mice. TFC and TNC can effectively suppress the growth of lung cancer cells in vitro, ex vivo and in vivo by targeting EGFR/VEGFR-Akt/NF-κB pathways. Our study has suggested that TFC and TNC may have the therapeutic and/or adjuvant therapeutic applications in the treatment of lung cancers and other cancer. PMID:25138052

  5. Thallium-201-chloride and technetium-99m-MIBI SPECT of primary and metastatic lung carcinoma.

    PubMed

    Kashitani, N; Makihara, S; Maeda, T; Eda, R; Takeyama, H; Hiraki, Y

    1999-01-01

    We compared technetium-99m-MIBI (Tc-99m MIBI) with thallium-201-chloride (Tl-201) SPECT imaging in patients with lung carcinoma. In addition, we compared the imaging characteristics of Tl-201 and Tc-99m MIBI after radiation therapy. Thirty-seven patients with primary lung carcinoma were evaluated with SPECT imaging for metastasis to the mediastinal lymph nodes and brain. Patients were imaged with Tl-201 chloride images 10 and 180 min after injection. Patients were also imaged 10 min after injection of Tc-99m MIBI. The sensitivity of Tl-201 SPECT for the primary lesion and brain metastasis was 97.1% and 70.0% respectively at 10 min and 97.1% and 60.0% at 180 min. The sensitivity of Tc-99m MIBI SPECT was 97.1% (for the identification of the primary lesion) and 50.0% (for the detection of brain metastasis) at 10 min. The uptake ratios (count in tumor/count in normal lung or brain) at 10 min on the Tl-201 SPECT and on the Tc-99m MIBI SPECT were not significantly different for the primary tumor or for brain metastasis. The uptake ratios were better for Tc-99m MIBI than for Tl-201 [2.82 vs. 1.99 (p<0.05)] for mediastinal lymph nodes. Decreasing uptake ratios and retention index with both agents after radiation therapy are concordant to the follow-up clinical course. Tc-99m MIBI SPECT is more sensitive in the detection of metastasis to mediastinal lymph nodes than Tl-201 SPECT.

  6. A Cross-Sectional Comparison of Druggable Mutations in Primary Tumors, Metastatic Tissue, Circulating Tumor Cells, and Cell-Free Circulating DNA in Patients with Metastatic Breast Cancer: The MIRROR Study Protocol

    PubMed Central

    Picornell, Antoni C; Alvarez, Enrique L; Martin, Miguel

    2016-01-01

    Background Characterization of the driver mutations in an individual metastatic breast cancer (MBC) patient is critical to selecting effective targeted therapies. Currently, it is believed that the limited efficacy of many targeted drugs may be due to the expansion of drug resistant clones with different genotypes that were already present in the primary tumor. Identifying the genomic alterations of these clones, and introducing combined or sequential targeted drug regimens, could lead to a significant increase in the efficacy of currently available targeted therapies. Objective The primary objective of this study is to assess the concordance/discordance of mutations between the primary tumor and metastatic tissue in MBC patients. Secondary objectives include comparing the genomic profiles of circulating tumor cells (CTCs) and circulating free DNA (cfDNA) from peripheral blood with those of the primary tumor and metastatic tissue for each patient, evaluating these mutations in the signaling pathways that are relevant to the disease, and testing the feasibility of introducing liquid biopsy as a translational laboratory tool in clinical practice. Methods The multicenter, transversal, observational MIRROR study is currently ongoing in three participating hospitals. All consecutive patients with MBC confirmed by radiologic findings will be screened for eligibility, either at first relapse or if tumor regrowth occurs while on treatment for metastatic disease. Results Patient recruitment is currently ongoing. To date, 41 patients have a complete set of tissue samples available (plasma, CTCs, and formalin-fixed, paraffin-embedded primary tumor and metastatic tumor). However, none of these samples have undergone nucleic acids extraction or targeted deep sequencing. Conclusions The results of this study may have a significant influence on the practical management of patients with MBC, and may provide clues to clinicians that lead towards a better stratification of patients

  7. Inflammatory myofibroblastic tumor of the lung in pregnancy mimicking carcinoid tumor.

    PubMed

    Maturu, Venkata Nagarjuna; Bal, Amanjit; Singh, Navneet

    2016-01-01

    Inflammatory myofibroblastic tumors (IMT) are uncommon neoplasms of the lung in adults. They constitute less than 1% of all lung neoplasms and usually present as parenchymal masses. Diagnosis requires a high index of suspicion. They are characterized by spindle-shaped tumor cells (fibroblasts/myofibroblasts) in a background of lymphoplasmacytic infiltrate. About 50% of the tumors harbor an ALK gene rearrangement. They have to be differentiated from inflammatory pseudotumors (IPT), which show increased number of IgG4 plasma cells on immunostaining and are negative for anaplastic lymphoma kinase (ALK) protein. Herein, we present a case of a 28-year old female who presented with hemoptysis and was diagnosed with an IMT of lung in the first trimester of pregnancy. We have not only reviewed the occurrence of IMT during pregnancy but also discuss the management options for IMT during pregnancy. PMID:26933315

  8. Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils

    PubMed Central

    Zhu, Ha; Xu, Junfang; Zheng, Yuanyuan; Cao, Xuetao

    2016-01-01

    Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs) play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth. PMID:27446967

  9. CAVEOLIN-1 expression in brain metastasis from lung cancer predicts worse outcome and radioresistance, irrespective of tumor histotype.

    PubMed

    Duregon, Eleonora; Senetta, Rebecca; Pittaro, Alessandra; Verdun di Cantogno, Ludovica; Stella, Giulia; De Blasi, Pierpaolo; Zorzetto, Michele; Mantovani, Cristina; Papotti, Mauro; Cassoni, Paola

    2015-10-01

    Brain metastases develop in one-third of patients with non-small-cell lung cancer and are associated with a dismal prognosis, irrespective of surgery or chemo-radiotherapy. Pathological markers for predicting outcomes after surgical resection and radiotherapy responsiveness are still lacking. Caveolin 1 has been associated with chemo- and radioresistance in various tumors, including non-small-cell lung cancer. Here, caveolin 1 expression was assessed in a series of 69 brain metastases from non-small-cell lung cancer and matched primary tumors to determine its role in predicting survival and radiotherapy responsiveness. Only caveolin 1 expression in brain metastasis was associated with poor prognosis and an increased risk of death (log rank test, p = 0.015). Moreover, in the younger patients (median age of <54 years), caveolin 1 expression neutralized the favorable effect of young age on survival compared with the older patients. Among the radiotherapy-treated patients, an increased risk of death was detected in the group with caveolin 1-positive brain metastasis (14 out of 22 patients, HR=6.839, 95% CI 1.849 to 25.301, Wald test p = 0.004). Overall, caveolin 1 expression in brain metastasis from non-small-cell lung cancer is independently predictive of worse outcome and radioresistance and could become an additional tool for personalized therapy in the critical subset of brain-metastatic non-small-cell lung cancer patients.

  10. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer

    PubMed Central

    Tie, J.; Kinde, I.; Wang, Y.; Wong, H. L.; Roebert, J.; Christie, M.; Tacey, M.; Wong, R.; Singh, M.; Karapetis, C. S.; Desai, J.; Tran, B.; Strausberg, R. L.; Diaz, L. A.; Papadopoulos, N.; Kinzler, K. W.; Vogelstein, B.; Gibbs, P.

    2015-01-01

    Background Early indicators of treatment response in metastatic colorectal cancer (mCRC) could conceivably be used to optimize treatment. We explored early changes in circulating tumor DNA (ctDNA) levels as a marker of therapeutic efficacy. Patients and methods This prospective study involved 53 mCRC patients receiving standard first-line chemotherapy. Both ctDNA and CEA were assessed in plasma collected before treatment, 3 days after treatment and before cycle 2. Computed tomography (CT) scans were carried out at baseline and 8–10 weeks and were centrally assessed using RECIST v1.1 criteria. Tumors were sequenced using a panel of 15 genes frequently mutated in mCRC to identify candidate mutations for ctDNA analysis. For each patient, one tumor mutation was selected to assess the presence and the level of ctDNA in plasma samples using a digital genomic assay termed Safe-SeqS. Results Candidate mutations for ctDNA analysis were identified in 52 (98.1%) of the tumors. These patient-specific candidate tissue mutations were detectable in the cell-free DNA from the plasma of 48 of these 52 patients (concordance 92.3%). Significant reductions in ctDNA (median 5.7-fold; P < 0.001) levels were observed before cycle 2, which correlated with CT responses at 8–10 weeks (odds ratio = 5.25 with a 10-fold ctDNA reduction; P = 0.016). Major reductions (≥10-fold) versus lesser reductions in ctDNA precycle 2 were associated with a trend for increased progression-free survival (median 14.7 versus 8.1 months; HR = 1.87; P = 0.266). Conclusions ctDNA is detectable in a high proportion of treatment naïve mCRC patients. Early changes in ctDNA during first-line chemotherapy predict the later radiologic response. PMID:25851626

  11. Detection and Characterization of Circulating Tumor Associated Cells in Metastatic Breast Cancer

    PubMed Central

    Mu, Zhaomei; Benali-Furet, Naoual; Uzan, Georges; Znaty, Anaëlle; Ye, Zhong; Paolillo, Carmela; Wang, Chun; Austin, Laura; Rossi, Giovanna; Fortina, Paolo; Yang, Hushan; Cristofanilli, Massimo

    2016-01-01

    The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial–mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively. PMID:27706044

  12. Surgery Followed by Radiotherapy Versus Radiotherapy Alone for Metastatic Spinal Cord Compression From Unfavorable Tumors

    SciTech Connect

    Rades, Dirk; Huttenlocher, Stefan; Bajrovic, Amira; Karstens, Johann H.; Adamietz, Irenaeus A.; Kazic, Nadja; Rudat, Volker; Schild, Steven E.

    2011-12-01

    Purpose: Despite a previously published randomized trial, controversy exists regarding the benefit of adding surgery to radiotherapy for metastatic spinal cord compression (MSCC). It is thought that patients with MSCC from relatively radioresistant tumors or tumors associated with poor functional outcome after radiotherapy alone may benefit from surgery. This study focuses on these tumors. Methods and Materials: Data from 67 patients receiving surgery plus radiotherapy (S+RT) were matched to 134 patients (1:2) receiving radiotherapy alone (RT). Groups were matched for 10 factors and compared for motor function, ambulatory status, local control, and survival. Additional separate matched-pair analyses were performed for patients receiving direct decompressive surgery plus stabilization of involved vertebrae (DDSS) and patients receiving laminectomy (LE). Results: Improvement of motor function occurred in 22% of patients after S+RT and 16% after RT (p = 0.25). Posttreatment ambulatory rates were 67% and 61%, respectively (p = 0.68). Of nonambulatory patients, 29% and 19% (p = 0.53) regained ambulatory status. One-year local control rates were 85% and 89% (p = 0.87). One-year survival rates were 38% and 24% (p = 0.20). The matched-pair analysis of patients receiving LE showed no significant differences between both therapies. In the matched-pair analysis of patients receiving DDSS, improvement of motor function occurred more often after DDSS+RT than RT (28% vs. 19%, p = 0.024). Posttreatment ambulatory rates were 86% and 67% (p = 0.30); 45% and 18% of patients regained ambulatory status (p = 0.29). Conclusions: Patients with MSCC from an unfavorable primary tumor appeared to benefit from DDSS but not LE when added to radiotherapy in terms of improved functional outcome.

  13. [Haemoabdomen and haemothorax in a cow with metastatic granulosa cell tumor].

    PubMed

    Trösch, L; Müller, K; Brosinski, K; Braun, U

    2015-06-01

    This case report describes the clinical, ultrasonographic, pathological and histological findings in a two-year-old Swiss Braunvieh cow with granulosa cell tumor and metastases in the abdomen and thorax. The cow was ill and had tachycardia, coughing, increased breath sounds, positive reticular foreign body tests and a tense abdominal wall. Ultrasonography revealed a massive accumulation of hypoechoic fluid in the thorax and abdomen, and abdomino- and thoracocentesis yielded red fluid indicative of abdominal and thoracic haemorrhage. Because of a poor prognosis, the cow was euthanized and examined postmortem. Multiple nodular lesions were seen in the omentum, liver, spleen and lungs. The left ovary was grossly enlarged and nodular in appearance. Histological examination of the lesions revealed granulosa cell tumour of the left ovary and metastases in the omentum, liver, spleen and lungs.

  14. Unusual False-Positive Mesenteric Lymph Nodes Detected by PET/CT in a Metastatic Survey of Lung Cancer.

    PubMed

    Kamiyama, Hirohiko; Sakamoto, Kazuhiro; Niwa, Koichiro; Ishiyama, Shun; Takahashi, Makoto; Kojima, Yutaka; Goto, Michitoshi; Tomiki, Yuichi; Nakamichi, Itsuko; Oh, Shiaki; Suzuki, Kenji

    2016-01-01

    Positron emission tomography/computed tomography (PET/CT) is a credible diagnostic modality for detecting primary and metastatic malignancy. PET/CT sometimes shows false positives and negatives, which make clinical diagnosis difficult. A 42-year-old man who had undergone right upper lobectomy for lung cancer 1 year previously had PET/CT for a metastatic survey of the lung. The lung cancer was stage IB (pT2N0M0) bronchioloalveolar carcinoma. PET/CT showed massive (18)F-fluorodeoxyglucose (FDG) uptake in the mesenteric lymph nodes. Because the mesentery is an unusual site of metastasis, the patient was under watchful observation. Another PET/CT after 6 months still showed FDG uptake in the same location, with a slightly increased standard uptake value. A systemic survey was performed, but it did not reveal any malignancies or inflammatory diseases. Eventually, the patient underwent probing laparoscopic surgery. For complete resection of the lymph nodes, laparoscopic ileocecal resection was performed. Histologically, the resected lymph nodes showed reactive lymphadenitis. Glucose transporter 1 immunostainings of the lung cancer and the lymph node were positive and partially positive, respectively. Although PET/CT is a powerful diagnostic modality, clinical interpretation of unusual results is difficult. PMID:27462197

  15. Unusual False-Positive Mesenteric Lymph Nodes Detected by PET/CT in a Metastatic Survey of Lung Cancer

    PubMed Central

    Kamiyama, Hirohiko; Sakamoto, Kazuhiro; Niwa, Koichiro; Ishiyama, Shun; Takahashi, Makoto; Kojima, Yutaka; Goto, Michitoshi; Tomiki, Yuichi; Nakamichi, Itsuko; Oh, Shiaki; Suzuki, Kenji

    2016-01-01

    Positron emission tomography/computed tomography (PET/CT) is a credible diagnostic modality for detecting primary and metastatic malignancy. PET/CT sometimes shows false positives and negatives, which make clinical diagnosis difficult. A 42-year-old man who had undergone right upper lobectomy for lung cancer 1 year previously had PET/CT for a metastatic survey of the lung. The lung cancer was stage IB (pT2N0M0) bronchioloalveolar carcinoma. PET/CT showed massive 18F-fluorodeoxyglucose (FDG) uptake in the mesenteric lymph nodes. Because the mesentery is an unusual site of metastasis, the patient was under watchful observation. Another PET/CT after 6 months still showed FDG uptake in the same location, with a slightly increased standard uptake value. A systemic survey was performed, but it did not reveal any malignancies or inflammatory diseases. Eventually, the patient underwent probing laparoscopic surgery. For complete resection of the lymph nodes, laparoscopic ileocecal resection was performed. Histologically, the resected lymph nodes showed reactive lymphadenitis. Glucose transporter 1 immunostainings of the lung cancer and the lymph node were positive and partially positive, respectively. Although PET/CT is a powerful diagnostic modality, clinical interpretation of unusual results is difficult. PMID:27462197

  16. Case Report: Metabolic Profiling Identifies Lung Tumor Responsiveness to Erlotinib

    PubMed Central

    Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M; Bousamra, Michael; Kloecker, Goetz; Miller, Donald M.

    2009-01-01

    A subtype of non-small cell lung cancer, bronchioalveolar adenocarcinoma (BAC), is more prevalent in Asian female non-smokers, and is more likely to respond to treatment with tyrosine kinase inhibitors such as erlotinib and gefitinib. Nuclear magnetic resonance and mass spectrometry-based metabolomic analysis of extracts from two different lung lesions and surrounding non-cancerous tissues of a BAC patient showed novel protein and phospholipid-associated metabolic differences that correlated with tumor development as well as PET and erlotinib sensitivity. PMID:19409891

  17. Metabolic profiling identifies lung tumor responsiveness to erlotinib.

    PubMed

    Fan, Teresa W-M; Lane, Andrew N; Higashi, Richard M; Bousamra, Michael; Kloecker, Goetz; Miller, Donald M

    2009-08-01

    A subtype of non-small cell lung cancer, bronchioalveolar adenocarcinoma (BAC), is more prevalent in Asian female non-smokers, and is more likely to respond to treatment with tyrosine kinase inhibitors such as erlotinib and gefitinib. Nuclear magnetic resonance and mass spectrometry-based metabolomic analysis of extracts from two different lung lesions and surrounding non-cancerous tissues of a BAC patient showed novel protein and phospholipid-associated metabolic differences that correlated with tumor development as well as PET and erlotinib sensitivity.

  18. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma.

    PubMed

    Bidard, François-Clément; Madic, Jordan; Mariani, Pascale; Piperno-Neumann, Sophie; Rampanou, Aurore; Servois, Vincent; Cassoux, Nathalie; Desjardins, Laurence; Milder, Maud; Vaucher, Isabelle; Pierga, Jean-Yves; Lebofsky, Ronald; Stern, Marc-Henri; Lantz, Olivier

    2014-03-01

    Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.

  19. Recombinant EphB4-HSA Fusion Protein With Standard Chemotherapy Regimens in Treating Patients With Advanced or Metastatic Solid Tumors

    ClinicalTrials.gov

    2016-07-15

    Head and Neck Squamous Cell Carcinoma; Metastatic Pancreatic Adenocarcinoma; Non-Resectable Cholangiocarcinoma; Pancreatic Adenocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Non-Small Cell Lung Carcinoma; Stage III Pancreatic Cancer; Stage IIIA Gallbladder Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIB Gallbladder Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IV Gallbladder Cancer; Stage IV Non-Small Cell Lung Cancer; Stage IV Pancreatic Cancer; Unresectable Gallbladder Carcinoma; Unresectable Pancreatic Cancer

  20. Effective palliative treatment of metastatic carcinoid tumors with intra-arterial chemotherapy/chemoembolization combined with octreotide acetate.

    PubMed

    Hajarizadeh, H; Ivancev, K; Mueller, C R; Fletcher, W S; Woltering, E A

    1992-05-01

    Survival in patients with metastatic carcinoid tumors is dependent on control of tumor growth and adequate palliation of vasoactive amine-induced symptoms of flushing, diarrhea, wheezing, and valvular heart disease. Eight patients with carcinoid tumors metastatic to the liver were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), intra-arterial 5-fluorouracil infusion (2 g/day x 5 days), and hepatic tumor chemoembolization. All eight patients became asymptomatic and have remained so with a mean follow-up duration of 22 months from the time of first infusion. Following institution of subcutaneous octreotide acetate, intra-arterial infusion, and tumor chemoembolization, all patients are alive with a mean survival of 40 months from the time of diagnosis of carcinoid syndrome (range: 2 to 108 months). Four patients had greater than a 50% decrease in tumor size after therapy (mean follow-up duration: 10.6 months), and the other four patients have had stable disease after institution of therapy. It appears that combinations of long-term subcutaneous administration of octreotide acetate, intra-arterial 5-fluorouracil, and tumor chemoembolization effectively control progressive liver metastasis and provide excellent symptomatic palliation in patients with hepatic metastasis from functional carcinoid tumors.

  1. Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors

    PubMed Central

    Goswami, Rashmi S.; Patel, Keyur P.; Singh, Rajesh R.; Meric-Bernstam, Funda; Kopetz, E. Scott; Subbiah, Vivek; Alvarez, Ricardo H.; Davies, Michael A.; Jabbar, Kausar J.; Roy-Chowdhuri, Sinchita; Lazar, Alexander J.; Medeiros, L. Jeffrey; Broaddus, Russell R.; Luthra, Rajyalakshmi; Routbort, Mark J.

    2016-01-01

    Purpose We used a clinical next-generation sequencing hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors. Experimental Design A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status. Results 227 of 265 (85.7%) tumor-metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n=20, 7.5%) than primary tumors (n=12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples. Conclusions Clinical next-generation sequencing hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4 and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases. PMID:25695693

  2. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors.

    PubMed

    Cives, M; Ghayouri, M; Morse, B; Brelsford, M; Black, M; Rizzo, A; Meeker, A; Strosberg, J

    2016-09-01

    The capecitabine and temozolomide (CAPTEM) regimen is active in the treatment of metastatic pancreatic neuroendocrine tumors (pNETs), with response rates ranging from 30 to 70%. Small retrospective studies suggest that O(6)-methylguanine DNA methyltransferase (MGMT) deficiency predicts response to temozolomide. High tumor proliferative activity is also commonly perceived as a significant predictor of response to cytotoxic chemotherapy. It is unclear whether chromosomal instability (CIN), which correlates with alternative lengthening of telomeres (ALT), is a predictive factor. In this study, we evaluated 143 patients with advanced pNET who underwent treatment with CAPTEM for radiographic and biochemical response. MGMT expression (n=52), grade (n=128) and ALT activation (n=46) were investigated as potential predictive biomarkers. Treatment with CAPTEM was associated with an overall response rate (ORR) of 54% by RECIST 1.1. Response to CAPTEM was not influenced by MGMT expression, proliferative activity or ALT pathway activation. Based on these results, no biomarker-driven selection criteria for use of the CAPTEM regimen can be recommended at this time.

  3. Lung tumors masquerading as desquamative interstitial pneumonia (DIP): report of 7 cases and review of the literature.

    PubMed

    Raparia, Kirtee; Ketterer, James; Dalurzo, Mercedes L; Chang, Yu-Hui; Colby, Thomas V; Leslie, Kevin O

    2014-07-01

    Malignant tumors in the lung (both primary and metastatic) rarely may be associated with markedly discohesive tumor cells, resulting in airspace filling reminiscent of "desquamative interstitial pneumonia" (DIP) on histopathology evaluation. A peculiar aspect of this growth pattern is the relatively bland appearance of the tumor cells, in many cases simulating benign alveolar macrophages at scanning magnification. We searched the Charles Carrington Memorial consultation files in the Department of Laboratory Medicine and Pathology at Mayo Clinic Arizona for instances of malignant tumors in lung simulating DIP, from 1992 to 2011. We identified 7 cases involving transbronchial biopsies, needle core samples, or resected lung specimens. Clinical, histopathologic, and immunohistochemical analyses of these 7 patients were performed, including detailed morphometric analysis of the individual tumor cells using calibrated measurement tools on digital images. We compared the results with those of a control group of 4 patients with benign DIP-macrophage reactions in smoking-related lung disease. The study group comprised 5 male and 2 female patients, 48 to 86 years in age (median: 67 y). The radiologic findings included lobar consolidation, localized ground-glass opacities, and 1 or more nodules. None of the patients had typical bilateral infiltrates of DIP. Microscopically, the lung parenchyma was dominated by the presence of prominent tumor cells filling alveolar spaces. Four patients had primary lung carcinoma (adenocarcinoma), whereas 3 had metastases from other sites, including a melanoma. Immunohistochemical staining studies were performed on 6 of 7 cases to establish the diagnosis. Nuclear diameter, cytoplasmic diameter, and nuclear/cytoplasmic (N/C) ratios in patient and control groups were compared using the Wilcoxon rank sum test. No significant difference in the diameters of nucleus and cytoplasm between cases and control groups (P=0.3447 and 0.7055, respectively

  4. Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients

    PubMed Central

    Martino, EC; Misso, G; Pastina, P; Costantini, S; Vanni, F; Gandolfo, C; Botta, C; Capone, F; Lombardi, A; Pirtoli, L; Tassone, P; Ulivieri, C; Tagliaferri, P; Cusi, MG; Caraglia, M; Correale, P

    2016-01-01

    The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved in vivo and in vitro cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients. PMID:27752361

  5. Can PPH3 be helpful to assess the discordant grade in primary and metastatic enteropancreatic neuroendocrine tumors?

    PubMed

    Dumars, Clotilde; Foubert, Fanny; Touchefeu, Yann; Regenet, Nicolas; Senellart, Hélène; Matysiak-Budnik, Tamara; Heymann, Marie-Françoise

    2016-08-01

    Therapeutic strategy in neuroendocrine tumors (NETs) is based on histological characteristics of the primary tumor (PT), even in case of metastatic disease. Our aim was to compare the tumor grade between PT and their liver metastases (LM) in patients with enteropancreatic NETs. Forty-one patients treated for sporadic NETs (10 pancreatic, 31 intestinal) were included. All presented synchronous (35) or metachronous (6) LM. Tumor grade was evaluated for PT and LM according to the WHO classification, using Ki-67 labeling and mitotic count (MC) evaluated with or without phospho-histone H3 (PPH3). Tumor grade differed between primary and metastatic tumor in 16/41 patients (39 %), with an increase of grade in 13 of them (32 %). The median Ki-67, MC, and PPH3 in metastases were statistically higher than in PT (p = 0.0002, 0.02, and 0.01). In 17 of 65 cases tested with PPH3 (26 %), this antibody was more efficient in assessing the grade compared to the usual MC, and in 2/65 cases compared to the Ki-67. A better correlation was observed between Ki-67 and PPH3 (p = 0.0001) than between Ki-67 and MC without immunohistochemistry. There is a significant difference in tumor grade between primary and metastatic NETs, underlining the necessity of a systematic biopsy on LM for patient management. Moreover, PPH3 appears to be a powerful antibody to assess the MC and the tumor grade much more accurately when associated with Ki-67. PMID:27048356

  6. Tumor and Plasma Met Levels in Non-Metastatic Prostate Cancer

    PubMed Central

    Kaye, Deborah R.; Pinto, Peter A.; Cecchi, Fabiola; Reilly, Joseph; Semerjian, Alice; Rabe, Daniel C.; Gupta, Gopal; Choyke, Peter L.

    2016-01-01

    Objective To measure Met protein content in prostate biopsies guided by fused magnetic resonance and ultrasound imaging, and to measure soluble Met (sMet) protein concentration in plasma samples from patients presenting evidence of prostate cancer. Patients and Methods 345 patients had plasma samples drawn prior to image-guided biopsy of the prostate. Of these, 32% had benign biopsies. Of the 236 that were positive for prostate adenocarcinoma (PCa), 132 treated by total prostatectomy had Gleason scores of 6 (17%), 7, (55%), 8 (16%), or 9–10 (12%). 23% had evidence of local invasion. Plasma samples were also obtained from 80 healthy volunteers. Tissue Met and plasma sMet were measured by two-site immunoassay; values were compared among clinically defined groups using non-parametric statistical tests to determine significant differences or correlations. Results PCa tumor Met correlated significantly with plasma sMet, but median values were similar among benign and malignant groups. Median plasma sMet values were also similar among those groups, although both medians were significantly above normal. Median Met content in primary PCa tumors and sMet concentrations were independent of Gleason score, final pathologic stage and age. Conclusion Plasma sMet is not predictive of PCa or its severity in patients with organ-confined or locally invasive disease. Quantitative analysis of Met protein content and activation state in PCa tumor biopsy samples was highly feasible and may have value in follow-up to genomic and/or transcriptomic-based screens that show evidence of oncogenically relevant MET gene features that occur at relatively low frequency in non-metastatic PCa. PMID:27300295

  7. Three-Staged Stereotactic Radiotherapy Without Whole Brain Irradiation for Large Metastatic Brain Tumors

    SciTech Connect

    Higuchi, Yoshinori Serizawa, Toru; Nagano, Osamu; Matsuda, Shinji; Ono, Junichi; Sato, Makoto; Iwadate, Yasuo; Saeki, Naokatsu

    2009-08-01

    Purpose: To evaluate the efficacy and toxicity of staged stereotactic radiotherapy with a 2-week interfraction interval for unresectable brain metastases more than 10 cm{sup 3} in volume. Patients and Methods: Subjects included 43 patients (24 men and 19 women), ranging in age from 41 to 84 years, who had large brain metastases (> 10 cc in volume). Primary tumors were in the colon in 14 patients, lung in 12, breast in 11, and other in 6. The peripheral dose was 10 Gy in three fractions. The interval between fractions was 2 weeks. The mean tumor volume before treatment was 17.6 {+-} 6.3 cm{sup 3} (mean {+-} SD). Mean follow-up interval was 7.8 months. The local tumor control rate, as well as overall, neurological, and qualitative survivals, were calculated using the Kaplan-Meier method. Results: At the time of the second and third fractions, mean tumor volumes were 14.3 {+-} 6.5 (18.8% reduction) and 10.6 {+-} 6.1 cm{sup 3} (39.8% reduction), respectively, showing significant reductions. The median overall survival period was 8.8 months. Neurological and qualitative survivals at 12 months were 81.8% and 76.2%, respectively. Local tumor control rates were 89.8% and 75.9% at 6 and 12 months, respectively. Tumor recurrence-free and symptomatic edema-free rates at 12 months were 80.7% and 84.4%, respectively. Conclusions: The 2-week interval allowed significant reduction of the treatment volume. Our results suggest staged stereotactic radiotherapy using our protocol to be a possible alternative for treating large brain metastases.

  8. Endoscopic ultrasound-guided ethanol ablation of a large metastatic carcinoid tumor: success with a note of caution.

    PubMed

    Mathers, Bradley W; Harvey, Harold A; Dye, Charles E; Dougherty-Hamod, Brandy; Moyer, Matthew T

    2014-12-01

    Endoscopic ultrasonography with fine needle infusion (EUS-FNI) of alcohol is the most reported method for EUS-guided tumor ablation. Several studies have reported successful EUS-guided ablation of pancreatic neuroendocrine tumors. However, these tumors have been relatively small (< 3 cm). In this report, a 50-year-old man with a metastatic carcinoid tumor with a large porta hepatis mass was referred to our clinic for EUS-guided ethanol ablation. After two separate EUS-FNI ablations, there was a 36 % reduction in tumor size (9.0 × 11.4 cm to 6.7 × 9.8 cm) with associated tumor lysis syndrome. Chromogranin A levels decreased from 460 to 132 ng/mL. The patient reported complete resolution of abdominal pain within 2 weeks, but only mild improvement in flushing and diarrhea. In conclusion, large metastatic neuroendocrine tumors can be successfully treated with EUS-guided ethanol ablation. Evidence-based guidelines are needed with regard to the appropriate volume of ethanol injected in EUS-guided ablation to promote the efficacy and safety of this emerging procedure. PMID:26135103

  9. Talazoparib in Treating Patients With Advanced or Metastatic Solid Tumors That Cannot Be Removed by Surgery and Liver or Kidney Dysfunction

    ClinicalTrials.gov

    2016-10-05

    Estrogen Receptor Negative; Head and Neck Squamous Cell Carcinoma; HER2/Neu Negative; Hormone-Resistant Prostate Cancer; Metastatic Pancreatic Adenocarcinoma; Progesterone Receptor Negative; Solid Neoplasm; Stage III Mesothelioma; Stage IIIA Gastric Cancer; Stage IIIA Non-Small Cell Lung Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Small Cell Lung Carcinoma; Stage IIIB Gastric Cancer; Stage IIIB Non-Small Cell Lung Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Small Cell Lung Carcinoma; Stage IIIC Gastric Cancer; Stage IIIC Ovarian Cancer; Stage IV Mesothelioma; Stage IV Non-Small Cell Lung Cancer; Stage IV Ovarian Cancer; Stage IV Small Cell Lung Carcinoma; Triple-Negative Breast Carcinoma

  10. Trebananib And Temsirolimus in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

    ClinicalTrials.gov

    2015-10-05

    Adult Solid Neoplasm; Lung Carcinoid Tumor; Recurrent Digestive System Neuroendocrine Tumor G1; Recurrent Renal Cell Carcinoma; Recurrent Uterine Corpus Sarcoma; Stage III Renal Cell Cancer; Stage IIIB Uterine Sarcoma; Stage IIIC Uterine Sarcoma; Stage IV Renal Cell Cancer; Stage IVA Uterine Sarcoma; Stage IVB Uterine Sarcoma

  11. The anti-tumor effect of a polypeptide extracted from Tegillarca granosa Linnaeus on renal metastatic tumor OS-RC-2 cells

    PubMed Central

    Kong, Xiaoying; Jiang, Changqing; Liu, Xiaoyan; Xu, Luo

    2015-01-01

    Introduction Renal cell carcinoma is a type of malignant tumor often diagnosed in the urinary system. The aim of this study is to evaluate the anti-tumor effects and mechanisms of a polypeptide, Haishengsu (TG-1), with different concentrations (125, 250, 500 mg/kg) on renal metastatic tumor OS-RC-2 cells. Material and methods We first established the renal metastatic tumor model. After being administered with TG-1, the weight of tumors was measured and the microstructural changes of renal carcinoma OS-RC-2 cells were compared using transmission electron microscopy before and after the therapy. The Ki67 expression in renal carcinoma OS-RC-2 cells was analyzed by RT-PCR and downstream signal molecule caspase-3 was measured by Western blot assay. Results After treatment with different doses of TG-1, the tumor weights in the positive control group and experimental groups were smaller than those in the untreated control group, suggesting that TG-1 could effectively inhibit tumor growth in mice. The transmission electron microscopy and flow cytometry results indicated that TG-1 induces tumor cell apoptosis (p < 0.05). The tumor cells exhibited polymorphism changes and chromatin edge clustering. TG-1 also inhibited Ki67 expression and promoted caspase-3 expression in the tumor significantly (p < 0.05). Conclusions TG-1 inhibits the growth of the tumor and induces apoptosis of the tumor cells by inducing caspase-3 expression. The results provide a basis for clinical application of TG-1 in the future. PMID:26322097

  12. Quality of Life After Stereotactic Body Radiation Therapy for Primary and Metastatic Liver Tumors

    SciTech Connect

    Mendez Romero, Alejandra Wunderink, Wouter; Os, Rob M. van; Nowak, Peter J.C.M.; Heijmen, Ben J.M.; Nuyttens, Joost J.; Brandwijk, Rene P.; Verhoef, Cornelis; IJzermans, Jan N.M.; Levendag, Peter C.

    2008-04-01

    Purpose: Stereotactic body radiation therapy (SBRT) provides a high local control rate for primary and metastatic liver tumors. The aim of this study is to assess the impact of this treatment on the patient's quality of life. This is the first report of quality of life associated with liver SBRT. Methods and Materials: From October 2002 to March 2007, a total of 28 patients not suitable for other local treatments and with Karnofsky performance status of at least 80% were entered in a Phase I-II study of SBRT for liver tumors. Quality of life was a secondary end point. Two generic quality of life instruments were investigated, EuroQol-5D (EQ-5D) and EuroQoL-Visual Analogue Scale (EQ-5D VAS), in addition to a disease-specific questionnaire, the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ C-30). Points of measurement were directly before and 1, 3, and 6 months after treatment. Mean scores and SDs were calculated. Statistical analysis was performed using paired-samples t-test and Student t-test. Results: The calculated EQ-5D index, EQ-5D VAS and QLQ C-30 global health status showed that mean quality of life of the patient group was not significantly influenced by treatment with SBRT; if anything, a tendency toward improvement was found. Conclusions: Stereotactic body radiation therapy combines a high local control rate, by delivering a high dose per fraction, with no significant change in quality of life. Multicenter studies including larger numbers of patients are recommended and under development.

  13. 4D Proton treatment planning strategy for mobile lung tumors

    SciTech Connect

    Kang Yixiu; Zhang Xiaodong; Chang, Joe Y.; Wang He; Wei Xiong; Liao Zhongxing; Komaki, Ritsuko; Cox, James D.; Balter, Peter A.; Liu, Helen; Zhu, X. Ronald; Mohan, Radhe; Dong Lei . E-mail: ldong@mdanderson.org

    2007-03-01

    Purpose: To investigate strategies for designing compensator-based 3D proton treatment plans for mobile lung tumors using four-dimensional computed tomography (4DCT) images. Methods and Materials: Four-dimensional CT sets for 10 lung cancer patients were used in this study. The internal gross tumor volume (IGTV) was obtained by combining the tumor volumes at different phases of the respiratory cycle. For each patient, we evaluated four planning strategies based on the following dose calculations: (1) the average (AVE) CT; (2) the free-breathing (FB) CT; (3) the maximum intensity projection (MIP) CT; and (4) the AVE CT in which the CT voxel values inside the IGTV were replaced by a constant density (AVE{sub R}IGTV). For each strategy, the resulting cumulative dose distribution in a respiratory cycle was determined using a deformable image registration method. Results: There were dosimetric differences between the apparent dose distribution, calculated on a single CT dataset, and the motion-corrected 4D dose distribution, calculated by combining dose distributions delivered to each phase of the 4DCT. The AVE{sub R}IGTV plan using a 1-cm smearing parameter had the best overall target coverage and critical structure sparing. The MIP plan approach resulted in an unnecessarily large treatment volume. The AVE and FB plans using 1-cm smearing did not provide adequate 4D target coverage in all patients. By using a larger smearing value, adequate 4D target coverage could be achieved; however, critical organ doses were increased. Conclusion: The AVE{sub R}IGTV approach is an effective strategy for designing proton treatment plans for mobile lung tumors.

  14. A Genomics-Based Classification of Human Lung Tumors

    PubMed Central

    2014-01-01

    We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer. PMID:24174329

  15. Four-dimensional proton treatment planning for lung tumors

    SciTech Connect

    Engelsman, Martijn . E-mail: martijn.engelsman@maastro.nl; Rietzel, Eike; Kooy, Hanne M.

    2006-04-01

    Purpose: In proton radiotherapy, respiration-induced variations in density lead to changes in radiologic path lengths and will possibly result in geometric misses. We compared different treatment planning strategies for lung tumors that compensate for respiratory motion. Methods and Materials: Particle-specific treatment planning margins were applied to standard helical computed tomography (CT) scans as well as to 'representative' CT scans. Margins were incorporated beam specific laterally by aperture widening and longitudinally by compensator smearing. Furthermore, treatment plans using full time-resolved 4D-computed tomography data were generated. Results: Four-dimensional treatment planning guaranteed target coverage throughout a respiratory cycle. Use of a standard helical CT data set resulted in underdosing the target volume to 36% of the prescribed dose. For CT data representing average target positions, coverage can be expected but not guaranteed. In comparison to this strategy, 4D planning decreased the mean lung dose by up to 16% and the lung volume receiving 20 Gy (prescribed target dose 72 Gy) by up to 15%. Conclusion: When the three planning strategies are compared, only 4D proton treatment planning guarantees delivery of the prescribed dose throughout a respiratory cycle. Furthermore, the 4D planning approach results in equal or reduced dose to critical structures; even the ipsilateral lung is spared.

  16. Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung.

    PubMed

    Petersen, S; Aninat-Meyer, M; Schlüns, K; Gellert, K; Dietel, M; Petersen, I

    2000-01-01

    Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas (SCC) of the lung to define chromosomal imbalances that are associated with the metastatic phenotype. In total, 64 lung SCC from 50 patients were investigated, 25 each with or without evidence of metastasis formation. The chromosomal imbalances summarized by a CGH histogram of the 50 cases revealed deletions most frequently on chromosomes 1p21-p31, 2q34-q36, 3p, 4p, 4q, 5q, 6q14-q24, 8p, 9p, 10q, 11p12-p14, 13q13-qter, 18q12-qter and 21q21. DNA over-representations were most pronounced for chromosomes 1q11-q25, 1q32-q41, 3q, 5p, 8q22-qter, 11q13, 12p, 17q21-q22, 17q24-q25, 19, 20q and 22q. In ten cases, paired samples of primaries and at least one metastasis were analysed. The comparison revealed a considerable chromosomal instability and genetic heterogeneity; however, the CGH pattern indicated a clonal relationship in each case. The difference in histograms from the metastatic and non-metastatic tumour groups was most useful in pinpointing chromosomal imbalances associated with the metastatic phenotype, indicating that the deletions at 3p12-p14, 3p21, 4p15-p16, 6q24-qter, 8p22-p23, 10q21-qter and 21q22, as well as the over-representations at 1q21-q25, 8q, 9q34, 14q12 and 15q12-q15, occurred significantly more often in the metastatic tumour group. The comparison of the paired samples confirmed these findings in individual cases and suggested distinct genetic changes, in particular the extension of small interstitial deletions, during tumour progression. Importantly, metastasis-associated lesions were frequently detectable in the primary tumour providing a method of identifying patients at risk for tumour dissemination. Individual profiles and histograms are accessible at our web site http://amba.charite.de/cgh.

  17. Dasatinib, Ifosfamide, Carboplatin, and Etoposide in Treating Young Patients With Metastatic or Recurrent Malignant Solid Tumors

    ClinicalTrials.gov

    2016-08-10

    Brain and Central Nervous System Tumors; Childhood Germ Cell Tumor; Extragonadal Germ Cell Tumor; Kidney Cancer; Liver Cancer; Lymphoma; Neuroblastoma; Ovarian Cancer; Sarcoma; Testicular Germ Cell Tumor; Unspecified Childhood Solid Tumor, Protocol Specific

  18. Miscellaneous cancers (lung, thyroid, renal cancer, myeloma, and neuroendocrine tumors): role of SPECT and PET in imaging bone metastases.

    PubMed

    Chua, Sue; Gnanasegaran, Gopinath; Cook, Gary J R

    2009-11-01

    In this review, we assess the current role of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in the imaging of skeletal metastatic disease from a miscellaneous group of malignancies, including lung, thyroid, and renal carcinomas; multiple myeloma; and neuroendocrine tumors, and consider how recent advances may enhance their effectiveness in this area. Bone scintigraphy using technetium-labeled diphosphonates has long been the mainstay of functional imaging of bony metastases, but is of limited value in myeloma and aggressive osteolytic metastases, and has the limitation of relatively poor specificity. SPECT, as a tomographic imaging technique, produces three-dimensional images of tracer distribution from multiplanar images. Its application to bone scintigrams greatly aids accurate anatomic localization and sensitivity in detection of foci of tracer uptake. SPECT can equally be applied to scintigrams using radiotracers, which are specific for particular groups of tumors, such as somatostatin analogs for neuroendocrine tumors. The advent of combined SPECT/computed tomography (CT) systems has further enhanced the accuracy of SPECT in all these malignancies. PET uses positron-emitting radiotracers and achieves a higher spatial resolution than single-photon imaging. Its high resolution and coverage of the entire body have made it a highly effective technique for the evaluation of skeletal metastatic disease, particularly when combined with CT. (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/CT now forms part of routine staging for many carcinomas, such as non-small-cell lung carcinomas, and may obviate the need for routine staging scintigraphy in these patients. As uptake of the most common PET radiotracer, (18)F-FDG, is dependent on the increased cellular metabolism of most tumors, it may enable earlier detection of metastatic foci than bone scintigraphy, which relies on detecting an osteoblastic response. Another significant

  19. Identifying metastatic breast tumors using textural kinetic features of a contrast based habitat in DCE-MRI

    NASA Astrophysics Data System (ADS)

    Chaudhury, Baishali; Zhou, Mu; Goldgof, Dmitry B.; Hall, Lawrence O.; Gatenby, Robert A.; Gillies, Robert J.; Drukteinis, Jennifer S.

    2015-03-01

    The ability to identify aggressive tumors from indolent tumors using quantitative analysis on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) would dramatically change the breast cancer treatment paradigm. With this prognostic information, patients with aggressive tumors that have the ability to spread to distant sites outside of the breast could be selected for more aggressive treatment and surveillance regimens. Conversely, patients with tumors that do not have the propensity to metastasize could be treated less aggressively, avoiding some of the morbidity associated with surgery, radiation and chemotherapy. We propose a computer aided detection framework to determine which breast cancers will metastasize to the loco-regional lymph nodes as well as which tumors will eventually go on to develop distant metastses using quantitative image analysis and radiomics. We defined a new contrast based tumor habitat and analyzed textural kinetic features from this habitat for classification purposes. The proposed tumor habitat, which we call combined-habitat, is derived from the intersection of two individual tumor sub-regions: one that exhibits rapid initial contrast uptake and the other that exhibits rapid delayed contrast washout. Hence the combined-habitat represents the tumor sub-region within which the pixels undergo both rapid initial uptake and rapid delayed washout. We analyzed a dataset of twenty-seven representative two dimensional (2D) images from volumetric DCE-MRI of breast tumors, for classification of tumors with no lymph nodes from tumors with positive number of axillary lymph nodes. For this classification an accuracy of 88.9% was achieved. Twenty of the twenty-seven patients were analyzed for classification of distant metastatic tumors from indolent cancers (tumors with no lymph nodes), for which the accuracy was 84.3%.

  20. Metastatic tumors in the jaw bones: A retrospective clinicopathological study of 12 cases at Tertiary Cancer Center

    PubMed Central

    Nawale, Kundan Kisanrao; Vyas, Monika; Kane, Shubhada; Patil, Asawari

    2016-01-01

    Introduction: The metastatic disease of the jaw bones is very uncommon and accounts for approximately 1% of all malignancies of jaw. The most common location is molar region of mandible. Metastasis may go undetected on a routine skeletal survey for assessment of metastasis and rarely includes jaw bones. Aims and Objective: The aim of the study is to analyze primary malignancies in metastatic jaw tumors. Materials and Methods: We retrospectively studied clinicopathological features of 12 patients of metastasis to jaw bones diagnosed at tertiary cancer center between 2003 and 2011. All H and E and immunohistochemical slides were reviewed by two pathologists and relevant details were noted. Results: There were eight female and four male patients, with age range 12–71 years with metastases to jaws. All of them involved mandible with one case also showing the involvement of frontal sinuses. The types of metastatic tumors include adenocarcinoma (six cases), papillary thyroid carcinoma (four cases), carcinoma with neuroendocrine differentiation (one case) and neuroblastoma (one case). The diagnosis was made on biopsies in eight cases and on hemimandibulectomy in four cases. The primary site was known at the time of presentation only in four cases, all of them being thyroid carcinomas. Primary site was determined in seven cases after immunohistochemical workup on metastatic tumor and further investigations, whereas the primary site of carcinoma with neuroendocrine differentiation was unknown. Conclusion: Metastasis to jaw bones is rare and may be the first manifestation of unknown primary. A lesion predominantly involving bone with unusual morphology should raise a possibility of metastasis. PMID:27601818

  1. Markerless tracking of small lung tumors for stereotactic radiotherapy

    SciTech Connect

    Sörnsen de Koste, John R. van Dahele, Max; Senan, Suresh; Slotman, Ben J.; Verbakel, Wilko F. A. R.; Mostafavi, Hassan; Sloutsky, Alex

    2015-04-15

    Purpose: (1) To validate retrospective markerless tracking software for small lung tumors by comparing tracked motion in 4-dimensional planning computed tomography (4DCT) derived kV projection images and known tumor motion in the same 4DCT. (2) To evaluate variability of tumor motion using kV projection images from cone-beam computed tomography (CBCT) scans acquired on different days. Methods: Nonclinical tumor tracking software (TTS) used a normalized cross correlation algorithm to track the tumor on enhanced kV projection images (e.g., from a CBCT scan). The reference dataset consisted of digitally reconstructed radiographs (DRRs) from one phase of a planning 4DCT. TTS matches two in-plane coordinates and obtains the out-of-plane coordinate by triangulating with match results from other projections. (1) To validate TTS, tracking results were compared with known 4DCT tumor motion for two patients (A and B). Projection images (1 image/1°) were digitally reconstructed for each 4DCT phase. From these, kV projection series were composed simulating full breathing cycles every 20° of gantry rotation [breathing period = 20°/(6°/s) = 3.33 s]. Reference templates were 360 “tumor enhanced” DRRs from the 4DCT expiration phase. TTS-derived tumor motion was compared to known tumor motion on 4DCT. (2) For five patients, TTS-assessed motion during clinical CBCT acquisition was compared with motion on the planning 4DCT, and the motion component in the Y (cranio–caudal)-direction was compared with the motion of an external marker box (RPM, real-time position management). Results: (1) Validation results: TTS for case A (tumor 6.2 cm{sup 3}, 32 mm axial diameter) over 360° showed mean motion X (medial–lateral) = 3.4, Y = 11.5, and Z (ventral–dorsal) = 4.9 mm (1 SD < 1.0 mm). Corresponding 4DCT motion was X = 3.1, Y = 11.3, and Z = 5.1 mm. Correlation coefficients between TTS tumor motion and displacement of the tumor’s center of mass (CoM) on 4DCT were 0.64, 0

  2. Integrated quantitative proteomic and transcriptomic analysis of lung tumor and control tissue: a lung cancer showcase

    PubMed Central

    Huwer, Hanno; Hildebrandt, Andreas; Lenhof, Hans-Peter; Wesse, Tanja; Franke, Andre; Keller, Andreas

    2016-01-01

    Proteomics analysis of paired cancer and control tissue can be applied to investigate pathological processes in tumors. Advancements in data-independent acquisition mass spectrometry allow for highly reproducible quantitative analysis of complex proteomic patterns. Optimized sample preparation workflows enable integrative multi-omics studies from the same tissue specimens. We performed ion mobility enhanced, data-independent acquisition MS to characterize the proteome of 21 lung tumor tissues including adenocarcinoma and squamous cell carcinoma (SCC) as compared to control lung tissues of the same patient each. Transcriptomic data were generated for the same specimens. The quantitative proteomic patterns and mRNA abundances were subsequently analyzed using systems biology approaches. We report a significantly (p = 0.0001) larger repertoire of proteins in cancer tissues. 12 proteins were higher in all tumor tissues as compared to matching control tissues. Three proteins, CAV1, CAV2, and RAGE, were vice versa higher in all controls. We also identified characteristic SCC and adenocarcinoma protein patterns. Principal Component Analysis provided evidence that not only cancer from control tissue but also tissue from adenocarcinoma and SCC can be differentiated. Transcriptomic levels of key proteins measured from the same matched tissue samples correlated with the observed protein patterns. The applied study set-up with paired lung tissue specimens of which different omics are measured, is generally suited for an integrated multi-omics analysis. PMID:26930711

  3. Synchronous solitary fibrous tumor of the pleura and lung cancer.

    PubMed

    Watanabe, Shun-Ichi; Nakamura, Yoshihiro; Sakasegawa, Koh-Ichi; Kariatsumari, Kota; Yotsumoto, Daisuke; Sakata, Ryuzo; Gezima, Kentaro

    2003-01-01

    We report herein on a 57-year-old woman with comorbid malignant solitary fibrous tumor (SFT) of the pleura and adenocarcinoma of the lung. To the best of our knowledge, this is the first report of a patient presenting with these two pathological entities simultaneously. The patient was treated successfully for both diseases via a one-stage operation through median sternotomy with good results. Although the incidence of multiple primary malignancy is rare, clinicians should be cautious not to discount the possibility of two coexisting primary malignancies.

  4. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging.

    PubMed

    Fecher, David; Hofmann, Elisabeth; Buck, Andreas; Bundschuh, Ralph; Nietzer, Sarah; Dandekar, Gudrun; Walles, Thorsten; Walles, Heike; Lückerath, Katharina; Steinke, Maria

    2016-01-01

    Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and -testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. PMID:27501455

  5. Human Organotypic Lung Tumor Models: Suitable For Preclinical 18F-FDG PET-Imaging

    PubMed Central

    Fecher, David; Hofmann, Elisabeth; Buck, Andreas; Bundschuh, Ralph; Nietzer, Sarah; Dandekar, Gudrun; Walles, Thorsten; Walles, Heike; Lückerath, Katharina; Steinke, Maria

    2016-01-01

    Development of predictable in vitro tumor models is a challenging task due to the enormous complexity of tumors in vivo. The closer the resemblance of these models to human tumor characteristics, the more suitable they are for drug-development and –testing. In the present study, we generated a complex 3D lung tumor test system based on acellular rat lungs. A decellularization protocol was established preserving the architecture, important ECM components and the basement membrane of the lung. Human lung tumor cells cultured on the scaffold formed cluster and exhibited an up-regulation of the carcinoma-associated marker mucin1 as well as a reduced proliferation rate compared to respective 2D culture. Additionally, employing functional imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) these tumor cell cluster could be detected and tracked over time. This approach allowed monitoring of a targeted tyrosine kinase inhibitor treatment in the in vitro lung tumor model non-destructively. Surprisingly, FDG-PET assessment of single tumor cell cluster on the same scaffold exhibited differences in their response to therapy, indicating heterogeneity in the lung tumor model. In conclusion, our complex lung tumor test system features important characteristics of tumors and its microenvironment and allows monitoring of tumor growth and -metabolism in combination with functional imaging. In longitudinal studies, new therapeutic approaches and their long-term effects can be evaluated to adapt treatment regimes in future. PMID:27501455

  6. The diagnostic utility of the triple markers Napsin A, TTF-1, and PAX8 in differentiating between primary and metastatic lung carcinomas.

    PubMed

    El-Maqsoud, Nehad M R Abd; Tawfiek, Ehab Rifat; Abdelmeged, Ayman; Rahman, Mohamed Fathy Abdel; Moustafa, Alaa A E

    2016-03-01

    Napsin A and thyroid transcription factor-1 (TTF-1) are useful biomarkers for differentiating lung adenocarcinoma from squamous cell carcinoma and also for differentiating primary lung adenocarcinoma from metastatic lung carcinoma. Pair-boxed 8 (PAX8) can help in distinguishing primary lung carcinoma from metastatic carcinomas and help to determine the primary sites of metastatic carcinomas. Immunohistochemistry for Napsin A, TTF-1, and PAX8 were performed on 193 cases of carcinoma: 50 primary lung carcinoma and 143 carcinomas from other sites. Napsin A and TTF-1 were positive in 54, 52 % of lung carcinomas cases, respectively. While in adenocarcinoma cases, their expressions were 86.7 and 83.3 %, respectively. PAX8 was negative in all lung carcinomas. TTF-1 and PAX8 were positive in 93.3 and 96.7 % of thyroid carcinoma cases and in 87.5 and 93.8 % of papillary carcinoma respectively, and both were positive in 100 % of follicular carcinoma. Napsin A was negative in all thyroid carcinomas. Napsin A and PAX8 were positive in 50 and 93.3 % of renal carcinoma cases and in 81.8 and 100 % of papillary carcinoma, 38.5 and 92.3 % of clear cell carcinoma, and 16.7 and 83.3 % of chromophobe carcinoma respectively. TTF-1 was negative in all renal carcinomas. PAX8 was positive in 80 % of ovarian carcinoma cases; 100 and 60 % of serous mucinous carcinomas, respectively. It was also positive in 100 % of endometrial carcinoma. Napsin A and TTF-1 were negative in both ovarian and endometrial carcinomas. Our data demonstrated that combined use of Napsin A, TTF-1, and PAX8 may help in differentiating between primary lung adenocarcinoma and metastatic lung carcinomas.

  7. [Salivary gland-type lung tumor: An update].

    PubMed

    Gibault, Laure; Badoual, Cécile

    2016-01-01

    "Salivary gland-type" tumors arising from the bronchi and lung are rare but not exceptional entities. They are mostly represented by malignant entities such as cystic adenoid carcinoma, mucoepidermoid carcinoma and epithelial/myoepithelial carcinoma. Benign tumors are rare, mainly encompassing pleomorphic adenomas, which are to differentiate from mucous gland adenomas, another entity arising specifically from the peri-bronchial glands. These tumours develop in the proximal bronchi and are not associated with smoke abuse. Their main treatment is surgery. It is important to differentiate them from other broncho-pulmonary tumours as they do not share the same prognosis and therapeutic. This article will review the WHO 2015 classification of these tumours as well as recent updates from the literature to help define diagnosis criteria for these uncommon entities. PMID:26774826

  8. Problems with the diagnosis of metastatic neuroendocrine neoplasms. Which diagnostic criteria should we use to determine tumor origin and help guide therapy?

    PubMed

    Koo, Jamie; Dhall, Deepti

    2015-11-01

    Neuroendocrine neoplasms (NENs) can often present with metastatic disease before the primary tumor is discovered. Metastatic lesions are generally classified as well differentiated and poorly differentiated for prognostic and therapeutic purposes. In addition, for well-differentiated neuroendocrine tumors (WDNETs), pathologists are expected to determine the site of origin, if not already known, and grade the tumors. However, it is often difficult for pathologists to provide this information with certainty without knowing the site of tumor origin, as different criteria have been proposed by WHO for classification of gastrointestinal and pulmonary NENs. In this review, we will discuss the current classification and grading schema of NENs and their impact on clinical care, the differential diagnosis of NENs, the use of immunohistochemical stains that help identify tumor site of origin, and a proposed approach for the diagnosis and classification of metastatic NENs.

  9. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer

    PubMed Central

    Schneck, Helen; Gierke, Berthold; Uppenkamp, Frauke; Behrens, Bianca; Niederacher, Dieter; Stoecklein, Nikolas H.; Templin, Markus F.; Pawlak, Michael; Fehm, Tanja; Neubauer, Hans

    2015-01-01

    Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far–including the gold standard CellSearch—rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT). Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture an EpCAMlow/neg cell line and EpCAMneg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAMpos (e.g. MCF7, SKBR3) and EpCAMlow/neg (MDA-MB-231) breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) for capturing EpCAMneg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAMpos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAMlow/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAMlow/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAMneg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK)-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69%) from 25 metastatic breast cancer patients additional EpCAMneg CTCs could be identified [range of 1–24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. Ep

  10. Expression of the p16{sup INK4a} tumor suppressor gene in rodent lung tumors

    SciTech Connect

    Swafford, D.S.; Tesfaigzi, J.; Belinsky, S.A.

    1995-12-01

    Aberrations on the short arm of chromosome 9 are among the earliest genetic changes in human cancer. p16{sup INK4a} is a candidate tumor suppressor gene that lies within human 9p21, a chromosome region associated with frequent loss of heterozygosity in human lung tumors. The p16{sup INK4a} protein functions as an inhibitor of cyclin D{sub 1}-dependent kinases that phosphorylate the retinoblastoma (Rb) tumor suppressor gene product enabling cell-cycle progression. Thus, overexpression of cyclin D{sub 1}, mutation of cyclin-dependent kinase genes, or loss of p16{sup INK4a} function, can all result in functional inactivation of Rb. Inactivation of Rb by mutation or deletion can result in an increase in p16{sup INK4a} transcription, suggesting that an increased p16{sup INK4a} expression in a tumor cell signals dysfunction of the pathway. The p16{sup (INK4a)} gene, unlike some tumor suppressor genes, is rarely inactivated by mutation. Instead, the expression of this gene is suppressed in some human cancers by hypermethylation of the CpG island within the first exon or by homozygous deletion: 686. Chromosome losses have been observed at 9p21 syntenic loci in tumors of the mouse and rat, two species often used as animal models for pulmonary carcinogenesis. Expression of p16{sup INK4a} is lost in some mouse tumor cell lines, often due to homozygous deletion. These observations indicate that p16{sup INK4a} dysfunction may play a role in the development of neoplasia in rodents as well as humans. The purpose of the current investigation was to define the extent to which p16{sup INK4a} dysfunction contributes to the development of rodent lung tumors and to determine the mechanism of inactivation of the gene. There is no evidence to suggest a loss of function of the p16{sup INK4a} tumor suppressor gene in these primary murine lung tumors by mutation, deletion, or methylation.

  11. A rare benign tumor of the lung: Inflammatory myofibroblastic tumor – Case report

    PubMed Central

    Demirhan, Ozkan; Ozkara, Selvinaz; Yaman, Mustafa; Kaynak, Kamil

    2013-01-01

    A fifty year old lady who was operated for thyroid cancer two years ago and completed adjuvant therapy, underwent a computer tomography (CT) of the chest during her follow up. The CT showed a mass lesion in the right lung, located to the lateral segment of the middle lobe. There were no intrabronchial lesions on bronchoscopy. Positron emission CT (PET CT) showed a dense hypermetabolic mass located in the right middle lobe lateral segment and having malignant characteristics. A videothorascopic wedge resection was performed and the specimen was sent for frozen section, which showed no evidence of malignancy. Pathology report revealed an inflammatory myofibroblastic tumor (IMT). Since IMT is a rare benign tumor of the lung, we herein report this patient along with a discussion of the relevant literature. PMID:26029612

  12. Circulating Tumor Cells and Response to Chemotherapy in Metastatic Breast Cancer: SWOG S0500

    PubMed Central

    Smerage, Jeffrey B.; Barlow, William E.; Hortobagyi, Gabriel N.; Winer, Eric P.; Leyland-Jones, Brian; Srkalovic, Gordan; Tejwani, Sheela; Schott, Anne F.; O'Rourke, Mark A.; Lew, Danika L.; Doyle, Gerald V.; Gralow, Julie R.; Livingston, Robert B.; Hayes, Daniel F.

    2014-01-01

    Purpose Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). Patients and Methods Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Results Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). Conclusion This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy. PMID:24888818

  13. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436)

    PubMed Central

    Nathanson, Katherine L.; Martin, Anne-Marie; Wubbenhorst, Bradley; Greshock, Joel; Letrero, Richard; D’Andrea, Kurt; O’Day, Steven; Infante, Jeffrey R.; Falchook, Gerald S.; Arkenau, Hendrik-Tobias; Millward, Michael; Brown, Michael P.; Pavlick, Anna; Davies, Michael A.; Ma, Bo; Gagnon, Robert; Curtis, Martin; Lebowitz, Peter F.; Kefford, Richard; Long, Georgina V.

    2014-01-01

    Purpose Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently demonstrated improved progression free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. The current study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib. Experimental Design Baseline (pre-treatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available. Results All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response (BOR) to dabrafenib, but it showed a trend for shorter median progression free survival (PFS) (18.3 [95% confidence interval (CI) 9.1–24.3] vs. 32.1 weeks [95% CI 24.1–33], p=0.059). Higher copy number of CCND1 (p=0.009) and lower copy number of CDKN2A (p=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors. Conclusions Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. PMID:23833299

  14. Pazopanib in metastatic multiply treated progressive gastrointestinal stromal tumors: feasible and efficacious

    PubMed Central

    Ramaswamy, Anant; Pande, Nikhil; Shetty, Omshree; Shetty, Nitin; Gupta, Sudeep

    2016-01-01

    Background A median progression free survival (PFS) of 18–20 months and median overall survival (OS) of 51–57 months can be achieved with the use of imatinib, in metastatic or advanced gastrointestinal stromal tumor (GIST). Sunitinib and regorafenib are approved options for patients progressing on imatinib, but with markedly decreased survival. pazopanib is a broad spectrum TKI targeting KIT, PDGFR and VEGFR receptors and has shown promising activity in phase 2 trials in GIST. Methods All patients who received pazopanib for GIST between March 2014 and September 2015 in our institution were reviewed. Patients were assessed for response with CT or PET CT scans. Patients continued pazopanib until progression or unacceptable toxicity. Survival was evaluated by Kaplan Meier product method. Results A total of 11 consecutive patients were included in our study. Median duration of follow up was seven months. The median lines of prior therapy was 2 [1-5]. Partial response (PR) was observed in seven patients and two had stable disease (SD). Two patients died within one month of start of pazopanib. Five of ten patients had progressed during the study with eight patients still alive. The median PFS was 11.9 months and the median OS was not reached. Common adverse events seen were hand-foot-syndrome (HFS) in four patients, anemia in four patients and fatigue in three patients. Grade 3/4 adverse events were uncommon. Three patients required dose modification of pazopanib. Conclusions Pazopanib is a reasonably efficacious well tolerated TKI and can be explored as a treatment option in advanced GIST that has progressed on imatinib. PMID:27563456

  15. Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by 12 weeks.

    PubMed

    Shantha, Ghanshyam Palamaner Subash; Kumar, Anita A; Jeyachandran, Vijay; Rajamanickam, Deepan; Bhaskar, Emmanuel; Paniker, Vinod K; Abraham, Georgi

    2009-01-01

    Clinically evident adrenal insufficiency associated with lung cancer is a rare entity. Among reported cases, adrenal insufficiency has occurred with or succeeded the primary lung cancer. Adrenal insufficiency has also been secondary to metastasis to the adrenal gland. The present report concerns a 61-year-old man, a chronic smoker, who presented to us with symptomatic adrenal insufficiency. He had no evidence of lung cancer during this visit. The primary lung cancer was only identified 12 weeks later. Additionally, his adrenals showed no evidence of metastasis. Hence his adrenal insufficiency had been a paraneoplastic manifestation of the lung cancer, and it had also preceded the primary by 12 weeks.

  16. Paraneoplastic (non-metastatic) adrenal insufficiency preceded the onset of primary lung cancer by 12 weeks

    PubMed Central

    Shantha, Ghanshyam Palamaner Subash; Kumar, Anita A; Jeyachandran, Vijay; Rajamanickam, Deepan; Bhaskar, Emmanuel; Paniker, Vinod K; Abraham, Georgi

    2009-01-01

    Clinically evident adrenal insufficiency associated with lung cancer is a rare entity. Among reported cases, adrenal insufficiency has occurred with or succeeded the primary lung cancer. Adrenal insufficiency has also been secondary to metastasis to the adrenal gland. The present report concerns a 61-year-old man, a chronic smoker, who presented to us with symptomatic adrenal insufficiency. He had no evidence of lung cancer during this visit. The primary lung cancer was only identified 12 weeks later. Additionally, his adrenals showed no evidence of metastasis. Hence his adrenal insufficiency had been a paraneoplastic manifestation of the lung cancer, and it had also preceded the primary by 12 weeks. PMID:21686682

  17. Clear Cell “Sugar” Tumor of the Lung: Benign or Malignant?

    PubMed Central

    Olivencia-Yurvati, Albert H.; Rodriguez, Abraham Elias

    2015-01-01

    Clear cell “sugar” tumors of the lung are rare pulmonary tumors. This case study illustrates a patient who was found to have a persistent nodule in the left-upper lobe of the lung. Positron emission tomographic scanning showed mild-moderate 18-fluorodeoxyglucose uptake. Based on these findings, a video-assisted resection of the tumor was undertaken. The mass was identified histologically, as a clear cell “sugar” tumor of the lung. This case report discusses the benign versus malignant nature of this rare tumor. PMID:26011217

  18. [Clinical perspectives of the study of RANK/RANKL/OPG system components in primary and metastatic bone tumor].

    PubMed

    Kushlinskiĭ, N E; Timofeev, Iu S; Gershteĭn, E S; Solov'ev, Iu N

    2014-01-01

    Disbalance of bone homeostasis, associated with malfunctioning of RANK/RANKL/OPG system underlies the oncological processes such as the destruction of bone, metastasis development, tumor progression. Pathological activity of system was described in such conditions, as breast cancer, prostate cancer, multiple myeloma, squamous cell carcinoma, Hodgkin's disease, and also metastasis in bones from lung cancer and other malignant diseases. In the literature, there is evidence of involvement of RANK/RANKL/OPG system in the pathogenesis of bone tumors (osteosarcoma, giant cell tumor of bone, chondroblastoma). Experimental data show that RANKL inhibitors can play a role in reducing tumor-induced lesions of bone in multiple myeloma, breast cancer, prostate cancer and lung cancer. Also this review presents data from clinical studies of the drug efficacy targeted on RANK/RANKL/OPG system and results of authors' study of the levels of this system's components and proinflammatory cytokines in blood serum of primary bone sarcoma patients. PMID:25552059

  19. KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer.

    PubMed

    Yu, T; Chen, X; Zhang, W; Liu, J; Avdiushko, R; Napier, D L; Liu, A X; Neltner, J M; Wang, C; Cohen, D; Liu, C

    2016-02-01

    Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras(LSL-G12D/+);Klf4(fl/fl) mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

  20. Primitive neuroectodermal tumor originating from the lung: A case report

    PubMed Central

    Jin, Xin; Cao, Jianfeng; Liu, Yong; Bian, Fang; Zhao, Qingqing; Wang, Yan; Lv, Xu; Huang, Yayong

    2016-01-01

    Primitive neuroectodermal tumors (PNETs) are small, round cell tumors that may be classified as peripheral or central, based on their site of origin. PNETs often arise in the soft tissue or bone of young adults. Although not common, PNETs have been described in other organs, including the gonads, kidneys, myocardium and pancreas, but rarely in the lungs without chest wall or pleural involvement. The present study reports a rare case of peripheral PNET (pPNET), which originated in the lung. A 37-year-old female patient presented at Xuzhou Central Hospital (Xuzhou, China) with a history of a dry cough, mild dyspnea and slight pain in the left chest. Histopathological and immunohistochemical analyses permitted the diagnosis of a pPNET. The patient was treated with surgical resection, followed by chemotherapy (including cyclophosphamide, cisplatin and vincristine), radiotherapy and traditional Chinese medicine (including Kanglaite and Shenqi Fuzheng injections). At the time of writing, the patient was alive with no sign of recurrence and under regular follow-ups at the Outpatient Clinic of Xuzhou Central Hospital.

  1. Complete Regression of Metastatic Cervical Cancer After Treatment With Human Papillomavirus–Targeted Tumor-Infiltrating T Cells

    PubMed Central

    Stevanović, Sanja; Draper, Lindsey M.; Langhan, Michelle M.; Campbell, Tracy E.; Kwong, Mei Li; Wunderlich, John R.; Dudley, Mark E.; Yang, James C.; Sherry, Richard M.; Kammula, Udai S.; Restifo, Nicholas P.; Rosenberg, Steven A.; Hinrichs, Christian S.

    2015-01-01

    Purpose Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer. Patients and Methods Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin. Results Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238). Conclusion Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted. PMID:25823737

  2. Minimizing metastatic risk in radiotherapy fractionation schedules

    NASA Astrophysics Data System (ADS)

    Badri, Hamidreza; Ramakrishnan, Jagdish; Leder, Kevin

    2015-11-01

    Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor α /β values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger α /β values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the α /β values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.

  3. Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.

    PubMed

    Santos, Mark F; Mannam, Venkat K R; Craft, Barbara S; Puneky, Louis V; Sheehan, Natale T; Lewis, Robert E; Cruse, Julius M

    2014-06-01

    In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i

  4. Noninvasive theranostic imaging of HSV1-sr39TK-NTR/GCV-CB1954 dual-prodrug therapy in metastatic lung lesions of MDA-MB-231 triple negative breast cancer in mice.

    PubMed

    Sekar, Thillai V; Foygel, Kira; Ilovich, Ohad; Paulmurugan, Ramasamy

    2014-01-01

    Metastatic breast cancer is an obdurate cancer type that is not amenable to chemotherapy regimens currently used in clinic. There is a desperate need for alternative therapies to treat this resistant cancer type. Gene-Directed Enzyme Prodrug Therapy (GDEPT) is a superior gene therapy method when compared to chemotherapy and radiotherapy procedures, proven to be effective against many types of cancer in pre-clinical evaluations and clinical trials. Gene therapy that utilizes a single enzyme/prodrug combination targeting a single cellular mechanism needs significant overexpression of delivered therapeutic gene in order to achieve therapy response. Hence, to overcome this obstacle we recently developed a dual therapeutic reporter gene fusion that uses two different prodrugs, targeting two distinct cellular mechanisms in order to achieve effective therapy with a limited expression of delivered transgenes. In addition, imaging therapeutic reporter genes offers additional information that indirectly correlates gene delivery, expression, and functional effectiveness as a theranostic approach. In the present study, we evaluate the therapeutic potential of HSV1-sr39TK-NTR fusion dual suicide gene therapy system that we recently developed, in MDA-MB-231 triple negative breast cancer lung-metastatic lesions in a mouse model. We compared the therapeutic potential of HSV1-sr39TK-NTR fusion with respective dual prodrugs GCV-CB1954 with HSV1-sr39TK/GCV and NTR/CB1954 single enzyme prodrug system in this highly resistant metastatic lesion of the lungs. In vitro optimization of dose and duration of exposure to GCV and CB1954 was performed in MDA-MB-231 cells. Drug combinations of 1 μg/ml GCV and 10 μM CB1954 for 3 days was found to be optimal regimen for induction of significant cell death, as assessed by FACS analysis. In vivo therapeutic evaluation in animal models showed a complete ablation of lung metastatic nodules of MDA-MB-231 triple negative breast cancer cells following

  5. Metastatic Malignant Melanoma of Parotid Gland with a Regressed Primary Tumor

    PubMed Central

    Aynali, Giray; Ceyhan, Ali Murat; Çiriş, Metin

    2016-01-01

    Malignant melanoma of the parotid gland is often metastatic and mainly originates from malignant melanomas in the head and neck. Nevertheless, some malignant melanomas may metastasize and subsequently regress. Therefore, it may not be possible to observe a metastatic malignant melanoma and its primary melanoma simultaneously. The investigation of a patient's old photographs may help in the detection of preexisting and regressed pigmented lesions in the facial and neck regions. PMID:27478668

  6. Alvespimycin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors

    ClinicalTrials.gov

    2013-04-09

    and Oral Cavity; Stage III Squamous Cell Carcinoma of the Nasopharynx; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage III Verrucous Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Oral Cavity; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Basal Cell Carcinoma of the Lip; Stage IV Breast Cancer; Stage IV Colon Cancer; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Gastric Cancer; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Melanoma; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Ovarian Epithelial Cancer; Stage IV Prostate Cancer; Stage IV Renal Cell Cancer; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Unspecified Adult Solid Tumor, Protocol Specific; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  7. SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

    SciTech Connect

    Wang, Jia-lei; Lu, Fan-zhen; Shen, Xiao-Yong; Wu, Yun; Zhao, Li-ting

    2014-12-12

    Highlights: • SAMHD1 expression level is down regulated in lung adenocarcinoma. • The promoter of SAMHD1 is methylated in lung adenocarcinoma. • Over expression of SAMHD1 inhibits the proliferation of lung cancer cells. - Abstract: The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells.

  8. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and NF-κB

    PubMed Central

    Min, Junxia; Zaslavsky, Alexander; Fedele, Giuseppe; McLaughlin, Sara K.; Reczek, Elizabeth E.; De Raedt, Thomas; Guney, Isil; Strochlic, David E.; Laura, E.; Beroukhim, Rameen; Bronson, Roderick T.; Ryeom, Sandra; Hahn, William C.; Loda, Massimo; Cichowski, Karen

    2010-01-01

    Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer initiation and metastasis by coordinately activating Ras and NF-κB. Specifically, we show that loss of the RasGAP gene DAB2IP induces metastatic prostate cancer in a murine model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-κB through distinct domains to promote tumor initiation and metastasis, respectively. DAB2IP is suppressed in human prostate cancer where expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein EZH2 activates Ras, NF-κB, and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis. PMID:20154697

  9. Low Infection Rate after Tumor Hip Arthroplasty for Metastatic Bone Disease in a Cohort Treated with Extended Antibiotic Prophylaxis

    PubMed Central

    Hettwer, Werner H.; Horstmann, Peter Frederik; Hovgaard, Thea Bechmann; Grum-Scwensen, Tomas Andreas; Petersen, Michael M.

    2015-01-01

    Background. Compared to conventional hip arthroplasty, endoprosthetic reconstruction after tumor resection is associated with a substantially increased risk of periprosthetic joint infection (PJI), with reported rates of around 10% in a recent systematic review. The optimal duration of antibiotic prophylaxis for this patient population remains unknown. Material and Methods. To establish the infection rate associated with prolonged antibiotic prophylaxis in our department, we performed a retrospective review of all adult patients who underwent endoprosthetic reconstruction of the proximal femur after tumor resection for metastatic bone disease during a 4-year period from 2010 to 2013 (n = 105 patients). Results. Intravenous antibiotic prophylaxis was administrated for an extended duration of a mean of 7.4 days. The overall infection rate was 3.6% (4/111 implants), infection free survival was 96% at 2 years, and the risk of amputation associated with infection was 25% (1/4 patients). Discussion. Preemptive eradication of bacterial contamination may be of value in certain clinical situations, where the risk level and consequences of implant-associated infection are unacceptable. Our findings suggest that extended postoperative antibiotic prophylaxis may reduce the risk of PJI in patients undergoing tumor resection and endoprosthetic replacement for metastatic bone disease associated impending or de facto pathologic fractures of the proximal femur. PMID:25705521

  10. Low infection rate after tumor hip arthroplasty for metastatic bone disease in a cohort treated with extended antibiotic prophylaxis.

    PubMed

    Hettwer, Werner H; Horstmann, Peter Frederik; Hovgaard, Thea Bechmann; Grum-Scwensen, Tomas Andreas; Petersen, Michael M

    2015-01-01

    Background. Compared to conventional hip arthroplasty, endoprosthetic reconstruction after tumor resection is associated with a substantially increased risk of periprosthetic joint infection (PJI), with reported rates of around 10% in a recent systematic review. The optimal duration of antibiotic prophylaxis for this patient population remains unknown. Material and Methods. To establish the infection rate associated with prolonged antibiotic prophylaxis in our department, we performed a retrospective review of all adult patients who underwent endoprosthetic reconstruction of the proximal femur after tumor resection for metastatic bone disease during a 4-year period from 2010 to 2013 (n = 105 patients). Results. Intravenous antibiotic prophylaxis was administrated for an extended duration of a mean of 7.4 days. The overall infection rate was 3.6% (4/111 implants), infection free survival was 96% at 2 years, and the risk of amputation associated with infection was 25% (1/4 patients). Discussion. Preemptive eradication of bacterial contamination may be of value in certain clinical situations, where the risk level and consequences of implant-associated infection are unacceptable. Our findings suggest that extended postoperative antibiotic prophylaxis may reduce the risk of PJI in patients undergoing tumor resection and endoprosthetic replacement for metastatic bone disease associated impending or de facto pathologic fractures of the proximal femur.

  11. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

    PubMed Central

    Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

    2012-01-01

    Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

  12. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors.

    PubMed

    Rao, Chandra G; Chianese, David; Doyle, Gerald V; Miller, M Craig; Russell, Thomas; Sanders, Renouard A; Terstappen, Leon W M M

    2005-07-01

    The epithelial cell adhesion molecule (EpCAM) is involved in homophilic cell-cell adhesion in normal epithelia and is frequently overexpressed in primary and metastatic adenocarcinomas. It has been postulated that during detachment and dissemination of tumor cells, EpCAM may be down-regulated. Circulating tumor cells (CTC) may demonstrate this phenomenon as they have successfully escaped their local microenvironment and entered the circulation. EpCAM expression of CTC was compared to tumor cells in paraffin-embedded tissue arrays containing various benign diseases and carcinomas. EpCAM expression on CTC was determined by flow cytometry (FCM) and by immunohistochemistry (IHC) in paraffin-embedded tissue. To permit comparison of FCM results to those derived by IHC, EpCAM was quantified on cancer cell lines by FCM and then paraffin-embedded cell-blocks of these lines were used as staining guides for IHC analysis of tissue arrays. By IHC, 97% (384/397) of solid tissues analyzed had detectable EpCAM, with 72% of tissues showing antigen expression levels of > or =400,000 EpCAM molecules per cell. FCM analysis of CTC from 100 metastatic carcinoma patients with > or =2 CTC/90 microl blood showed EpCAM expression ranging from 9,900 to 246,000 (mean 49,700) antigens per cell. EpCAM expression was approximately 10-fold lower on CTC as compared to primary and metastatic tissues, suggesting that EpCAM expression is transient and dependent upon the local micro-environment. This supports the hypothesis that this adhesion molecule is down-regulated on carcinoma cells in the circulation.

  13. A GPU-based framework for modeling real-time 3D lung tumor conformal dosimetry with subject-specific lung tumor motion

    NASA Astrophysics Data System (ADS)

    Min, Yugang; Santhanam, Anand; Neelakkantan, Harini; Ruddy, Bari H.; Meeks, Sanford L.; Kupelian, Patrick A.

    2010-09-01

    In this paper, we present a graphics processing unit (GPU)-based simulation framework to calculate the delivered dose to a 3D moving lung tumor and its surrounding normal tissues, which are undergoing subject-specific lung deformations. The GPU-based simulation framework models the motion of the 3D volumetric lung tumor and its surrounding tissues, simulates the dose delivery using the dose extracted from a treatment plan using Pinnacle Treatment Planning System, Phillips, for one of the 3DCTs of the 4DCT and predicts the amount and location of radiation doses deposited inside the lung. The 4DCT lung datasets were registered with each other using a modified optical flow algorithm. The motion of the tumor and the motion of the surrounding tissues were simulated by measuring the changes in lung volume during the radiotherapy treatment using spirometry. The real-time dose delivered to the tumor for each beam is generated by summing the dose delivered to the target volume at each increase in lung volume during the beam delivery time period. The simulation results showed the real-time capability of the framework at 20 discrete tumor motion steps per breath, which is higher than the number of 4DCT steps (approximately 12) reconstructed during multiple breathing cycles.

  14. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

    PubMed

    Amirkhosravi, M; Francis, J L

    1995-01-01

    Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Chemically-induced mouse lung tumors: applications to human health assessments [Poster 2014

    EPA Science Inventory

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to discuss issues related to the use of mouse lung tumor data in human health assessments. Naphthalene, styrene, and ethylbenzene were chosen for the anal...

  16. Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments

    EPA Science Inventory

    A state-of-the-science workshop on chemically-induced mouse lung tumors was conducted by U.S. Environmental Protection Agency to better understand the mouse lung tumor data’s role in human health assessments. Three environmental chemicals - naphthalene, styrene, and ethylbe...

  17. Coagulation activation by MC28 fibrosarcoma cells facilitates lung tumor formation.

    PubMed

    Amirkhosravi, M; Francis, J L

    1995-01-01

    Tumor cells interact with the hemostatic system in various ways and may thus influence malignant growth and spread. MC28 fibrosarcoma cells possess a potent procoagulant activity (PCA) and form lung tumors following intravenous injection. The aim of this work was to study the relationship between PCA, intravascular coagulation and lung seeding in the MC28 model. MC28 cells were injected into control, warfarinized and heparinized hooded Lister rats. Coagulation changes were monitored by thromboelastography (TEG) and Sonoclot analysis (SA), lung fibrin formation by light and electron microscopy, tumor seeding by macroscopic counting and tumor cell and platelet deposition in the lungs by radiolabelling. PCA was measured by chromogenic assay. MC28 PCA was characterized as a tissue factor-factor VIIa complex that probably arose during cell culture or disaggregation of solid tumors. Injection of tumor cells caused marked coagulopathy and was rapidly (within 30 min) followed by fibrin deposition in the lungs and accumulation of radiolabelled platelets. Heparin and warfarin significantly reduced lung seeding (p < 0.001) and reduced retention of radiolabelled tumor cells in the pulmonary circulation (p < 0.01). Inhibition of cellular PCA by prior treatment with concanavalin A markedly reduced intravascular coagulation and lung seeding. We conclude that MC28 cells cause intravascular coagulation as a direct result of their procoagulant activity. The data suggest that tumor cells form complexes with platelets and fibrin which are retained in the lungs long enough for extravasation and seeding to occur.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7740497

  18. Severe Tumor Lysis Syndrome and Acute Pulmonary Edema Requiring Extracorporeal Membrane Oxygenation Following Initiation of Chemotherapy for Metastatic Alveolar Rhabdomyosarcoma.

    PubMed

    Sanford, Ethan; Wolbrink, Traci; Mack, Jennifer; Rowe, R Grant

    2016-05-01

    We present an 8-year-old male with metastatic alveolar rhabdomyosarcoma (ARMS) who developed precipitous cardiopulmonary collapse with severe tumor lysis syndrome (TLS) 48 hr after initiation of chemotherapy. Despite no detectable pulmonary metastases, acute hypoxemic respiratory failure developed, requiring extracorporeal membrane oxygenation (ECMO). Although TLS has been reported in disseminated ARMS, this singular case of life-threatening respiratory deterioration developing after initiation of chemotherapy presented unique therapeutic dilemmas. We review the clinical aspects of this case, including possible mechanisms of respiratory failure, and discuss the role of ECMO utilization in pediatric oncology. PMID:26713672

  19. Receptor tyrosine kinase expression of circulating tumor cells in small cell lung cancer

    PubMed Central

    Hamilton, Gerhard; Rath, Barbara; Klameth, Lukas; Hochmair, Maximilian

    2015-01-01

    Small cell lung cancer (SCLC) has a poor prognosis and is found disseminated at first presentation in the majority of cases. The cell biological mechanisms underlying metastasis and drug resistance are not clear. SCLC is characterized by high numbers of circulating tumor cells (CTCs) and we were able to expand several CTC lines ex vivo and to relate chitinase-3-like-1/YKL-40 (CHI3L1) as marker. Availability of expanded SCLC CTC cells allowed for a screening of receptor tyrosine kinases (RTKs) expressed. The metastatic CHI3L1-negative SCLC cell line SCLC26A, established from a pleural effusion was used for comparison. The CTC cell line BHGc10 was found to exhibit increased expression of RYK, AXL, Tie-1, Dtk, ROR1/2, several ephrins (Eph) and FGF/EGF receptors compared to SCLC26A. All of these RTKs have been associated with cell motility, invasion and poor prognosis in diverse cancer entities without knowledge of their association with CTCs. The identification of RYK, AXL and ROR1/2 as pseudokinases, lacking activity, seems to be related to the observed failure of RTK inhibitors in SCLC. These kinases are involved in the noncanonical WNT pathway and their expression in SCLC CTCs represents a cancer stem cell-like phenotype. PMID:26328272

  20. Lung Volume Reduction After Stereotactic Ablative Radiation Therapy of Lung Tumors: Potential Application to Emphysema

    SciTech Connect

    Binkley, Michael S.; Shrager, Joseph B.; Leung, Ann N.; Popat, Rita; Trakul, Nicholas; Atwood, Todd F.; Chaudhuri, Aadel; Maxim, Peter G.; Diehn, Maximilian; Loo, Billy W.

    2014-09-01

    Purpose: Lung volume reduction surgery (LVRS) improves dyspnea and other outcomes in selected patients with severe emphysema, but many have excessive surgical risk for LVRS. We analyzed the dose-volume relationship for lobar volume reduction after stereotactic ablative radiation therapy (SABR) of lung tumors, hypothesizing that SABR could achieve therapeutic volume reduction if applied in emphysema. Methods and Materials: We retrospectively identified patients treated from 2007 to 2011 who had SABR for 1 lung tumor, pre-SABR pulmonary function testing, and ≥6 months computed tomographic (CT) imaging follow-up. We contoured the treated lobe and untreated adjacent lobe(s) on CT before and after SABR and calculated their volume changes relative to the contoured total (bilateral) lung volume (TLV). We correlated lobar volume reduction with the volume receiving high biologically effective doses (BED, α/β = 3). Results: 27 patients met the inclusion criteria, with a median CT follow-up time of 14 months. There was no grade ≥3 toxicity. The median volume reduction of the treated lobe was 4.4% of TLV (range, −0.4%-10.8%); the median expansion of the untreated adjacent lobe was 2.6% of TLV (range, −3.9%-11.6%). The volume reduction of the treated lobe was positively correlated with the volume receiving BED ≥60 Gy (r{sup 2}=0.45, P=.0001). This persisted in subgroups determined by high versus low pre-SABR forced expiratory volume in 1 second, treated lobe CT emphysema score, number of fractions, follow-up CT time, central versus peripheral location, and upper versus lower lobe location, with no significant differences in effect size between subgroups. Volume expansion of the untreated adjacent lobe(s) was positively correlated with volume reduction of the treated lobe (r{sup 2}=0.47, P<.0001). Conclusions: We identified a dose-volume response for treated lobe volume reduction and adjacent lobe compensatory expansion after lung tumor SABR, consistent across

  1. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients

    PubMed Central

    Aktas, Bahriye; Tewes, Mitra; Fehm, Tanja; Hauch, Siegfried; Kimmig, Rainer; Kasimir-Bauer, Sabine

    2009-01-01

    Introduction The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody – or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy. Methods 2 × 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kα] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample. Results 97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively. Conclusions Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis. PMID:19589136

  2. Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors

    ClinicalTrials.gov

    2016-10-05

    Recurrent Colorectal Carcinoma; Recurrent Lung Carcinoma; Recurrent Pancreatic Carcinoma; Solid Neoplasm; Stage III Lung Cancer; Stage III Pancreatic Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Colorectal Cancer; Stage IIIC Colorectal Cancer; Stage IV Lung Cancer; Stage IV Pancreatic Cancer; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer

  3. Processes of Discontinuing Chemotherapy for Metastatic Non–Small-Cell Lung Cancer at the End of Life

    PubMed Central

    Pirl, William F.; Greer, Joseph A.; Irwin, Kelly; Lennes, Inga T.; Jackson, Vicki A.; Park, Elyse R.; Fujisawa, Daisuke; Wright, Alexi A.; Temel, Jennifer S.

    2015-01-01

    Purpose: Administration of chemotherapy close to death is widely recognized as poor-quality care. Prior research has focused on predictors and outcomes of chemotherapy administration at the end of life. This study describes processes of chemotherapy discontinuation and examines their relationships with timing before death, hospice referral, and hospital death. Patients and Methods: We reviewed health records of a prospective cohort of 151 patients with newly diagnosed metastatic non–small-cell lung cancer who participated in a trial of early palliative care. Chemotherapy treatments during final regimen were qualitatively analyzed to identify categories of discontinuation processes. We then quantitatively compared predictors and outcomes of the process categories. Results: A total of 144 patients died, with 81 and 48 receiving intravenous (IV) and oral chemotherapies as their final regimen, respectively. Five processes were identified for IV chemotherapy: definitive decisions (19.7%), deferred decisions or breaks (22.2%), disruptions for radiation therapy (22.2%), disruptions resulting from hospitalization (27.2%), and no decisions (8.6%). The five processes occurred at significantly different times before death and, except for definitive decisions, ultimate decisions for no further chemotherapy and referral to hospice were often made months later. Among patients receiving oral chemotherapy, 83.3% (40 of 48) were switched from IV to oral delivery as their final regimen, sometimes concurrent with or even after hospice referral. Conclusion: Date of last chemotherapy is not a proxy for when a decision to stop treatment is made. Patients with metastatic non–small-cell lung cancer stop their final chemotherapy regimen via different processes, which significantly vary in time before death and subsequent end-of-life care. PMID:25829525

  4. Lung Epithelial Cell-Specific Expression of Human Lysosomal Acid Lipase Ameliorates Lung Inflammation and Tumor Metastasis in Lipa(-/-) Mice.

    PubMed

    Zhao, Ting; Ding, Xinchun; Du, Hong; Yan, Cong

    2016-08-01

    Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa(-/-)) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell-specific expression of human LAL (hLAL) in Lipa(-/-) mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa(-/-) mice (CCSP-Tg/KO). hLAL expression in lung epithelial cells not only reduced tumor-promoting myeloid-derived suppressor cells in the lung, but also down-regulated the synthesis and secretion of tumor-promoting cytokines and chemokines into the bronchoalveolar lavage fluid of Lipa(-/-) mice. hLAL expression reduced the immunosuppressive functions of bronchoalveolar lavage fluid cells, inhibited bone marrow cell transendothelial migration, and inhibited endothelial cell proliferation and migration in Lipa(-/-) mice. As a result, hLAL expression in CCSP-Tg/KO mice corrected pulmonary damage, and inhibited tumor cell proliferation and migration in vitro, and tumor metastasis to the lung in vivo. These results support a concept that LAL is a critical metabolic enzyme in lung epithelial cells that regulates lung homeostasis, immune response, and tumor metastasis. PMID:27461363

  5. Intrathoracic Desmoid Tumor Presenting as Multiple Lung Nodules 13 Years after Previous Resection of Abdominal Wall Desmoid Tumor.

    PubMed

    Koo, Gun Woo; Chung, Sung Jun; Kwak, Joo Hee; Oh, Chang Kyo; Park, Dong Won; Kwak, Hyeon Jung; Moon, Ji-Yong; Kim, Sang-Heon; Sohn, Jang Won; Yoon, Ho Joo; Shin, Dong Ho; Park, Sung Soo; Oh, Young-Ha; Pyo, Ju Yeon; Kim, Tae-Hyung

    2015-07-01

    Desmoid tumors are rare soft tissue tumors considered to have locally infiltrative features without distant metastasis until now. Although they are most commonly intraabdominal, very few cases have extra-abdominal locations. The origin of intrathoracic desmoid tumors is predominantly the chest wall with occasional involvement of pleura. True intrathoracic primary desmoid tumors with no involvement of the chest wall or pleura are extremely rare. We recently experienced a case of true intrathoracic desmoid tumor presenting as multiple lung nodules at 13 years after resection of a previous intraabdominal desmoid tumor.

  6. Genomic Profiling of Metastatic Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET) Patients in the Personalized-Medicine Era

    PubMed Central

    Kim, Seung Tae; Lee, Su Jin; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Lee, Jeeyun; Park, Young Suk

    2016-01-01

    Background: We have conducted molecular profiling through a high-throughput molecular test as part of our clinical practice for patients with advanced gastrointestinal (GI) cancer or rare cancers including gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Herein, we report on the molecular characterization of 14 metastatic GEP-NET patients. Methods: We conducted the Ion AmpliSeq Cancer Hotspot Panel v2 (detecting 2,855 oncogenic mutations in 50 commonly mutated genes) and nCounter Copy Number Variation Assay, which was designed with 21 genes based on available targeted agents, as a high throughput genomic platform in 14 patients with metastatic GEP-NETs. Results: Among the 14 GEP-NET patients analyzed in this study, 8 patients had grade III neuroendocrine carcinoma (NEC) and 6 had grade I/II NET. Primary sites included pancreas (n=3), small intestine and ascending colon (n=3), distal colon and rectum (n=5), and unknown primary origin (n=3). The most common metastatic site was the liver. Of 14 GEP-NET patients available for mutational profiling, 7 (50.0%) patients had one or more aberrations detected. Common aberrations were as follows: SMARCB1 mutation (n=2), TP53 mutation (n=2), STK11 mutation (n=1), RET mutation (n=1), and BRAF mutation (n=1). Gene amplification by nCounter was detected in only 1 patient, showing CCNE1 amplification, and this patient also had a TP53 mutation. Conclusions: This high throughput genomic test may be useful to identify new drug targets in metastatic GEP-NET patients. Currently, we plan to conduct further genomic analysis to develop predictive and prognostic biomarkers in a larger number of GEP-NET patients. PMID:27326246

  7. Micro FT-IR Characterization Of Human Lung Tumor Cells

    NASA Astrophysics Data System (ADS)

    Benedetti, Enzo; Teodori, L.; Vergamini, Piergiorgio; Trinca, M. L.; Mauro, F.; Salvati, F.; Spremolla, Giuliano

    1989-12-01

    FT-IR spectroscopy has opened up a new approach to the analytical study of cell transformation. Investigations carried out in normal and leukemic lymphocytes have evidenced an increase in DNA with respect to proteic components in neoplastic cells.(1) The evaluation of the ratio of the integrated areas(A) of the bands at 1080 cm-1 (mainly DNA) and at 1540 cm-1 (proteic components) has allowed us to establish a parameter which indicates, for values above 1.5, the neoplastic nature of cells. Recently, this approach has been applied to the study of human lung tumor cells. Several monocellular suspension procedures of the tissue fragment (mechanical and/or chemical) were tested to obtain reproducible and reliable spectra able to differentiate clearly between normal and patological cells. Chemical treatment (EDTA, Pepsin, Collagenase, etc.) produced additional bands in the spectra of the cells causing distortion of the profiles of some absorptions, and as a result, mechanical treatment was preferred. The normal and neoplastic cells homogeneously distributed by cytospin preparation on BaF2 windows were examined by means of FT-IR microscopy. An examination of several microareas of each sample yielded reproducible spectra, with values of the A 1080 cm-1 / A 1540 cm-1 parameter within a very narrow range for each sample, even if certain differences still remained among the different cases, in good agreement with the results obtained for leukemic cells.(1) The value of this parameter was found to be lower for cells isolated from the normal area of lung, than in the case of those corresponding to the tumoral area, meaning that an increase occurs in DNA with respect to the proteic components. These insights, which provide a basis to obtain indications at the molecular level, can open up new possibilities in clinical practice, in order to obtain diagnosis confirmation, to detect early stages of disease and to offer additional indications in cases of dubious interpretation.

  8. FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy

    PubMed Central

    Suzman, Daniel L.; Blumenthal, Gideon; Mushti, Sirisha; He, Kun; Libeg, Meredith; Keegan, Patricia; Pazdur, Richard

    2016-01-01

    On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7–15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0–10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%–24%) in the nivolumab arm and 12% (95% CI: 9%–17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. Implications for Practice: Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in

  9. Local Control and Toxicity in a Large Cohort of Central Lung Tumors Treated With Stereotactic Body Radiation Therapy

    SciTech Connect

    Modh, Ankit; Rimner, Andreas; Williams, Eric; Foster, Amanda; Shah, Mihir; Shi, Weiji; Zhang, Zhigang; Gelblum, Daphna Y.; Rosenzweig, Kenneth E.; Yorke, Ellen D.; Jackson, Andrew; Wu, Abraham J.

    2014-12-01

    Purpose: Stereotactic body radiation therapy (SBRT) in central lung tumors has been associated with higher rates of severe toxicity. We sought to evaluate toxicity and local control in a large cohort and to identify predictive dosimetric parameters. Methods and Materials: We identified patients who received SBRT for central tumors according to either of 2 definitions. Local failure (LF) was estimated using a competing risks model, and multivariate analysis (MVA) was used to assess factors associated with LF. We reviewed patient toxicity and applied Cox proportional hazard analysis and log-rank tests to assess whether dose-volume metrics of normal structures correlated with pulmonary toxicity. Results: One hundred twenty-five patients received SBRT for non-small cell lung cancer (n=103) or metastatic lesions (n=22), using intensity modulated radiation therapy. The most common dose was 45 Gy in 5 fractions. Median follow-up was 17.4 months. Incidence of toxicity ≥ grade 3 was 8.0%, including 5.6% pulmonary toxicity. Sixteen patients (12.8%) experienced esophageal toxicity ≥ grade 2, including 50% of patients in whom PTV overlapped the esophagus. There were 2 treatment-related deaths. Among patients receiving biologically effective dose (BED) ≥80 Gy (n=108), 2-year LF was 21%. On MVA, gross tumor volume (GTV) was significantly associated with LF. None of the studied dose-volume metrics of the lungs, heart, proximal bronchial tree (PBT), or 2 cm expansion of the PBT (“no-fly-zone” [NFZ]) correlated with pulmonary toxicity ≥grade 2. There were no differences in pulmonary toxicity between central tumors located inside the NFZ and those outside the NFZ but with planning target volume (PTV) intersecting the mediastinum. Conclusions: Using moderate doses, SBRT for central lung tumors achieves acceptable local control with low rates of severe toxicity. Dosimetric analysis showed no significant correlation between dose to the lungs, heart, or NFZ and

  10. Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas

    PubMed Central

    2014-01-01

    Background To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases. Methods We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval). Results In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65–221 structural variations (SVs) in primary tumors and 60–232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis. Conclusions We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments. PMID:24405831

  11. Solitary fibrous tumor of the lung: three rare cases of intraparenchymal nodules.

    PubMed

    Cardinale, L; Ardissone, F; Cataldi, A; Familiari, U; Solitro, F; Fava, C

    2009-05-01

    Solitary fibrous tumor (SFT) of the pleura usually presents as a peripheral mass, in contact with the surface of the pleura. However, on occasion, it can occur separately from the pleura, in the lung parenchyma. We describe the radiological and imaging features of three SFTs of the lung, diagnosed in our department, with relevant clinical data. The diagnosis of SFT of the lung, although rare, should be considered in a slow-growing solitary lung parenchymal nodule.

  12. Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab.

    PubMed

    Truong, Phu; Rahal, Ahmad; Kallail, K James

    2016-06-04

    Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib.

  13. Natural Course of an Untreated Metastatic Perirectal Lymph Node After the Endoscopic Resection of a Rectal Neuroendocrine Tumor

    PubMed Central

    Kim, Sang Hyung; Lee, Jung Su; Park, Soyoung; Lee, Ho-Su; Lee, Hyojeong; Park, Sang Hyoung; Kim, Kyung-Jo; Ye, Byong Duk; Byeon, Jeong-Sik; Myung, Seung-Jae; Yang, Suk-Kyun; Kim, Jin-Ho; Kim, Chan Wook; Kim, Jihun

    2015-01-01

    Lymph node metastasis is rare in small (i.e., <10 mm) rectal neuroendocrine tumors (NETs). In addition to tumor size, pathological features such as the mitotic or Ki-67 proliferation index are associated with lymph node metastasis in rectal NETs. We recently treated a patient who underwent endoscopic treatment of a small, grade 1 rectal NET that recurred in the form of perirectal lymph node metastasis 7 years later. A 7-mm-sized perirectal lymph node was noted at the time of the initial endoscopic treatment. The same lymph node was found to be slightly enlarged on follow-up and finally confirmed as a metastatic NET. Therefore, the perirectal lymph node metastasis might have been present at the time of the initial diagnosis. However, the growth rate of the lymph node was extremely low, and it took 7 years to increase in size from 7 to 10 mm. NETs with low Ki-67 proliferation index and without mitotic activity may grow extremely slowly even if they are metastatic. PMID:25932004

  14. Anti-tumor Properties of cis-Resveratrol Methylated Analogues in Metastatic Mouse Melanoma Cells

    PubMed Central

    Morris, Valery L.; Toseef, Tayyaba; Nazumudeen, Fathima B.; Rivoira, Christian; Spatafora, Carmela; Tringali, Corrado; Rotenberg, Susan A.

    2015-01-01

    Resveratrol (E-3,5,4’-trihydroxystilbene) is a polyphenol found in red wine that has been shown to have multiple anti-cancer properties. Although cis (Z) and trans (E) isomers of resveratrol occur in nature, the cis form is not biologically active. However, methylation at key positions of the cis form results in more potent anti-cancer properties. This study determined that synthetic cis-polymethoxystilbenes (methylated analogues of cis-resveratrol) inhibited cancer-related phenotypes of metastatic B16 F10 and non-metastatic B16 F1 mouse melanoma cells. In contrast with cis or trans-resveratrol and trans-polymethoxystilbene which were ineffective at 10 μM, cis-polymethoxystilbenes inhibited motility and proliferation of melanoma cells with low micromolar specificity (IC50 <10 μM). Inhibitory effects by cis-polymethoxystilbenes were significantly stronger with B16 F10 cells and were accompanied by decreased expression of β-tubulin and pleckstrin homology domain-interacting protein, a marker of metastatic B16 cells. Thus, cis-polymethoxystilbenes have potential as chemotherapeutic agents for metastatic melanoma. PMID:25567208

  15. Colon carcinoma metastatic to the thyroid gland

    SciTech Connect

    Lester, J.W. Jr.; Carter, M.P.; Berens, S.V.; Long, R.F.; Caplan, G.E.

    1986-09-01

    Metastatic carcinoma to the thyroid gland rarely is encountered in clinical practice; however, autopsy series have shown that it is not a rare occurrence. A case of adenocarcinoma of the colon with metastases to the thyroid is reported. A review of the literature reveals that melanoma, breast, renal, and lung carcinomas are the most frequent tumors to metastasize to the thyroid. Metastatic disease must be considered in the differential diagnosis of cold nodules on radionuclide thyroid scans, particularly in patients with a known primary.

  16. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases.

    PubMed

    Tsuda, H; Takarabe, T; Hasegawa, F; Fukutomi, T; Hirohashi, S

    2000-02-01

    High-grade invasive ductal carcinomas (IDCs) of the breast with large, central acellular zones on their cut surfaces are usually associated with the myoepithelial immunophenotype of carcinoma cells, which includes the expression of S-100 protein, alpha-smooth muscle actin, and keratin 14. To clarify the clinical significance of these features of IDCs, the authors compared the incidence of the myoepithelial immunophenotype immunohistochemically, patient prognosis, and metastatic sites of the tumor between 20 high-grade IDCs with large, central acellular zones and 40 control high-grade IDCs without these zones. The myoepithelial immunophenotype was detected in 16 IDCs (80%) with large, central acellular zones but in only seven IDCs (18%) without. The risk ratio of metastasis, especially in the brain and lung, and death from cancer were significantly higher (p = 0.0096 and p = 0.030) for the 20 IDCs with large, central acellular zones than for those without by Cox's univariate analysis. Using Cox's multivariate analysis, large, central acellular zones in IDCs were an indicator of high risk of brain and lung metastases and of death by cancer independent of nodal status and tumor size. Examination of large, central acellular zones and myoepithelial immunophenotype in high-grade IDCs appears helpful in predicting patient prognosis and preferential metastatic sites of the tumors.

  17. Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review.

    PubMed

    Sherwood, James; Dearden, Simon; Ratcliffe, Marianne; Walker, Jill

    2015-01-01

    Increased understanding of the genetic aetiology of advanced non-small-cell lung cancer (aNSCLC) has facilitated personalised therapies that target specific molecular aberrations associated with the disease. Biopsy samples for mutation testing may be taken from primary or metastatic sites, depending on which sample is most accessible, and upon differing diagnostic practices between territories. However, the mutation status concordance between primary tumours and corresponding metastases is the subject of debate. This review aims to ascertain whether molecular diagnostic testing of either the primary or metastatic tumours is equally suitable to determine patient eligibility for targeted therapies. A literature search was performed to identify articles reporting studies of mutations in matched primary and metastatic aNSCLC tumour samples. Clinical results of mutation status concordance between matched primary and metastatic tumour samples from patients with aNSCLC were collated. Articles included in this review (N =26) all reported mutation status data from matched primary and metastatic tumour samples obtained from adult patients with aNSCLC. Generally, substantial concordance was observed between primary and metastatic tumours in terms of EGFR, KRAS, BRAF, p16 and p53 mutations. However, some level of discordance was seen in most studies; mutation testing methodologies appeared to play a key role in this, along with underlying tumour heterogeneity. Substantial concordance in mutation status observed between primary and metastatic tumour sites suggests that diagnostic testing of either tumour type may be suitable to determine a patient's eligibility for personalised therapies. As with all diagnostic testing, highly sensitive and appropriately validated mutation analysis methodologies are desirable to ensure accuracy. Additional work is also required to define how much discordance is clinically significant given natural tumour heterogeneity. The ability of both

  18. Toward a clinical application of ex situ boron neutron capture therapy for lung tumors at the RA-3 reactor in Argentina

    SciTech Connect

    Farías, R. O.; Trivillin, V. A.; Portu, A. M.; Schwint, A. E.; González, S. J.; Garabalino, M. A.; Monti Hughes, A.; Pozzi, E. C. C.; Thorp, S. I.; Curotto, P.; Miller, M. E.; Santa Cruz, G. A.; Saint Martin, G.; Ferraris, S.; Santa María, J.; Rovati, O.; Lange, F.; Bortolussi, S.; Altieri, S.

    2015-07-15

    quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46 ± 0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. Conclusions: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life.

  19. Evaluation of the results of surgery treatment in patients with benign lung tumors

    PubMed Central

    Bagheri, Reza; Haghi, Seyed Ziaollah; Dalouee, Marziyeh Nouri; Nasiri, Zakiyeh; Rajabnejad, Ata’ollah

    2015-01-01

    Background: Lung tumors are among the common tumors and can be benign or malignant. Benign lung tumors are less common compared to the malignant types. Recognition of the clinical symptoms, types of tumors, paraclinical findings, and treatment approaches can bring better therapeutic results. The present study aims to evaluate the characteristics, diagnosis methods, and therapeutic approaches of different benign lung tumors. Materials and Methods: In this retrospective study, 32 patients with a diagnosis of benign lung tumor, who had been referred to the Mashhad University of Medical Sciences between 1981 and 2009, were studied. Some of the studied variables were symptoms, the pulmonary location involved, surgery technique, pathology findings, recurrence, and surgery complications. Data were analyzed by SPSS package version 16. Results: The average age of the patients was 51.69 ± 20.5 years. Prevalence of benign lung tumors was equal in both genders. The most common symptom was cough (31.2%); right lung involvement was more common (71.9%), and the most common sampling technique was transbronchial lung biopsy (TBLB) (62.5%); 53.1% of the patients were operated on by thoracotomy and the wedge resection technique. In 78.1% of the patients, no complications occurred after surgery. There was no recurrence. Most operations were performed in one month after the start of the symptoms (68.8%). Conclusions: Benign lung tumors are commonly diagnosed by routine radiography because most of them are asymptomatic. The most common finding in radiography is the presence of mass in the lungs. Transbronchial lung biopsy is a valuable technique to be used for diagnosis. We chose thoracotomy and wedge resection for the treatment of patients. We recommend this approach as a useful method. PMID:25624593

  20. Recapitulating the Tumor Ecosystem Along the Metastatic Cascade Using 3D Culture Models

    PubMed Central

    Kim, Jiyun; Tanner, Kandice

    2015-01-01

    Advances in cancer research have shown that a tumor can be likened to a foreign species that disrupts delicately balanced ecological interactions, compromising the survival of normal tissue ecosystems. In efforts to mitigate tumor expansion and metastasis, experimental approaches from ecology are becoming more frequently and successfully applied by researchers from diverse disciplines to reverse engineer and re-engineer biological systems in order to normalize the tumor ecosystem. We present a review on the use of 3D biomimetic platforms to recapitulate biotic and abiotic components of the tumor ecosystem, in efforts to delineate the underlying mechanisms that drive evolution of tumor heterogeneity, tumor dissemination, and acquisition of drug resistance. PMID:26284194

  1. Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer

    PubMed Central

    Spanholtz, Jan; Tordoir, Marleen; Thijssen, Victor L.; Heideman, Daniëlle A. M.; Verheul, Henk M. W.; de Gruijl, Tanja D.; van der Vliet, Hans J.

    2016-01-01

    The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy. It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG1 mAbs through Fc receptors (CD16/FcγRIIIa) on their surface, thereby mediating antibody dependent cellular cytotoxicity (ADCC). In the current study, activated Peripheral Blood NK cells (PBNK) were combined with anti-EGFR mAbs to study their effect on the killing of EGFR+/- cancer cell lines, including those with RAS mutations. In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320, Caco-2, SW620, SW480 and HT-29, demonstrated that PBNK cells are cytotoxic for a range of tumor cells, regardless of EGFR, RAS or BRAF status and at low E:T ratios. Cetuximab enhanced the cytotoxic activity of NK cells on EGFR+ tumor cells (either RASwt, RASmut or BRAFmut) in a CD16 dependent manner, whereas it could not increase the killing of EGFR- COLO320. Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients. PMID:27314237

  2. Combination of an Integrin-Targeting NIR Tracer and an Ultrasensitive Spectroscopic Device for Intraoperative Detection of Head and Neck Tumor Margins and Metastatic Lymph Nodes

    PubMed Central

    Yoon, Younghyoun; Mohs, Aaron M.; Mancini, Michael C.; Nie, Shuming; Shim, Hyunsuk

    2016-01-01

    Despite major advances in targeted drug therapy and radiation therapy, surgery remains the most effective treatment for most solid tumors. The single most important predictor of patient survival is a complete surgical resection of the primary tumor, draining lymph nodes, and metastatic lesions. Presently, however, 20%–30% of patients with head and neck cancer who undergo surgery still leave the operating room without complete resection because of missed lesions. Thus, major opportunities exist to develop advanced imaging tracers and intraoperative instrumentation that would allow surgeons to visualize microscopic tumors during surgery. The cell adhesion molecule integrin αvβ3 is specifically expressed by tumor neovasculature and invading tumor cells, but not by quiescent vessels or normal cells. Here we report the combined use of an integrin-targeting near-infrared tracer (RGD-IRDye800CW) and a handheld spectroscopic device, an integrated point spectroscopy with wide-field imaging system, for highly sensitive detection of integrin overexpression on infiltrating cancer cells. By using an orthotopic head and neck cancer animal model, we show that this tracer–device combination allows intraoperative detection of not only invasive tumor margins but also metastatic lymph nodes. Correlated histological analysis further reveals that microscopic clusters of 50–100 tumor cells can be detected intraoperatively with high sensitivity and specificity, raising new possibilities in guiding surgical resection of microscopic tumors and metastatic lymph nodes. PMID:27738656

  3. SOX30, a novel epigenetic silenced tumor suppressor, promotes tumor cell apoptosis by transcriptional activating p53 in lung cancer.

    PubMed

    Han, F; Liu, W; Jiang, X; Shi, X; Yin, L; Ao, L; Cui, Z; Li, Y; Huang, C; Cao, J; Liu, J

    2015-08-13

    Although members of SOX family have been well documented for their essential roles in embryonic development, cell proliferation and disease, the functional role and molecular mechanism of SOX30 in cancer are largely unexplored. Here, we first identified SRY-box containing gene 30 (SOX30) as a novel preferentially methylated gene using genome-wide methylation screening. SOX30 hypermethylation was detected in 100% of lung cancer cell lines (9/9) and 70.83% (85/120) of primary lung tumor tissues compared with none (0/20) of normal and 8.0% (2/25) of peri-tumoral lung tissues (P<0.01). SOX30 was expressed in normal and peri-tumoral lung tissues in which SOX30 was unmethylated, but was silenced or downregulated in lung cancer cell lines and primary lung tumor tissues harboring a hypermethylated SOX30. De-methylation experiments further confirmed that silence of SOX30 was regulated by its hypermethylation. Ectopic expression of SOX30 induces cancer cell apoptosis with inhibiting proliferation in vitro and represses tumor formation in vivo, whereas knockdown of SOX30 demonstrates a reversed effect both in vitro and in vivo. At the molecular level, the antitumorigenic effect of SOX30 is mediated by directly binding to CACTTTG (+115 to +121) of p53 promoter region and activating p53 transcription, suggesting that SOX30 is a novel transcriptional activating factor of p53. Indeed, blockade of p53 attenuates the tumor inhibition of SOX30. Overall, these findings demonstrate that SOX30 is a novel epigenetic silenced tumor suppressor acting through direct regulation of p53 transcription and expression. This study provides novel insights on the mechanism of tumorigenesis in lung cancer. PMID:25435374

  4. Contrast Agents for Quantitative MicroCT of Lung Tumors in Mice

    PubMed Central

    Lalwani, Kush; Giddabasappa, Anand; Li, Danan; Olson, Peter; Simmons, Brett; Shojaei, Farbod; Arsdale, Todd Van; Christensen, James; Jackson-Fisher, Amy; Wong, Anthony; Lappin, Patrick B; Eswaraka, Jeetendra

    2013-01-01

    The identification and quantitative evaluation of lung tumors in mouse models is challenging and an unmet need in preclinical arena. In this study, we developed a noninvasive contrast-enhanced microCT (μCT) method to longitudinally evaluate and quantitate lung tumors in mice. Commercially available μCT contrast agents were compared to determine the optimal agent for visualization of thoracic blood vessels and lung tumors in naïve mice and in non-small-cell lung cancer models. Compared with the saline control, iopamidol and iodinated lipid agents provided only marginal increases in contrast resolution. The inorganic nanoparticulate agent provided the best contrast and visualization of thoracic vascular structures; the density contrast was highest at 15 min after injection and was stable for more than 4 h. Differential contrast of the tumors, vascular structures, and thoracic air space by the nanoparticulate agent enabled identification of tumor margins and accurate quantification. μCT data correlated closely with traditional histologic measurements (Pearson correlation coefficient, 0.995). Treatment of ELM4–ALK mice with crizotinib yielded 65% reduction in tumor size and thus demonstrated the utility of quantitative μCT in longitudinal preclinical trials. Overall and among the 3 agents we tested, the inorganic nanoparticulate product was the best commercially available contrast agent for visualization of thoracic blood vessels and lung tumors. Contrast-enhanced μCT imaging is an excellent noninvasive method for longitudinal evaluation during preclinical lung tumor studies. PMID:24326223

  5. Anti-metastatic Potential of Amide-linked Local Anesthetics: Inhibition of Lung Adenocarcinoma Cell Migration and Inflammatory Src Signaling Independent of Sodium Channel Blockade

    PubMed Central

    Piegeler, Tobias; Votta-Velis, E. Gina; Liu, Guoquan; Place, Aaron T.; Schwartz, David E.; Beck-Schimmer, Beatrice; Minshall, Richard D.; Borgeat, Alain

    2012-01-01

    Background Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have anti-inflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells. Methods NCI-H838 lung cancer cells were incubated with Tumor Necrosis Factor-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1nM-100μM). Cell migration and total cell lysate Src-activation and Intercellular Adhesion Molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated. Results Ropivacaine treatment (100μM) of H838 cells for 20 minutes decreased basal Src activity by 62% (p=0.003), and both ropivacaine and lidocaine co-administered with Tumor Necrosis Factor-α statistically significantly decreased Src-activation and Intercellular Adhesion Molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 hours was inhibited by 26% (p=0.005) in presence of 1μM ropivacaine and 21% by 1μM lidocaine (p=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition. Conclusions This study indicates that amide-, but not ester-linked local anesthetics may provide beneficial anti-metastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of Tumor Necrosis Factor-α-induced Src-activation and Intercellular Adhesion Molecule-1 phosphorylation, providing the first evidence of a molecular mechanism which appears to be independent of their

  6. Effect of Audio Coaching on Correlation of Abdominal Displacement With Lung Tumor Motion

    SciTech Connect

    Nakamura, Mitsuhiro Narita, Yuichiro; Matsuo, Yukinori; Narabayashi, Masaru; Nakata, Manabu; Sawada, Akira; Mizowaki, Takashi; Nagata, Yasushi; Hiraoka, Masahiro

    2009-10-01

    Purpose: To assess the effect of audio coaching on the time-dependent behavior of the correlation between abdominal motion and lung tumor motion and the corresponding lung tumor position mismatches. Methods and Materials: Six patients who had a lung tumor with a motion range >8 mm were enrolled in the present study. Breathing-synchronized fluoroscopy was performed initially without audio coaching, followed by fluoroscopy with recorded audio coaching for multiple days. Two different measurements, anteroposterior abdominal displacement using the real-time positioning management system and superoinferior (SI) lung tumor motion by X-ray fluoroscopy, were performed simultaneously. Their sequential images were recorded using one display system. The lung tumor position was automatically detected with a template matching technique. The relationship between the abdominal and lung tumor motion was analyzed with and without audio coaching. Results: The mean SI tumor displacement was 10.4 mm without audio coaching and increased to 23.0 mm with audio coaching (p < .01). The correlation coefficients ranged from 0.89 to 0.97 with free breathing. Applying audio coaching, the correlation coefficients improved significantly (range, 0.93-0.99; p < .01), and the SI lung tumor position mismatches became larger in 75% of all sessions. Conclusion: Audio coaching served to increase the degree of correlation and make it more reproducible. In addition, the phase shifts between tumor motion and abdominal displacement were improved; however, all patients breathed more deeply, and the SI lung tumor position mismatches became slightly larger with audio coaching than without audio coaching.

  7. Lung tumor promotion by chromium-containing welding particulate matter in a mouse model

    PubMed Central

    2013-01-01

    Background Epidemiology suggests that occupational exposure to welding particulate matter (PM) may increase lung cancer risk. However, animal studies are lacking to conclusively link welding with an increased risk. PM derived from stainless steel (SS) welding contains carcinogenic metals such as hexavalent chromium and nickel. We hypothesized that welding PM may act as a tumor promoter and increase lung tumor multiplicity in vivo. Therefore, the capacity of chromium-containing gas metal arc (GMA)-SS welding PM to promote lung tumors was evaluated using a two-stage (initiation-promotion) model in lung tumor susceptible A/J mice. Methods Male mice (n = 28-30/group) were treated either with the initiator 3-methylcholanthrene (MCA;10 μg/g; IP) or vehicle (corn oil) followed by 5 weekly pharyngeal aspirations of GMA-SS (340 or 680 μg/exposure) or PBS. Lung tumors were enumerated at 30 weeks post-initiation. Results MCA initiation followed by GMA-SS welding PM exposure promoted tumor multiplicity in both the low (12.1 ± 1.5 tumors/mouse) and high (14.0 ± 1.8 tumors/mouse) exposure groups significantly above MCA/sham (4.77 ± 0.7 tumors/mouse; p = 0.0001). Multiplicity was also highly significant (p < 0.004) across all individual lung regions of GMA-SS-exposed mice. No exposure effects were found in the corn oil groups at 30 weeks. Histopathology confirmed the gross findings and revealed increased inflammation and a greater number of malignant lesions in the MCA/welding PM-exposed groups. Conclusions GMA-SS welding PM acts as a lung tumor promoter in vivo. Thus, this study provides animal evidence to support the epidemiological data that show welders have an increased lung cancer risk. PMID:24107379

  8. Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology

    NASA Astrophysics Data System (ADS)

    Wendel, Marco; Bazhenova, Lyudmila; Boshuizen, Rogier; Kolatkar, Anand; Honnatti, Meghana; Cho, Edward H.; Marrinucci, Dena; Sandhu, Ajay; Perricone, Anthony; Thistlethwaite, Patricia; Bethel, Kelly; Nieva, Jorge; van den Heuvel, Michel; Kuhn, Peter

    2012-02-01

    Circulating tumor cell (CTC) counts are an established prognostic marker in metastatic prostate, breast and colorectal cancer, and recent data suggest a similar role in late stage non-small cell lung cancer (NSCLC). However, due to sensitivity constraints in current enrichment-based CTC detection technologies, there are few published data about CTC prevalence rates and morphologic heterogeneity in early-stage NSCLC, or the correlation of CTCs with disease progression and their usability for clinical staging. We investigated CTC counts, morphology and aggregation in early stage, locally advanced and metastatic NSCLC patients by using a fluid-phase biopsy approach that identifies CTCs without relying on surface-receptor-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. HD-CTCs were analyzed in blood samples from 78 chemotherapy-naïve NSCLC patients. 73% of the total population had a positive HD-CTC count (>0 CTC in 1 mL of blood) with a median of 4.4 HD-CTCs mL-1 (range 0-515.6) and a mean of 44.7 (±95.2) HD-CTCs mL-1. No significant difference in the medians of HD-CTC counts was detected between stage IV (n = 31, range 0-178.2), stage III (n = 34, range 0-515.6) and stages I/II (n = 13, range 0-442.3). Furthermore, HD-CTCs exhibited a uniformity in terms of molecular and physical characteristics such as fluorescent cytokeratin intensity, nuclear size, frequency of apoptosis and aggregate formation across the spectrum of staging. Our results demonstrate that despite stringent morphologic inclusion criteria for the definition of HD-CTCs, the HD-CTC assay shows high sensitivity in the detection and characterization of both early- and late-stage lung cancer CTCs. Extensive studies are warranted to investigate the prognostic value of CTC profiling in early-stage lung cancer. This finding has implications for the design of extensive studies examining screening, therapy and surveillance in

  9. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner

    PubMed Central

    Soares, Kevin C.; Rucki, Agnieszka A.; Kim, Victoria; Foley, Kelly; Solt, Sara; Wolfgang, Christopher L.; Jaffee, Elizabeth M.; Zheng, Lei

    2015-01-01

    Our neoadjuvant clinical trial of a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) revealed the development of tertiary lymphoid aggregates (TLAs) within the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment 2 weeks after GVAX treatment. Microarray studies revealed that multiple components of the TGF-β pathway were suppressed in TLAs from patients who survived greater than 3 years and who demonstrated vaccine-enhanced mesothelin-specific T cell responses. We tested the hypothesis that combining GVAX with TGF-β inhibitors will improve the anti-tumor immune response of vaccine therapy. In a metastatic murine model of pancreatic cancer, combination therapy with GVAX vaccine and a TGF-β blocking antibody improved the cure rate of PDA-bearing mice. TGF-β blockade in combination with GVAX significantly increased the infiltration of effector CD8+ T lymphocytes, specifically anti-tumor-specific IFN-γ producing CD8+ T cells, when compared to monotherapy controls (all p < 0.05). TGF-β blockade alone did not deplete T regulatory cells (Tregs), but when give in combination with GVAX, GVAX induced intratumoral Tregs were depleted. Therefore, our PDA preclinical model demonstrates a survival advantage in mice treated with an anti-TGF-β antibody combined with GVAX therapy and provides strong rational for testing this combinational therapy in clinical trials. PMID:26515728

  10. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease

    PubMed Central

    Olsson, Eleonor; Winter, Christof; George, Anthony; Chen, Yilun; Howlin, Jillian; Tang, Man-Hung Eric; Dahlgren, Malin; Schulz, Ralph; Grabau, Dorthe; van Westen, Danielle; Fernö, Mårten; Ingvar, Christian; Rose, Carsten; Bendahl, Pär-Ola; Rydén, Lisa; Borg, Åke; Gruvberger-Saal, Sofia K; Jernström, Helena; Saal, Lao H

    2015-01-01

    Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0–37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment. PMID:25987569

  11. Posterior thoracic corpectomy with cage reconstruction for metastatic spinal tumors: comparing the mini-open approach to the open approach.

    PubMed

    Lau, Darryl; Chou, Dean

    2015-08-01

    OBJECT Spinal metastases most commonly affect the vertebral bodies of the spinal column, and spinal cord compression is an indication for surgery. Commonly, an open posterior approach is employed to perform a transpedicular costotransversectomy or lateral extracavitary corpectomy. Because of the short life expectancies in patients with metastatic spinal disease, decreasing the morbidity of surgical treatment and recovery time is critical. One potential approach to decreasing morbidity is utilizing minimally invasive surgery (MIS). Although significant advances have been made in MIS of the spine, data supporting the utility of MIS are still emerging. This study compared outcomes of patients who underwent mini-open versus traditional open transpedicular corpectomy for spinal metastases in the thoracic spine. METHODS A consecutive cohort from 2006 to 2013 of 49 adult patients who underwent thoracic transpedicular corpectomies for spinal metastases was retrospectively identified. Patients were categorized into one of 2 groups: open surgery and mini-open surgery. Mini-open transpedicular corpectomy was performed with a midline facial incision over only the corpectomy level of interest and percutaneous instrumentation above and below that level. The open procedure consisted of a traditional posterior transpedicular corpectomy. Chi-square test, 2-tailed t-test, and ANOVA models were employed to compare perioperative and follow-up outcomes between the 2 groups. RESULTS In the analysis, there were 21 patients who had mini-open surgery and 28 patients who had open surgery. The mean age was 57.9 years, and 59.2% were male. The tumor types encountered were lung (18.3%), renal/bladder (16.3%), breast (14.3%), hematological (14.3%), gastrointestinal tract (10.2%), prostate (8.2%), melanoma (4.1%), and other/unknown (14.3%). There were no significant intergroup differences in demographics, comorbidities, neurological status (American Spinal Injury Association [ASIA] grade

  12. HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial.

    PubMed

    Fehm, Tanja; Müller, Volkmar; Aktas, Bahriye; Janni, Wolfgang; Schneeweiss, Andreas; Stickeler, Elmar; Lattrich, Claus; Löhberg, Christian R; Solomayer, Erich; Rack, Brigitte; Riethdorf, Sabine; Klein, Christoph; Schindlbeck, Christian; Brocker, Kerstin; Kasimir-Bauer, Sabine; Wallwiener, Diethelm; Pantel, Klaus

    2010-11-01

    There is a growing body of evidence that HER2 status can change during disease recurrence or progression in breast cancer patients. In this context, re-evaluation of HER2 status by assessment of HER2 expression on circulating tumor cells (CTCs) is a strategy with potential clinical application. The aim of this trial was to determine the HER2 status of CTCs in metastatic breast cancer patients comparing two CTC assays. A total of 254 patients with metastatic breast cancer from nine German university breast cancer centers were enrolled in this prospective study. HER2 status of CTCs was assessed using both the FDA-approved CellSearch® assay and AdnaTest BreastCancer™. Using the CellSearch assay, 122 of 245 (50%) patients had ≥5 CTCs, and HER2-positive CTCs were observed in 50 (41%) of these patients. Ninety of 229 (39%) patients were CTC positive using AdnaTest BreastCancer, and HER2 positivity rate was 47% (42 of 90). The rate of breast cancer patients with HER2-negative primary tumors but HER2-positive CTCs was 32% (25 of 78) and 49% (28 of 57) using the CellSearch assay and AdnaTest BreastCancer, respectively. Considering only those patients who had CTCs on both tests (n = 62), concordant results regarding HER2 positivity were obtained in 50% of the patients (31/62) (P = 0.96, κ = -0.006). HER2-positive CTCs can be detected in a relevant number of patients with HER2 negative primary tumors. Therefore, it will be mandatory to correlate the assay-dependent HER2 status of CTCs to the clinical response on HER2-targeted therapies.

  13. Colon Cancer Metastatic to the Biliary Tree

    PubMed Central

    Clayton, Steven B.; Markow, Michael; Mamel, Jay

    2016-01-01

    Metastasis of colon adenocarcinoma is commonly found in the lung, liver, or peritoneum. Common bile duct (CBD) tumors related to adenomas from familial adenomatous polyposis metastasizing from outside of the gastrointestinal tract have been reported. We report a case of biliary colic due to metastatic colon adenocarcinoma to the CBD. Obstructive jaundice with signs of acalculous cholecystitis on imaging in a patient with a history of colon cancer should raise suspicion for metastasis to CBD. PMID:27144209

  14. Large cell anaplastic medulloblastoma metastatic to the scalp: tumor and derived stem-like cells features

    PubMed Central

    2014-01-01

    Background Extraneural metastases (ENM) rarely occur in medulloblastoma (MBL) patients and only few cases of subcutaneous localizations have been described. ENM indicate an aggressive disease associated with a worse prognosis. The characterization of metastatic tumours might be useful to understand their pathogenesis and to identify the most appropriate therapeutic strategies. Case presentation We present the case of a child with Large Cell Anaplastic (LC/A) MBL, who developed multiple subcutaneous metastases in the scalp area after a ventriculo-peritoneal shunting procedure. The disease rapidly progressed and the child died despite chemotherapy and primary tumour surgical debulking. We molecularly classified the tumour as a group 3 MBL; in addition, we derived stem-like cells (SLC) from a metastatic lesion. Primary tumour, metastases and SLC were further analysed, particularly focusing on features linked to the cutaneous dissemination. Indeed, molecules involved in angiogenesis, cell invasion and epidermal growth factor signalling resulted highly expressed. Conclusions The present report describes a very rare case of subcutaneous metastatic MBL. The tumour, metastases and SLC have been clinically, pathologically and molecularly characterized. Our case is an example of multidisciplinary approach aiming to characterize MBL aggressive behaviour. PMID:24739212

  15. Dietary supplementation with curcumin enhances metastatic growth of Lewis lung carcinoma in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study investigated the effects of dietary supplementation with curcumin (the principal curcuminoid of the popular Indian spice turmeric) on spontaneous metastasis of Lewis lung carcinoma (LLC) in female C57/BL6 mice. Mice were fed the AIN93G control diet or that diet supplemented with 2...

  16. Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis

    SciTech Connect

    Wang, Yifan; Li, Shu Jie; Pan, Juncheng; Che, Yongzhe; Yin, Jian; Zhao, Qing

    2011-08-26

    Highlights: {yields} Hv1 is specifically expressed in highly metastatic human breast tumor tissues. {yields} Hv1 regulates breast cancer cytosolic pH. {yields} Hv1 acidifies extracellular milieu. {yields} Hv1 exacerbates the migratory ability of metastatic cells. -- Abstract: The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT-PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB-468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells.

  17. Intensity-Modulated Radiation Therapy in Treating Younger Patients With Lung Metastases

    ClinicalTrials.gov

    2013-09-23

    Adult Rhabdomyosarcoma; Lung Metastases; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Recurrent Wilms Tumor and Other Childhood Kidney Tumors; Stage IV Adult Soft Tissue Sarcoma; Stage IV Wilms Tumor; Stage V Wilms Tumor; Unspecified Adult Solid Tumor, Protocol Specific; Unspecified Childhood Solid Tumor, Protocol Specific

  18. Gene silencing in primary and metastatic tumors by small interfering RNA delivery in mice: quantitative analysis using melanoma cells expressing firefly and sea pansy luciferases.

    PubMed

    Takahashi, Yuki; Nishikawa, Makiya; Kobayashi, Naoki; Takakura, Yoshinobu

    2005-07-20

    Silencing of oncogenes or other genes contributing to tumor malignancy or progression by RNA interference (RNAi) offers a promising approach to treating tumor patients. To achieve RNAi-based tumor therapy, a small interfering RNA (siRNA) or siRNA-expressing vector needs to be delivered to tumor cells, but little information about its in vivo delivery has been reported. In this study, we examined whether the expression of the target gene in tumor cells can be suppressed by the delivery of RNAi effectors to primary and metastatic tumor cells. To quantitatively evaluate the RNAi effects in tumor cells, mouse melanoma B16-BL6 cells were stably transfected with both firefly (a model target gene) and sea pansy (an internal standard gene) luciferase genes to obtain B16-BL6/dual Luc cells. The target gene expression in subcutaneous primary tumors of B16-BL6/dual Luc cells was significantly suppressed by direct injection of the RNAi effectors followed by electroporation. The expression in metastatic hepatic tumors was also significantly reduced by an intravenous injection of either RNAi effector by the hydrodynamics-based procedure. These results indicate that the both RNAi effectors have a potential to silence target gene in tumor cells in vivo when successfully delivered to tumor cells. PMID:15936841

  19. Gefitinib in Treating Patients With Metastatic or Unresectable Head and Neck Cancer or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-11

    Anaplastic Thyroid Cancer; Insular Thyroid Cancer; Metastatic Parathyroid Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Parathyroid Cancer; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Thyroid Cancer; Recurrent Verrucous Carcinoma of the Larynx; Stage III Follicular Thyroid Cancer; Stage III Papillary Thyroid Cancer; Stage III Salivary Gland Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Squamous Cell Carcinoma of the Larynx; Stage III Verrucous Carcinoma of the Larynx; Stage IIIB Non-small Cell Lung Cancer; Stage IV Lymphoepithelioma of the Nasopharynx; Stage IV Non-small Cell Lung Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Adenoid Cystic Carcinoma of the Oral Cavity; Stage IVA Basal Cell Carcinoma of the Lip; Stage IVA Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Follicular Thyroid Cancer; Stage IVA Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage IVA Lymphoepithelioma of the Oropharynx; Stage IVA Midline Lethal Granuloma of the Paranasal Sinus

  20. Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors

    PubMed Central

    Esfahani, Shadi A.; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, Umar

    2016-01-01

    Purpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is

  1. Optical Imaging of Mesenchymal Epithelial Transition Factor (MET) for Enhanced Detection and Characterization of Primary and Metastatic Hepatic Tumors

    PubMed Central

    Esfahani, Shadi A.; Heidari, Pedram; Kim, Sun A.; Ogino, Shuji; Mahmood, Umar

    2016-01-01

    Purpose: To assess optical imaging of Mesenchymal-Epithelial Transition factor (MET) for delineation and characterization of intrahepatic models of human hepatocellular carcinoma (HCC) and metastatic colorectal cancer (CRC), and thereby demonstrate its potential use in precision oncology. Materials and Methods: MET expression in human CRC and HCC was assessed in tissue microarrays. We used GE-137, a modified cyanine 5-tagged peptide for MET targeting. HepG2 and Huh-7 (HCC) and HT-29 (CRC) cells with MET overexpression, and LNCaP cells (negative control) with minimal MET expression were incubated with the probe. Correlation between the relative fluorescence signal intensity and cellular MET expression level was assessed. Flow cytometry was used to assess probe specific binding and dissociation constant (Kd). Orthotopic xenograft models of human HCC and metastatic CRC were generated in nu/nu mice by subcapsular implantation of cells. Epifluorescence imaging was performed to capture the changes in deferential probe accumulation at different time points after injection. Target-to-liver background ratio (TBR) was calculated and the probe biodistribution within different organs was assessed. Histopathologic analysis of extracted xenografts was performed to correlate the tumors MET expression with probe uptake by cancer cells. Results: Approximately 91.5% of HCC and 81% of CRC microarray cores showed MET expression. HCC and CRC cells incubated with the probe showed substantial fluorescence compared to control LNCaP, with strong correlation between fluorescence signal and MET expression (R2 = 0.99, p < 0.001). Probe binding affinity to MET (Kd) was measured to be 2.9 ± 0.36 nM. Epifluorescence imaging showed intense uptake in subcapsular tumors with peak TBR of 5.46 ± 0.46 in Huh-7, 3.55 ± 0.38 in HepG2, and 15.93 ± 0.61 in HT-29 orthotopic xenografts at 4 hours post-injection (mean ± standard deviation). We demonstrated that in vivo probe uptake in xenografts is

  2. Efficacy of bisphosphonates and other bone-targeted agents in metastatic bone disease from solid tumors other than breast and prostate cancers.

    PubMed

    Karim, Syed Mustafa; Brown, Janet; Zekri, Jamal

    2013-05-01

    Metastatic bone disease complicates the course of malignancy in a substantial proportion of patients with advanced cancer. Bisphosphonates are now widely used to improve skeleton-related outcomes of patients with metastatic cancer to the bone. Most studies evaluating the efficacy of bisphosphonates and other bone-targeted agents have been performed in patients with metastatic breast and prostate cancer. Only a few studies have evaluated the role of bisphosphonates in other tumor types involving the skeletal system. We present a review of the clinical literature focusing on the current and potential roles of bisphosphonates (particularly zoledronic acid) and newer bone-targeted therapies in patients with metastasis to bone arising from solid tumors other than breast and prostate cancer.

  3. A Case of Metastatic Adamantinoma That Responded Well to Sunitinib

    PubMed Central

    Shields, Jenna; Shah, Rashmikant

    2016-01-01

    Adamantinoma is a rare low-grade malignant bone tumor of epithelial origin. Metastatic adamantinoma has been reported to be resistant to chemotherapy. We report a case of metastatic adamantinoma to the lung, 10 years after the initial diagnosis of tibial mass. The patient received radiation therapy to the lung with partial response. A surveillance PET scan revealed progression of the lung mass and biopsy confirmed to be progressive residual metastatic adamantinoma. He received carboplatin and etoposide for 7 months and achieved a partial response. Four months later, PET scan showed disease progression. We started him on sunitinib, a multikinase inhibitor. He achieved a good partial response for 3 years. He died due to pneumonia at the age of 72.

  4. A Case of Metastatic Adamantinoma That Responded Well to Sunitinib.

    PubMed

    Liman, Andrew D; Liman, Agnes K; Shields, Jenna; Englert, Becky; Shah, Rashmikant

    2016-01-01

    Adamantinoma is a rare low-grade malignant bone tumor of epithelial origin. Metastatic adamantinoma has been reported to be resistant to chemotherapy. We report a case of metastatic adamantinoma to the lung, 10 years after the initial diagnosis of tibial mass. The patient received radiation therapy to the lung with partial response. A surveillance PET scan revealed progression of the lung mass and biopsy confirmed to be progressive residual metastatic adamantinoma. He received carboplatin and etoposide for 7 months and achieved a partial response. Four months later, PET scan showed disease progression. We started him on sunitinib, a multikinase inhibitor. He achieved a good partial response for 3 years. He died due to pneumonia at the age of 72. PMID:27630780

  5. A Case of Metastatic Adamantinoma That Responded Well to Sunitinib

    PubMed Central

    Shields, Jenna; Shah, Rashmikant

    2016-01-01

    Adamantinoma is a rare low-grade malignant bone tumor of epithelial origin. Metastatic adamantinoma has been reported to be resistant to chemotherapy. We report a case of metastatic adamantinoma to the lung, 10 years after the initial diagnosis of tibial mass. The patient received radiation therapy to the lung with partial response. A surveillance PET scan revealed progression of the lung mass and biopsy confirmed to be progressive residual metastatic adamantinoma. He received carboplatin and etoposide for 7 months and achieved a partial response. Four months later, PET scan showed disease progression. We started him on sunitinib, a multikinase inhibitor. He achieved a good partial response for 3 years. He died due to pneumonia at the age of 72. PMID:27630780

  6. Dual targeting for metastatic breast cancer and tumor neovasculature by EphA2-mediated nanocarriers.

    PubMed

    Guo, Zhaoming; He, Bing; Yuan, Lan; Dai, Wenbing; Zhang, Hua; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2015-09-30

    EphA2 is a transmembrane receptor tyrosine kinase that is highly expressed on both tumor neovasculature and some kinds of tumor cells. Here, a homing peptide with a sequence of YSAYPDSVPMMSK (YSA) that binds specifically with EphA2 was utilized to modify the stealth liposomes (YSA-LP). With a particle size of about 85 nm, this functionalized nanocarrier was loaded with fluorescent probe or doxorubicin (DOX) and investigated in vitro and in vivo. In the cellular endocytosis studies in vitro, coumarin-6 loaded YSA-LP exhibited significant specificity to both EphA2-overexpressing tumor cells (MDA-MB-231) and human umbilical vein endothelial cells (HUVEC) via a YSA mediated interaction. In a MDA-MB-231 xenograft tumor mouse model, DiR-loaded YSA-LP showed more lasting accumulation in tumor tissue by small animal imaging compared to unmodified liposomes (LP). Further, YSA-LP greatly facilitated the efficacy of DOX loaded against both tumor cells and tumor angiogenesis in the same mouse model, evidenced by inhibiting tumor growth, metastasis and CD31 expression as well as inducing cancer cell apoptosis. Additionally, YSA-LP (DOX) showed relatively low systemic and cardiac toxicity compared with control groups. In conclusion, YSA might be a promising targeting motif for EphA2-overexpressing tumor cells and tumor neovasculature, which could be used to mediate drug delivery for chemotherapy agents. PMID:26004003

  7. Microscopic validation of whole mouse micro-metastatic tumor imaging agents using cryo-imaging and sliding organ image registration

    NASA Astrophysics Data System (ADS)

    Liu, Yiqiao; Zhou, Bo; Qutaish, Mohammed; Wilson, David L.

    2016-03-01

    We created a metastasis imaging, analysis platform consisting of software and multi-spectral cryo-imaging system suitable for evaluating emerging imaging agents targeting micro-metastatic tumor. We analyzed CREKA-Gd in MRI, followed by cryo-imaging which repeatedly sectioned and tiled microscope images of the tissue block face, providing anatomical bright field and molecular fluorescence, enabling 3D microscopic imaging of the entire mouse with single metastatic cell sensitivity. To register MRI volumes to the cryo bright field reference, we used our standard mutual information, non-rigid registration which proceeded: preprocess --> affine --> B-spline non-rigid 3D registration. In this report, we created two modified approaches: mask where we registered locally over a smaller rectangular solid, and sliding organ. Briefly, in sliding organ, we segmented the organ, registered the organ and body volumes separately and combined results. Though sliding organ required manual annotation, it provided the best result as a standard to measure other registration methods. Regularization parameters for standard and mask methods were optimized in a grid search. Evaluations consisted of DICE, and visual scoring of a checkerboard display. Standard had accuracy of 2 voxels in all regions except near the kidney, where there were 5 voxels sliding. After mask and sliding organ correction, kidneys sliding were within 2 voxels, and Dice overlap increased 4%-10% in mask compared to standard. Mask generated comparable results with sliding organ and allowed a semi-automatic process.

  8. Failure of ozone and nitrogen dioxide to enhance lung tumor development in hamsters

    SciTech Connect

    Witschi, H.; Breider, M.A.; Schuller, H.M. )

    1993-09-01

    We tested the hypothesis that the two common oxidant air pollutants, ozone and nitrogen dioxide, modulate the development of respiratory tract tumors in Syrian golden hamsters. The animals received subcutaneous injections of the carcinogen diethylnitrosamine (20 mg/kg) twice a week while being exposed continuously to an atmosphere of 0.8 parts per million (ppm)* of ozone or 15 ppm of nitrogen dioxide. Animals were killed 16 weeks or 24 to 32 weeks after the beginning of the treatment. Ozone delayed the appearance of tracheal tumors and reduced the incidence of tumors in the lung periphery. A suspected neuroendocrine differentiation of those lung tumors could not be established by immunocytochemistry due to overfixation of tissues. On the other hand, ozone seemed to mitigate development of hepatotoxic lesions mediated by diethylnitrosamine. In animals treated with diethylnitrosamine and exposed to nitrogen dioxide, fewer tracheal tumors and no lung tumors were found. Only a few lung tumors were produced in animals treated with diethylnitrosamine and kept in an atmosphere of 65% oxygen. The previously observed neuroendocrine nature of tumors induced by simultaneous exposure to diethylnitrosamine and hyperoxia could not be established because the long fixation of tissues precluded immunocytochemical stains. Animals treated with diethylnitrosamine and kept in filtered air while being housed in wire-mesh cages developed fewer lung tumors than animals given the same treatment and kept on conventional bedding in shoebox cages. Although all inhalants tested are known to produce substantial cell proliferation in the respiratory tract, it was not possible to document whether this would enhance lung tumor development. The role of the two common air pollutants, ozone and nitrogen dioxide, as possible additional risks in the pathogenesis of lung cancer in animals continues to remain uncertain.

  9. 7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

    ClinicalTrials.gov

    2013-09-27

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Estrogen Receptor-negative Breast Cancer; Extensive Stage Small Cell Lung Cancer; Gastrointestinal Stromal Tumor; HER2-negative Breast Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Progesterone Receptor-negative Breast Cancer; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Adult Primary Liver Cancer; Recurrent Anal Cancer; Recurrent Basal Cell Carcinoma of the Lip; Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor; Recurrent Breast Cancer; Recurrent Cervical Cancer; Recurrent Colon Cancer; Recurrent Endometrial Carcinoma; Recurrent Esophageal Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Prostate Cancer; Recurrent Rectal Cancer; Recurrent Salivary Gland Cancer; Recurrent Small Cell Lung Cancer; Recurrent Small Intestine Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral

  10. Regression of murine lung tumors by the let-7 microRNA

    PubMed Central

    Trang, Phong; Medina, Pedro P.; Wiggins, Jason F.; Ruffino, Lynnsie; Kelnar, Kevin; Omotola, Michael; Homer, Robert; Brown, David; Bader, Andreas G.; Weidhaas, Joanne B.; Slack, Frank J.

    2009-01-01

    MicroRNAs (miRNAs) have recently emerged as an important new class of cellular regulators that control various cellular processes and are implicated in human diseases, including cancer. Here, we show that loss of let-7 function enhances lung tumor formation in vivo, strongly supporting the hypothesis that let-7 is a tumor suppressor. Moreover, we report that exogenous delivery of let-7 to established tumors in mouse models of non-small cell lung cancer (NSCLC) significantly reduces tumor burden. These results demonstrate the therapeutic potential of let-7 in NSCLC and point to miRNA replacement therapy as a promising approach in cancer treatment. PMID:19966857

  11. 1,1-Bis (3'-indolyl)-1-(p-substitutedphenyl)methane compounds inhibit lung cancer cell and tumor growth in a metastasis model.

    PubMed

    Andey, Terrick; Patel, Apurva; Jackson, Tanise; Safe, Stephen; Singh, Mandip

    2013-10-01

    1,1-Bis(3-indolyl)-1-(p-substitutedphenyl)methane (C-DIM) compounds exhibit remarkable antitumor activity with low toxicity in various cancer cells including lung tumors. Two C-DIM analogs, DIM-C-pPhOCH3 (C-DIM-5) and DIM-C-pPhOH (C-DIM-8) while acting differentially on the orphan nuclear receptor, TR3/Nur77 inhibited cell cycle progression from G0/G1 to S-phase and induced apoptosis in A549 cells. Combinations of docetaxel (doc) with C-DIM-5 or C-DIM-8 showed synergistic anticancer activity in vitro and these results were consistent with their enhanced antitumor activities invivo. Respirable aqueous formulations of C-DIM-5 (mass median aerodynamic diameter of 1.92±0.22μm and geometric standard deviation of 2.31±0.12) and C-DIM-8 (mass median aerodynamic diameter of 1.84±0.31μm and geometric standard deviation of 2.11±0.15) were successfully delivered by inhalation to athymic nude mice bearing A549 cells as metastatic tumors. This resulted in significant (p<0.05) lung tumor regression and an overall reduction in tumor burden. Analysis of lung tumors from mice treated with inhalational formulations of C-DIM-5 and C-DIM-8 showed decreased mRNA and protein expression of mediators of tumor initiation, metastasis, and angiogenesis including MMP2, MMP9, c-Myc, β-catenin, c-Met, c-Myc, and EGFR. Microvessel density assessment of lung tissue sections showed significant reduction (p<0.05) in angiogenesis and metastasis as evidenced by decreased distribution of immunohistochemical staining of VEGF, and CD31. Our studies demonstrate both C-DIM-5 and C-DIM-8 have similar anticancer profiles in treating metastatic lung cancer and possibly work as TR3 inactivators.

  12. A biomechanical approach for in vivo lung tumor motion prediction during external beam radiation therapy

    NASA Astrophysics Data System (ADS)

    Karami, Elham; Gaede, Stewart; Lee, Ting-Yim; Samani, Abbas

    2015-03-01

    Lung Cancer is the leading cause of cancer death in both men and women. Among various treatment methods currently being used in the clinic, External Beam Radiation Therapy (EBRT) is used widely not only as the primary treatment method, but also in combination with chemotherapy and surgery. However, this method may lack desirable dosimetric accuracy because of respiration induced tumor motion. Recently, biomechanical modeling of the respiratory system has become a popular approach for tumor motion prediction and compensation. This approach requires reasonably accurate data pertaining to thoracic pressure variation, diaphragm position and biomechanical properties of the lung tissue in order to predict the lung tissue deformation and tumor motion. In this paper, we present preliminary results of an in vivo study obtained from a Finite Element Model (FEM) of the lung developed to predict tumor motion during respiration.

  13. Low-dose nicotine does not promote lung tumors in mouse models

    Cancer.gov

    Experiments in mice show that low levels of exposure to nicotine, equivalent to those in humans who use nicotine replacement therapy (NRT) to help them quit smoking, did not promote lung tumor growth.

  14. Intra-tumor Heterogeneity in Localized Lung Adenocarcinomas Delineated by Multi-region Sequencing

    PubMed Central

    Zhang, Jianjun; Fujimoto, Junya; Zhang, Jianhua; Wedge, David C.; Song, Xingzhi; Zhang, Jiexin; Seth, Sahil; Chow, Chi-Wan; Cao, Yu; Gumbs, Curtis; Gold, Kathryn A.; Kalhor, Neda; Little, Latasha; Mahadeshwar, Harshad; Moran, Cesar; Protopopov, Alexei; Sun, Huandong; Tang, Jiabin; Wu, Xifeng; Ye, Yuanqing; William, William N.; Lee, Jack J.; Heymach, John V.; Hong, Waun Ki; Swisher, Stephen; Wistuba, Ignacio I.; Futreal, P. Andrew

    2015-01-01

    Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intra-tumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multi-region whole exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were identified in all regions of individual tumors suggesting single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months post-surgery, 3 patients have relapsed and all 3 patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. PMID:25301631

  15. Angiogenesis and lung cancer: ramucirumab prolongs survival in 2(nd)-line metastatic NSCLC.

    PubMed

    Das, Millie; Wakelee, Heather

    2014-12-01

    In the REVEL trial, ramucirumab, a monoclonal antibody to VEGFR-2, improved overall survival in combination with docetaxel compared to docetaxel alone in the second-line setting of non-small cell lung cancer (NSCLC). Along with bevacizumab and nintedanib, ramucirumab is the third anti-angiogenic agent that has yielded positive overall survival results in a phase III trial of patients with advanced NSCLC. Given the lack of effective therapies in the relapsed setting and the disappointing results of many other VEGF-targeted agents in lung cancer, the results from REVEL are encouraging. One of the major remaining hurdles is the identification of reliable predictive biomarkers in order to predict which patients are most likely to benefit from anti-angiogenic therapies. Despite the positive results seen in REVEL, the exact role of ramucirumab in the treatment paradigm of lung cancer remains to be seen given the modest survival benefit of 1.4 months and the lack of predictive biomarkers at this time.

  16. [Metastatic non-small cell lung cancer: Systemic treatment of patients aged 70 and over].

    PubMed

    Quoix, Elisabeth; Ducoloné, Alain; Mennecier, Bertrand; Fraisse, Philippe

    2011-04-01

    Patients aged 70 and over represent the third of the population of patients with lung cancer. There has been for a long time a certain nihilism regarding the treatment of elderly patients with advanced lung cancer as well from medical doctors but also from families and patients themselves with the false belief of an indolent course of the disease in elderly patients. As a result, clinical trials devoted to elderly patients were quite scarce until the end of the last decade. Nevertheless, an important trial was published in 1999 with the comparison of vinorelbine as a single agent versus best supportive care only in patients aged 70 and over with an advanced non-small cell lung cancer. The survival benefit with vinorelbine was important. Then two trials were published comparing monotherapy with either vinorelbine or gemcitabine to the doublet vinorelbine and gemcitabine without convincing results. As a consequence, the ASCO 2004 recommendations were to treat elderly patients with a monotherapy (gemcitabine or vinorelbine). Recently an IFCT trial was presented at the plenary session of the ASCO 2010. A carboplatin (every 4weeks)+weekly paclitaxel doublet was compared to a vinorelbine or gemcitabine (choice of the center). The survival benefit was of such magnitude that the paradigm of treatment of elderly patients PS 0-2 with advanced NSCLC should be modified in favor of the tested doublet. There should be a reappraisal of the geriatric indexes recommended by the oncogeriatricians regarding their exact prognostic or predictive role. PMID:21388776

  17. SU-E-J-78: Internal Target Volume Delineation for Lung Tumors in Patients Treated with Robotic Radiosurgery

    SciTech Connect

    Descovich, M; Pinnaduwage, D; Kirby, N; Gottschalk, A; Yom, S; Pouliot, J; Braunstein, S

    2014-06-01

    Purpose: To compare different approaches for Internal Target Volume (ITV) delineation for patients treated with fiducial-free robotic radiosurgery for primary and metastatic lung tumors. Methods: Ten patients undergoing Lung-Optimized Treatment (LOT) for robotic radiosurgery were imaged with inhale and exhale breath-hold CT scans and 8-phase 4DCT scan. We evaluated the differences in internal target volume (ITV) delineated using three approaches: 1) maximum intensity projection (MIP) images reconstructed from 4DCT scan (ITV-MIP); 2) linear interpolation of Gross Tumor Volumes (GTV) segmented on inhale and exhale breath-hold scans (ITV-BH); 3) linear interpolation of GTV segmented on inhale and exhale phases of 4DCT scan (ITV-2Phase). All contours were independently generated by the same radiation oncologist using lung window settings. Patients had ITV-MIP volumes ranging from 1.5 to 146.9 cc (mean 36.8 cc) located in various parts of the lung. Volume overlap and matching index (MI) were calculated and compared. The MI between two volumes was defined as the ratio of their intersection to their union. MI of 1 indicates the volumes are identical; MI of 0 indicates that there is no overlap. Results: The three approaches generated very different results. The average (SD) MI for ITV-MIP and ITV-BH was 0.52 (0.24); for ITV-MIP and ITV-2Phase it was 0.69 (0.13); and for ITV-BH and ITV-2Phase was 0.57 (0.21), (ANOVA, p=0.16). Relative to the ITV-MIP, the percentage of volume overlap was 72% (26%) and 90% (7%) for ITV-BH and ITV-2Phase, respectively (t-test, p=0.05). Conclusion: Differences between ITV-BH and ITV-MIP are due to inconsistent lung filling at breath-hold and nonlinear tumor motion. Therefore, methods to check breath-hold scanning against regular patient breathing patterns should be developed. Whenever possible, ITV-BH generated by the LOT workflow should be verified by 4DCT data.

  18. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice

    PubMed Central

    Esteva-Font, Cristina; Jin, Byung-Ju; Verkman, A. S.

    2014-01-01

    Aquaporin 1 (AQP1) is a plasma membrane water-transporting protein expressed strongly in tumor microvascular endothelia. We previously reported impaired angiogenesis in implanted tumors in AQP1-deficient mice and reduced migration of AQP1-deficient endothelial cells in vitro. Here, we investigated the consequences of AQP1 deficiency in mice that spontaneously develop well-differentiated, luminal-type breast adenomas with lung metastases [mouse mammary tumor virus-driven polyoma virus middle T oncogene (MMTV-PyVT)]. AQP1+/+ MMTV-PyVT mice developed large breast tumors with total tumor mass 3.5 ± 0.5 g and volume 265 ± 36 mm3 (se, 11 mice) at age 98 d. Tumor mass (1.6±0.2 g) and volume (131±15 mm3, 12 mice) were greatly reduced in AQP1−/− MMTV-PyVT mice (P<0.005). CD31 immunofluorescence showed abnormal microvascular anatomy in tumors of AQP1−/− MMTV-PyVT mice, with reduced vessel density. HIF-1α expression was increased in tumors in AQP1−/− MMTV-PyVT mice. The number of lung metastases (5±1/mouse) was much lower than in AQP1+/+ MMTV-PyVT mice (31±8/mouse, P<0.005). These results implicate AQP1 as an important determinant of tumor angiogenesis and, hence, as a potential drug target for adjuvant therapy of solid tumors.—Esteva-Font, C., Jin, B.-J., Verkman, A. S. Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice. PMID:24334548

  19. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters.

    PubMed

    Tehrani, Joubin Nasehi; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-21

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation. PMID:26531324

  20. Sensitivity of tumor motion simulation accuracy to lung biomechanical modeling approaches and parameters

    NASA Astrophysics Data System (ADS)

    Nasehi Tehrani, Joubin; Yang, Yin; Werner, Rene; Lu, Wei; Low, Daniel; Guo, Xiaohu; Wang, Jing

    2015-11-01

    Finite element analysis (FEA)-based biomechanical modeling can be used to predict lung respiratory motion. In this technique, elastic models and biomechanical parameters are two important factors that determine modeling accuracy. We systematically evaluated the effects of lung and lung tumor biomechanical modeling approaches and related parameters to improve the accuracy of motion simulation of lung tumor center of mass (TCM) displacements. Experiments were conducted with four-dimensional computed tomography (4D-CT). A Quasi-Newton FEA was performed to simulate lung and related tumor displacements between end-expiration (phase 50%) and other respiration phases (0%, 10%, 20%, 30%, and 40%). Both linear isotropic and non-linear hyperelastic materials, including the neo-Hookean compressible and uncoupled Mooney-Rivlin models, were used to create a finite element model (FEM) of lung and tumors. Lung surface displacement vector fields (SDVFs) were obtained by registering the 50% phase CT to other respiration phases, using the non-rigid demons registration algorithm. The obtained SDVFs were used as lung surface displacement boundary conditions in FEM. The sensitivity of TCM displacement to lung and tumor biomechanical parameters was assessed in eight patients for all three models. Patient-specific optimal parameters were estimated by minimizing the TCM motion simulation errors between phase 50% and phase 0%. The uncoupled Mooney-Rivlin material model showed the highest TCM motion simulation accuracy. The average TCM motion simulation absolute errors for the Mooney-Rivlin material model along left-right, anterior-posterior, and superior-inferior directions were 0.80 mm, 0.86 mm, and 1.51 mm, respectively. The proposed strategy provides a reliable method to estimate patient-specific biomechanical parameters in FEM for lung tumor motion simulation.

  1. Evaluation and management of the pregnant patient with suspected primary musculoskeletal tumor or metastatic carcinoma to bone.

    PubMed

    Puvanesarajah, Varun; Spiker, Andrea M; Shannon, Brett A; Grundy, Maureen; Levin, Adam S; Morris, Carol D

    2016-09-01

    Primary musculoskeletal cancer and metastatic disease to bone in pregnant patients presents major treatment challenges. Although uncommon, musculoskeletal malignancies in pregnant women have been reported. When diagnosing and treating these patients, the mother's health must be managed appropriately while ensuring that fetal development is not deleteriously affected. Extensive radiographic imaging and more advanced techniques are often necessary to fully characterize the extent of disease. When possible, magnetic resonance imaging should be used instead of computed tomography to limit exposure of the conceptus to radiation. If treatment is needed, therapeutic radiation, chemotherapy, and surgery should be considered. Surgical resection is the foundation of treatment of early-stage primary bone tumors and soft-tissue sarcomas during pregnancy. With surgery, anesthesia and thromboprophylaxis are important considerations. If chemotherapy is required, administration should be avoided in the first trimester to limit harm to the fetus. Therapeutic radiation should similarly be avoided during the first trimester and often can be postponed until after delivery. PMID:27566025

  2. Metastatic Malignant Ovarian Steroid Cell Tumor: A Case Report and Review of the Literature

    PubMed Central

    Lee, Jessica; John, Veena S.; Liang, Sharon X.; D'Agostino, Catherine A.; Menzin, Andrew W.

    2016-01-01

    We report a case of malignant ovarian steroid cell tumor not otherwise specified (NOS) in a 47-year-old female who presented with hirsutism, virilization, and amenorrhea. At the time of laparotomy, the tumor had already spread to the pelvic cul-de-sac. She underwent a total hysterectomy, bilateral salpingo-oophorectomy, and tumor resection with no residual disease. She received three cycles of bleomycin, etoposide, and cisplatin (BEP) and is now free of disease 24 months after surgery. Literature review of ovarian steroid cell tumors NOS including clinicopathological features and clinical management was performed. PMID:27375912

  3. Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2016-09-21

    Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer

  4. Dissecting the Heterogeneity of Circulating Tumor Cells in Metastatic Breast Cancer: Going Far Beyond the Needle in the Haystack

    PubMed Central

    Bulfoni, Michela; Turetta, Matteo; Del Ben, Fabio; Di Loreto, Carla; Beltrami, Antonio Paolo; Cesselli, Daniela

    2016-01-01

    Although the enumeration of circulating tumor cells (CTC) defined as expressing both epithelial cell adhesion molecule and cytokeratins (EpCAM+/CK+) can predict prognosis and response to therapy in metastatic breast, colon and prostate cancer, its clinical utility (i.e., the ability to improve patient outcome by guiding therapy) has not yet been proven in clinical trials. Therefore, scientists are now focusing on the molecular characterization of CTC as a way to explore its possible use as a “surrogate” of tumor tissues to non-invasively assess the genomic landscape of the cancer and its evolution during treatment. Additionally, evidences confirm the existence of CTC in epithelial-to-mesenchymal transition (EMT) characterized by a variable loss of epithelial markers. Since the EMT process can originate cells with enhanced invasiveness, stemness and drug-resistance, the enumeration and characterization of this population, perhaps the one truly responsible of tumor recurrence and progression, could be more clinically useful. For these reasons, several devices able to capture CTC independently from the expression of epithelial markers have been developed. In this review, we will describe the types of heterogeneity so far identified and the key role played by the epithelial-to-mesenchymal transition in driving CTC heterogeneity. The clinical relevance of detecting CTC-heterogeneity will be discussed as well. PMID:27783057

  5. Pericardial effusion associated with metastatic disease from an unknown primary tumor in a dog.

    PubMed

    Kirsch, J A; Dhupa, S; Cornell, K K

    2000-01-01

    A 6.5-year-old, spayed female Siberian husky presented with signs of cardiac tamponade and weakness. Pleural, pericardial, and abdominal effusion were identified with radiographs and ultrasound. Pericardiocentesis relieved signs of tamponade, and the dog was clinically improved. Pericardial effusion recurred, and pericardiectomy was performed. Histopathological examination of excised tissues failed to reveal evidence of infectious or neoplastic disease. After pericardiectomy, clinically apparent thoracic effusion persisted. The dog was euthanized, and postmortem histopathological examination revealed emboli of metastatic carcinoma cells in the epicardium. The location of intrathoracic disease in this dog made antemortem diagnosis difficult, if not impossible.

  6. Toxicity, immunogenicity, and tumor radioimmunodetecting ability of two human monoclonal antibodies in patients with metastatic colorectal carcinoma

    SciTech Connect

    Steis, R.G.; Carrasquillo, J.A.; McCabe, R.; Bookman, M.A.; Reynolds, J.C.; Larson, S.M.; Smith, J.W. 2d.; Clark, J.W.; Dailey, V.; Del Vecchio, S. )

    1990-03-01

    Two human immunoglobulin M (IgM) monoclonal antibodies (MoAbs), 16.88 and 28A32, which react with cytoplasmic (28A32 and 16.88) or cell surface (28A32) determinants on human colon carcinoma cells, were administered intravenously to 26 patients with metastatic colorectal carcinoma to determine if they could localize to sites of metastatic disease, if they had any antitumor or toxic effects, and to determine whether they would elicit an antihuman MoAb response. Serial scans showed tumor uptake of radioisotope in 12 of 16 patients receiving 131I-labeled 28A32 and in nine of 12 patients receiving 131I-labeled 16.88. No antitumor effects were seen with either antibody. No antibody-related toxic effects were observed following administration of 16.88, but two patients developed localized urticarial reactions following injection with antibody 28A32. No patient developed an antibody response to 16.88. Anti-28A32 reactivity was found in five of 12 (42%) normal sera and in seven of 23 (30%) patients before receiving any antibody. Following administration of 28A32, a low titer (1:10 dilution) of anti-28A32 developed in four patients with no preexisting antibody, a decrease in the preexisting titer was seen in three other patients, the titer remained constant in one patient, and no anti-28A32 was ever detected in six patients. In most cases, anti-28A32 activity was lost at dilutions greater than 1:10 and did not appear to affect antibody half-life in the serum or whole body retention of the antibody. We conclude that these human IgM MoAbs are capable of localizing at sites of disease in vivo, are nontoxic, and are poorly immunogenic in humans. Further studies to determine the specificity of targeting and to improve the delivery of antibody to sites of tumor are indicated.

  7. A deformable lung tumor tracking method in fluoroscopic video using active shape models: a feasibility study.

    PubMed

    Xu, Qianyi; Hamilton, Russell J; Schowengerdt, Robert A; Jiang, Steve B

    2007-09-01

    A dynamic multi-leaf collimator (DMLC) can be used to track a moving target during radiotherapy. One of the major benefits for DMLC tumor tracking is that, in addition to the compensation for tumor translational motion, DMLC can also change the aperture shape to conform to a deforming tumor projection in the beam's eye view. This paper presents a method that can track a deforming lung tumor in fluoroscopic video using active shape models (ASM) (Cootes et al 1995 Comput. Vis. Image Underst. 61 38-59). The method was evaluated by comparing tracking results against tumor projection contours manually edited by an expert observer. The evaluation shows the feasibility of using this method for precise tracking of lung tumors with deformation, which is important for DMLC-based real-time tumor tracking.

  8. Dasatinib in Treating Patients With Recurrent or Metastatic Malignant Salivary Gland Tumors

    ClinicalTrials.gov

    2016-05-26

    High-grade Salivary Gland Mucoepidermoid Carcinoma; Low-grade Salivary Gland Mucoepidermoid Carcinoma; Recurrent Salivary Gland Cancer; Salivary Gland Acinic Cell Tumor; Salivary Gland Adenocarcinoma; Salivary Gland Adenoid Cystic Carcinoma; Salivary Gland Anaplastic Carcinoma; Salivary Gland Malignant Mixed Cell Type Tumor; Salivary Gland Poorly Differentiated Carcinoma; Salivary Gland Squamous Cell Carcinoma; Stage IV Salivary Gland Cancer

  9. Metastasis signatures: genes regulating tumor-microenvironment interactions predict metastatic behavior.

    PubMed

    Albini, Adriana; Mirisola, Valentina; Pfeffer, Ulrich

    2008-03-01

    The possibility of predicting clinical outcome of cancer patients through the analysis of gene expression profiles in the primary tumor is a kind of ideological revolution as the multistep carcinogenesis model postulates that the proportion of cells within the primary tumor that actually acquire metastasis driving mutation(s) is small; too small to leave its imprint on the gene expression profile. The data collected to date have brought a new paradigm to reality in the metastasis field: metastasis must at least in part rely on mutations and/or gene regulation events present in the majority of cells which constitute the primary tumor mass. By analyses of differential expression of primary tumors versus metastases or by functional analyses of putative metastasis genes in experimental metastasis, many metastasis-associated gene expression events have been identified that correlate with the development of metastases. Among genes "favoring" metastasis, we find many molecules that are expressed not by the tumor cell itself but by the cells of the microenvironment, as well as genes over-expressed in the primary tumor that have a principle role in mediating tumor-host interactions. Here we review these concepts and advance hypotheses on how gene expression of the primary tumor and the microenvironment can favor the spread of the metastasis seeds and how this knowledge can provide tools to secondary prevention.

  10. Model-based risk assessment for motion effects in 3D radiotherapy of lung tumors

    NASA Astrophysics Data System (ADS)

    Werner, René; Ehrhardt, Jan; Schmidt-Richberg, Alexander; Handels, Heinz

    2012-02-01

    Although 4D CT imaging becomes available in an increasing number of radiotherapy facilities, 3D imaging and planning is still standard in current clinical practice. In particular for lung tumors, respiratory motion is a known source of uncertainty and should be accounted for during radiotherapy planning - which is difficult by using only a 3D planning CT. In this contribution, we propose applying a statistical lung motion model to predict patients' motion patterns and to estimate dosimetric motion effects in lung tumor radiotherapy if only 3D images are available. Being generated based on 4D CT images of patients with unimpaired lung motion, the model tends to overestimate lung tumor motion. It therefore promises conservative risk assessment regarding tumor dose coverage. This is exemplarily evaluated using treatment plans of lung tumor patients with different tumor motion patterns and for two treatment modalities (conventional 3D conformal radiotherapy and step-&- shoot intensity modulated radiotherapy). For the test cases, 4D CT images are available. Thus, also a standard registration-based 4D dose calculation is performed, which serves as reference to judge plausibility of the modelbased 4D dose calculation. It will be shown that, if combined with an additional simple patient-specific breathing surrogate measurement (here: spirometry), the model-based dose calculation provides reasonable risk assessment of respiratory motion effects.

  11. Breast cancer metastatic to the kidney with renal vein involvement.

    PubMed

    Nasu, Hatsuko; Miura, Katsutoshi; Baba, Megumi; Nagata, Masao; Yoshida, Masayuki; Ogura, Hiroyuki; Takehara, Yasuo; Sakahara, Harumi

    2015-02-01

    The common sites of breast cancer metastases include bones, lung, brain, and liver. Renal metastasis from the breast is rare. We report a case of breast cancer metastatic to the kidney with extension into the renal vein. A 40-year-old woman had undergone left mastectomy for breast cancer at the age of 38. A gastric tumor, which was later proved to be metastasis from breast cancer, was detected by endoscopy. Computed tomography performed for further examination of the gastric tumor revealed a large left renal tumor with extension into the left renal vein. It mimicked a primary renal tumor. Percutaneous biopsy of the renal tumor confirmed metastasis from breast cancer. Surgical intervention of the stomach and the kidney was avoided, and she was treated with systemic chemotherapy. Breast cancer metastatic to the kidney may present a solitary renal mass with extension into the renal vein, which mimics a primary renal tumor.

  12. Ciliated muconodular papillary tumor of the lung: report of five cases.

    PubMed

    Ishikawa, Masashi; Sumitomo, Shinichi; Imamura, Naoto; Nishida, Tomoki; Mineura, Katsutaka; Ono, Kazuo

    2016-01-01

    We report five serial cases of ciliated muconodular papillary tumor (CMPT) of the lung. CMPT is characterized as a low-grade malignant tumor with ciliated columnar epithelial cells combined with goblet cells, typically presenting as peripheral lung tumor and often causing diagnostic or therapeutic problems. In the cases described here, all patients presented with abnormal chest shadow but no definitive symptoms. Although all tumors were peripheral, computed tomography (CT) revealed various radiographic findings including small lung nodules, ground-grass opacity or irregular-shaped consolidation. All patients underwent complete surgical resection, and no recurrence has been noted over follow-up. In all cases, pathological findings included columnar ciliated cells with mucus lakes, consistent with the immunohistochemical staining. As there are few reports on this tumor entity, which has not yet received a WHO classification, we believe our case series may be of interest. PMID:27562578

  13. Ciliated muconodular papillary tumor of the lung: report of five cases

    PubMed Central

    Ishikawa, Masashi; Sumitomo, Shinichi; Imamura, Naoto; Nishida, Tomoki; Mineura, Katsutaka; Ono, Kazuo

    2016-01-01

    We report five serial cases of ciliated muconodular papillary tumor (CMPT) of the lung. CMPT is characterized as a low-grade malignant tumor with ciliated columnar epithelial cells combined with goblet cells, typically presenting as peripheral lung tumor and often causing diagnostic or therapeutic problems. In the cases described here, all patients presented with abnormal chest shadow but no definitive symptoms. Although all tumors were peripheral, computed tomography (CT) revealed various radiographic findings including small lung nodules, ground-grass opacity or irregular-shaped consolidation. All patients underwent complete surgical resection, and no recurrence has been noted over follow-up. In all cases, pathological findings included columnar ciliated cells with mucus lakes, consistent with the immunohistochemical staining. As there are few reports on this tumor entity, which has not yet received a WHO classification, we believe our case series may be of interest. PMID:27562578

  14. Automatic FDG-PET-based tumor and metastatic lymph node segmentation in cervical cancer

    NASA Astrophysics Data System (ADS)

    Arbonès, Dídac R.; Jensen, Henrik G.; Loft, Annika; Munck af Rosenschöld, Per; Hansen, Anders Elias; Igel, Christian; Darkner, Sune

    2014-03-01

    Treatment of cervical cancer, one of the three most commonly diagnosed cancers worldwide, often relies on delineations of the tumour and metastases based on PET imaging using the contrast agent 18F-Fluorodeoxyglucose (FDG). We present a robust automatic algorithm for segmenting the gross tumour volume (GTV) and metastatic lymph nodes in such images. As the cervix is located next to the bladder and FDG is washed out through the urine, the PET-positive GTV and the bladder cannot be easily separated. Our processing pipeline starts with a histogram-based region of interest detection followed by level set segmentation. After that, morphological image operations combined with clustering, region growing, and nearest neighbour labelling allow to remove the bladder and to identify the tumour and metastatic lymph nodes. The proposed method was applied to 125 patients and no failure could be detected by visual inspection. We compared our segmentations with results from manual delineations of corresponding MR and CT images, showing that the detected GTV lays at least 97.5% within the MR/CT delineations. We conclude that the algorithm has a very high potential for substituting the tedious manual delineation of PET positive areas.

  15. Dietary soy isoflavones increase metastasis to lungs in an experimental model of breast cancer with bone micro-tumors.

    PubMed

    Yang, Xujuan; Belosay, Aashvini; Hartman, James A; Song, Huaxin; Zhang, Yukun; Wang, Wendan; Doerge, Daniel R; Helferich, William G

    2015-04-01

    Bone is one of the most common sites for metastasis in breast cancer (BC). Micro-metastasis in bone marrow was detected in 30% of patients with stage I, II, or III BC at primary surgery and is a strong indicator of poor prognosis. The role dietary soy isoflavones play in BC with bone micro-metastasis is unclear. In this study, we examined the effects of genistein, daidzein, (-)-equol or a mixture of soy isoflavones on BC with bone micro-metastasis using an experimental model of murine mammary cancer 4T1 cells engineered with luciferase. A small number (1000) of 4T1 cells were injected into the tibia of female Balb/c mice to establish micro-tumors in bone. Soy isoflavones were supplemented in the AIN-93G diet at 750 mg/kg and were provided to mice from 3 weeks before to 3 weeks after cell injection. Bioluminescent imaging was conducted on day 2 (D2), D6, D8, D16 and D20 post cell injection and the results indicated dietary soy isoflavones enhanced the growth of bone micro-tumors on D8. Furthermore, dietary soy isoflavones stimulated metastatic tumor formation in lungs and increased Ki-67 protein expression in these metastasized tumors. In vitro, soy isoflavones (<10 µM) had limited effects on the growth, motility or invasion of 4T1 cells. Thus, the in vivo stimulatory effect could be likely due to systemic effects between the host, 4T1 tumors and soy isoflavones. In conclusion, soy isoflavones stimulate BC with bone micro-metastasis in mice and further investigations are needed regarding their consumption by BC survivors.

  16. Stromal matrix metalloprotease-13 knockout alters Collagen I structure at the tumor-host interface and increases lung metastasis of C57BL/6 syngeneic E0771 mammary tumor cells

    PubMed Central

    2013-01-01

    Background Matrix metalloproteases and collagen are key participants in breast cancer, but their precise roles in cancer etiology and progression remain unclear. MMP13 helps regulate collagen structure and has been ascribed largely harmful roles in cancer, but some studies demonstrate that MMP13 may also protect against tumor pathology. Other studies indicate that collagen’s organizational patterns at the breast tumor-host interface influence metastatic potential. Therefore we investigated how MMP13 modulates collagen I, a principal collagen subtype in breast tissue, and affects tumor pathology and metastasis in a mouse model of breast cancer. Methods Tumors were implanted into murine mammary tissues, and their growth analyzed in Wildtype and MMP13 KO mice. Following extraction, tumors were analyzed for collagen I levels and collagen I macro- and micro-structural properties at the tumor-host boundary using immunocytochemistry and two-photon and second harmonic generation microscopy. Lungs were analyzed for metastases counts, to correlate collagen I changes with a clinically significant functional parameter. Statistical analyses were performed by t-test, analysis of variance, or Wilcoxon-Mann–Whitney tests as appropriate. Results We found that genetic ablation of host stromal MMP13 led to: 1. Increased mammary tumor collagen I content, 2. Marked changes in collagen I spatial organization, and 3. Altered collagen I microstructure at the tumor-host boundary, as well as 4. Increased metastasis from the primary mammary tumor to lungs. Conclusions These results implicate host MMP13 as a key regulator of collagen I structure and metastasis in mammary tumors, thus making it an attractive potential therapeutic target by which we might alter metastatic potential, one of the chief determinants of clinical outcome in breast cancer. In addition to identifying stromal MMP13 is an important regulator of the tumor microenvironment and metastasis, these results also suggest

  17. Molecular Testing for Treatment of Metastatic Non-Small Cell Lung Cancer: How to Implement Evidence-Based Recommendations.

    PubMed

    Levy, Benjamin P; Chioda, Marc D; Herndon, Dana; Longshore, John W; Mohamed, Mohamed; Ou, Sai-Hong Ignatius; Reynolds, Craig; Singh, Jaspal; Wistuba, Ignacio I; Bunn, Paul A; Hirsch, Fred R

    2015-10-01

    The recent discovery of relevant biomarkers has reshaped our approach to therapy selection for patients with non-small cell lung cancer. The unprecedented outcomes demonstrated with tyrosine kinase inhibitors in molecularly defined cohorts of patients has underscored the importance of genetic profiling in this disease. Despite published guidelines on biomarker testing, successful tumor genotyping faces significant hurdles at both academic and community-based practices. Oncologists are now faced with interpreting large-scale genomic data from multiple tumor types, possibly making it difficult to stay current with practice standards in lung cancer. In addition, physicians' lack of time, resources, and face-to-face opportunities can interfere with the multidisciplinary approach that is essential to delivery of care. Finally, several challenges exist in optimizing the amount and quality of tissue for molecular testing. Recognizing the importance of biomarker testing, a series of advisory boards were recently convened to address these hurdles and clarify best practices. We reviewed these challenges and established recommendations to help optimize tissue acquisition, processing, and testing within the framework of a multidisciplinary approach. PMID:26330460

  18. SU-E-J-269: Assessing the Precision of Dose Delivery in CBCT-Guided Stereotactic Body Radiation Therapy for Lung and Soft Tissue Metastatic Lesions

    SciTech Connect

    Parsai, S; Dalhart, A; Chen, C; Parsai, E; Pearson, D; Sperling, N; Reddy, K

    2014-06-01

    Purpose: Ensuring reproducibility of target localization is critical to accurate stereotactic body radiation treatment (SBRT) for lung and soft tissue metastatic lesions. To ch