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Sample records for metastatic poorly differentiated

  1. Metronomic temozolomide as second line treatment for metastatic poorly differentiated pancreatic neuroendocrine carcinoma.

    PubMed

    De Divitiis, C; von Arx, C; Grimaldi, A M; Cicala, D; Tatangelo, F; Arcella, A; Romano, G M; Simeone, E; Iaffaioli, R V; Ascierto, P A; Tafuto, S

    2016-01-01

    Neuroendocrine Neoplasms (NEN) are a group of heterogeneous malignancies derived from neuroendocrine cell compartment, with different roles in both endocrine and nervous system. Most NETs have gastroentero-pancreatic (GEP) origin, arising in the foregut, midgut, or hindgut. The 2010 WHO classification divides GEP-NETs into two main subgroups, neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), according with Ki-67 levels. NET are tumors with low (<20 %) Ki-67 value, and NECs, including small cell lung carcinomas and Merkel Cell carcinomas, are all NETs with high Ki-67 levels (>20 %-G3). Poorly differentiated neuroendocrine carcinomas (NEC) are usually treated with cisplatin-based chemotherapy regimens. Here we present a case of a patient with pancreatic NEC progressing after cisplatin and etoposide, treated with temozolomide as palliative, second line treatment. According with the poor Performance Status (PS = 2) and to reduce the toxicity of the treatment was chosen an intermittent dosing regimen of metronomic temozolomide (75 mg/m(2)/day-one-week-on/on-week-off). MGMT resulted methylated. On July 2014 the patient started the treatment. On August 2014 the patient obtained a significant clinical benefit (PS = 0) and the total body CT scan performed on October 2014 showed a RECIST partial response on all the sites of disease. No drug-related side effects were reported by the patient. After 18 months of therapy the treatment continues without significant toxicity, and with further remission of the metastases. Treatment with metronomic "one-week-on/on-week-off" Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pNEC with MGMT methylation. PMID:27142424

  2. 99mTc-Labeled-rhTSH Analogue (TR1401) for Imaging Poorly Differentiated Metastatic Thyroid Cancer

    PubMed Central

    Galli, Filippo; Manni, Isabella; Piaggio, Giulia; Balogh, Lajos; Weintraub, Bruce D.; Szkudlinski, Mariusz W.; Fremont, Valerie; Dierckx, Rudi A.J.O.

    2014-01-01

    Background: Differentiated thyroid carcinomas originating from thyroid follicular cells are frequent tumors of the thyroid with relatively good prognosis due to improved surgical techniques and follow-up procedures. Poorly differentiated thyroid cancers, which lose iodine uptake ability, in most cases still express thyrotropin (TSH) receptors (TSHR). Therefore, the aim of this study was to radiolabel a superagonist recombinant human TSH (rhTSH) analogue for imaging poorly differentiated thyroid cancer. Methods: The TSHR superagonist, TR1401, was labeled with 99mTc using an indirect method via succinimidyl-6-hydrazinonicotinate hydrochloride conjugation. In vitro quality controls included SDS-PAGE, cysteine challenge, and cell-binding assay on TSHR positive cell lines (JP09 and ML-1). In vivo studies included tumor targeting experiments in athymic nude CD-1 mice xenografted with several different TSHR positive cells (JP09, K1, and ML-1) and TSHR negative cells (JP02) as control. Results: The superagonist rhTSH analogue TR1401 was labeled with high labeling efficiency (>95%) and high specific activity (9250 MBq/mg). The labeled molecule retained its biologic activity and structural integrity. In tumor targeting experiments, a focal uptake of radiolabeled TR1401 was observed in TSHR positive cells but not in TSHR negative cells. The same observation was made in a dog with spontaneous intraglandular thyroid cancer. Conclusions: We were able to radiolabel the rhTSH superagonist analogue TR1401 with 99mTc efficiently with retention of in vitro and in vivo binding capacity to TSHR. The relative role of such novel radiopharmaceutical versus 131I scanning of thyroid cancer will require future histopathologic and clinical studies, but it may open new perspectives for presurgical staging of thyroid cancer, and diagnosis of radioiodine negative local relapses and/or distant metastases. PMID:24801227

  3. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation.

    PubMed

    Mohanty, Sambit K; Kim, Stacey A; DeLair, Deborah F; Bose, Shikha; Laury, Anna R; Chopra, Shefali; Mertens, Richard B; Dhall, Deepti

    2016-08-01

    Metastatic neuroendocrine neoplasms to the breast may show considerable morphologic overlap with primary mammary carcinomas, particularly those showing evidence of neuroendocrine differentiation, and may be misdiagnosed as such. Accurate distinction between these two entities is crucial for determination of appropriate clinical management. The histologic and immunohistochemical features of metastatic neuroendocrine neoplasms to the breast were studied and compared with the features of primary invasive mammary carcinomas with neuroendocrine differentiation, which served as controls. Of the metastatic neuroendocrine neoplasms, 15 were well-differentiated neuroendocrine tumors with carcinoid tumor-type morphology and 7 were poorly differentiated/high-grade neuroendocrine carcinomas with small-cell or large-cell neuroendocrine carcinoma morphology. The majority of the metastatic neoplasms originated in the lung and gastrointestinal tract. There were histologic similarities between metastatic neuroendocrine neoplasms and invasive mammary carcinomas with neuroendocrine differentiation, both of which exhibited neuroendocrine histologic features (nested and trabecular architecture, minimal tubular differentiation, and characteristic nuclear features). Only one case of the invasive mammary carcinomas with neuroendocrine differentiation was modified Bloom-Richardson grade 1 (largely due to minimal tubular differentiation on most such tumors), and the invasive mammary carcinomas with neuroendocrine differentiation were often associated with in situ carcinoma. Immunohistochemistry was helpful in distinguishing metastatic neuroendocrine neoplasms from invasive mammary carcinomas with neuroendocrine differentiation. Whereas the majority of invasive mammary carcinomas with neuroendocrine differentiation were positive for estrogen receptor and GATA3, metastatic neuroendocrine neoplasms were typically negative for estrogen receptor and GATA3, and metastatic well-differentiated

  4. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival.

    PubMed

    Olevian, Dane C; Nikiforova, Marina N; Chiosea, Simon; Sun, Weijing; Bahary, Nathan; Kuan, Shih-Fan; Pai, Reetesh K

    2016-03-01

    The molecular alterations in colorectal poorly differentiated neuroendocrine carcinoma remain incompletely characterized, particularly with respect to mutations in BRAF and KRAS. We analyzed 32 colorectal poorly differentiated neuroendocrine carcinomas and 40 colorectal poorly differentiated conventional adenocarcinomas for mutations in KRAS and BRAF and for DNA mismatch repair protein abnormalities to correlate histopathology with molecular alterations and survival. Compared with poorly differentiated conventional adenocarcinoma, poorly differentiated neuroendocrine carcinoma frequently harbored BRAF mutations (59% versus 5%; P < .001) and less frequently demonstrated KRAS codon 12 or 13 mutations (17% versus 43%; P = .03). BRAF mutations were identified in both pure poorly differentiated neuroendocrine carcinoma (60%) and poorly differentiated neuroendocrine carcinoma associated with a signet ring cell adenocarcinoma component (82%). Most (93%) poorly differentiated neuroendocrine carcinomas demonstrated proficient DNA mismatch repair by either microsatellite instability polymerase chain reaction or DNA mismatch repair immunohistochemistry. Patients with poorly differentiated neuroendocrine carcinoma had a significantly worse overall survival compared with patients with poorly differentiated conventional adenocarcinoma (P < .001). There was no significant difference in overall survival between patients with pure poorly differentiated neuroendocrine carcinoma and patients with both poorly differentiated neuroendocrine carcinoma and adenocarcinoma components (P = .5). In conclusion, colorectal poorly differentiated neuroendocrine carcinomas frequently harbor BRAF mutations and are associated with poor overall survival. PMID:26826419

  5. 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

  6. Clinicopathological significance of gastric poorly differentiated medullary carcinoma.

    PubMed

    Hirai, Hideaki; Yoshizawa, Tadashi; Morohashi, Satoko; Haga, Toshihiro; Wu, Yunyan; Ota, Rie; Takatsuna, Masafumi; Akasaka, Harue; Hakamada, Kenichi; Kijima, Hiroshi

    2016-01-01

    Poorly differentiated gastric adenocarcinoma of solid type is known to show a clinicopathological diversity, but its morphological characteristics have rarely been investigated. In this study, we defined poorly differentiated medullary carcinoma indicating the following three characteristics: (i) more than 90% of the entire tumor were composed of poorly differentiated adenocarcinoma in a medullary growth, (ii) the tumor exhibited an expansive growth at the tumor margin, and (iii) special types such as an α-fetoprotein-producing carcinoma, neuroendocrine carcinoma, and carcinoma with lymphoid stroma were excluded. Based on the definition, we subclassified the poorly differentiated gastric adenocarcinoma of solid type into the two groups: medullary carcinoma and non-medullary carcinoma, and clinicopathologically analyzed 23 cases of medullary carcinomas and 38 cases of non-medullary carcinomas. The medullary carcinomas less frequently displayed lymphatic invasion, venous invasion, and lymph node metastasis, compared with the non-medullary carcinoma (P < 0.001, P = 0.002, and P < 0.001, respectively). The patients with medullary carcinomas significantly showed better disease-free survival (P = 0.017). This is the first study to demonstrate that poorly differentiated adenocarcinoma of solid type can be subclassified into tumors with low and high malignant potentials. Gastric poorly differentiated medullary carcinoma is considered to be a novel histological type predicting good patients' prognosis. PMID:27108877

  7. A Unique Case of Intranasal Metastasis from Occult Poorly Differentiated Thyroid Carcinoma

    PubMed Central

    Kum, Rauf Oğuzhan; Aygenç, Erdinç; Somuk, Battal Tahsin; Börcek, Pelin; Özdem, Cafer

    2015-01-01

    Background: Poorly differentiated thyroid carcinomas (PDTCs) lie, both morphologically and behaviorally, between well-differentiated and undifferentiated carcinomas. Metastasis of poorly differentiated thyroid carcinoma to the intranasal cavity has not been reported previously in the literature. Case Report: A 48-year-old male patient presented with massive epistaxis and nasal obstruction. On nasal examination, a bleeding, vascular mass was seen filling the left nasal cavity. The histopathological report of the nasal mass was well-differentiated thyroid carcinoma metastasis. Whole body scintigraphy, ultrasonography and positron emission tomography were done to rule out other possible metastases in the body and determine the origin of the tumor, which was identified as the left lobe of the thyroid gland, and there were multiple metastases involving the lung, sacroiliac area, and left humerus. Histopathological examination of a thyroidectomy specimen revealed PDTC consisting of insular, follicular, and papillary components. Postoperatively, the patient received radioactive iodine ablation therapy (iodine-131) and a course of external beam radiation therapy to the sacroiliac area and other metastatic regions. No recurrences were observed in a follow-up period of 5 years after surgery. Conclusion: The metastasis of differentiated thyroid carcinoma as a component of PDTC to the intranasal cavity has not been reported before. It is interesting that the well-differentiated component of the tumor was metastasized in our patient. Due to the aggressiveness of PDTC and the poor survival rates in patients who undergo surgery alone, a multidisciplinary treatment approach is required. PMID:26185723

  8. Phosphorylated protein phosphatase 2A determines poor outcome in patients with metastatic colorectal cancer

    PubMed Central

    Cristóbal, I; Manso, R; Rincón, R; Caramés, C; Zazo, S; del Pulgar, T G; Cebrián, A; Madoz-Gúrpide, J; Rojo, F; García-Foncillas, J

    2014-01-01

    Background: Protein phosphatase 2A (PP2A) is a tumour suppressor frequently inactivated in human cancer and its tyrosine-307 phosphorylation has been reported as a molecular inhibitory mechanism. Methods: Expression of phosphorylated PP2A (p-PP2A) was evaluated in 250 metastatic colorectal cancer (CRC) patients. Chi-square, Kaplan–Meier and Cox analyses were used to determine correlations with clinical and molecular parameters and impact on clinical outcomes. Results: High p-PP2A levels were found in 17.2% cases and were associated with ECOG performance status (P=0.001) and presence of synchronous metastasis at diagnosis (P=0.035). This subgroup showed substantially worse overall survival (OS) (median OS, 6.0 vs 26.2 months, P<0.001) and progression-free survival (PFS) (median PFS, 3.8 vs 13.3 months, P<0.001). The prognostic impact of p-PP2A was particularly evident in patients aged <70 years (P<0.001). Multivariate analysis revealed that p-PP2A retained its prognostic impact for OS (hazard ratio 2.7; 95% confidence interval, 1.8–4.1; P<0.001) and PFS (hazard ratio 3.0; 95% confidence interval, 1.8–5.0; P<0.001). Conclusions: Phosphorylated PP2A is an alteration that determines poor outcome in metastatic CRC and represents a novel potential therapeutic target in this disease, thus enabling to define a subgroup of patients who could benefit from future treatments based on PP2A activators. PMID:25003662

  9. 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. PMID:26457350

  10. Primary High-Grade Poorly Differentiated Angiosarcoma of an Intra-parotid Lymph Node.

    PubMed

    Ducharne-Asuaje, Eugenia; Dorion, Dominique; Lamarre, Louis; Coindre, Jean Michel; Geha, Sameh

    2016-06-01

    Head and neck angiosarcoma is an infrequent malignant vascular tumor most commonly found in the skin and soft tissue of the head and neck. Most head and neck angiosarcomas are metastatic to cervical lymph nodes from other primitive location. We describe herein a case of primary high-grade poorly differentiated angiosarcoma arising in an intra-parotid lymph node, discuss the value of immunohistochemical stains for differential diagnosis, and review the literature concerning head and neck angiosarcoma. A 47-year-old man presented with a painless mass that had grown for a period of 6 months in the parotid area. The CT-scan revealed a left parotid lesion of 17 mm. Fine needle aspiration was considered suspicious for lymphoma or poorly differentiated carcinoma. A superficial parotidectomy was performed. On gross examination, the lesion was a well-defined, gray, homogeneous mass of 15 mm of diameter. Microscopic examination showed a normal parotid tissue and a poorly differentiated malignant neoplasm in an intra-parotid lymph node. The tumor had a pseudo-alveolar pattern, with large pleomorphic epithelioid cells, abundant eosinophilic cytoplasm, large vesicular nuclei, and one or more prominent nucleoli. Atypical mitoses were seen. Neoplastic malignant cells stained positive for Vimentin, CD31, D2-40, factor VIII, ERG, and partially for CD34. A positron emission tomography scan was made to search for a primary neoplasia, but no other tumor was localized. The diagnosis of primary high-grade, poorly differentiated, intra-parotid lymph node angiosarcoma was established. PMID:25930154

  11. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin

    PubMed Central

    Mitry, E; Baudin, E; Ducreux, M; Sabourin, J-C; Rufié, P; Aparicio, T; Lasser, P; Elias, D; Duvillard, P; Schlumberger, M; Rougier, P

    1999-01-01

    The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m–2 day–1 for 3 days and cisplatin 100 mg m–2 on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3–4 toxicity was observed in 60% of the cases with one treatment-related death, digestive grade 3–4 toxicity in 40% and grade 3 alopecia was constant. No severe renal, hearing and neurological toxicities were observed (grade 1 in 6%, 14%, 72% respectively and no grade >1). We confirm that poorly differentiated neuroendocrine tumours are chemosensitive to the etoposide plus cisplatin combination. However, the prognosis remains poor with a 2-year survival lower than 20% confirming that new therapeutic strategies have to be developed. © 1999 Cancer Research Campaign PMID:10604732

  12. Poorly Differentiated Gastric Adenocarcinoma Can Mimic Hilar Cholangiocarcinoma.

    PubMed

    Urasaki, Tetsuya; Kodaira, Makoto; Hibino, Masaki; Yamagata, Shingo; Watanabe, Yukihiro; Terazawa, Yasuyuki; Sano, Munetaka; Kuriki, Ken

    2016-01-01

    This report describes two cases with obstructive jaundice caused by poorly differentiated gastric adenocarcinoma. Computed tomography scans showed circumferential stenosis in the hilar bile ducts. Endoscopic retrograde cholangiopancreatography showed dilatation of the bilateral hepatic ducts and stenosis of the common hepatic ducts from the bifurcation of the bilateral hepatic ducts. The first diagnoses were hilar cholangiocarcinoma and biliary drainage decreased serum bilirubin; however, both patients died of cancer within a short period of time. Autopsies revealed lymphatic vessel invasion and possible subepithelial invasion by gastric adenocarcinoma into the hilar bile ducts. A differential diagnosis should thus be required in suspected cases of hilar cholangiocarcinoma. PMID:27301505

  13. Delineation of geological facies from poorly differentiated data

    SciTech Connect

    Wohlberg, Brendt; Tartakovsky, Daniel

    2008-01-01

    The ability to delineate geologic facies and to estima.te their properties from sparse data is essential for modeling physical and biochemical processes occurring in the 'ubsurface. If such data are poorly differentiated, this challcnrring task is complicated further by the absence of a clear distinction between different hydrofacies even at locations where data. are available. vVe consider three alt mative approaches for analysis of poorly differentiated data: a k-means clU!:iterinrr algorithm, an expectation-maximization algorithm, and a minimum-variance algorithm. Two distinct synthetically generated geological settings are used to r:tnalyze the ability of these algorithmti to as ign accurately the membership of such data in a given geologic facies. On average, the minimum-variance algorithm provides a more robust p rformance than its two counterparts and when combined with a nearest-neighbor algorithm, it also yields the most accurate reconstruction of the boundaries between the facies.

  14. Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma.

    PubMed

    Xu, Bin; Ghossein, Ronald

    2016-09-01

    Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid tumors associated with a high mortality rate of 38-57 % and almost 100 % respectively. Several recent studies utilizing next generation sequencing techniques have shed lights on the molecular pathogenesis of these tumors, providing evidence to support a stepwise tumoral progression from well-differentiated to poorly differentiated, and finally to anaplastic thyroid carcinomas. While BRAF (V600E) and RAS mutations remain the main drivers in aggressive thyroid carcinoma, PDTC and ATC gains additional mutations, e.g., TERT promoter mutation, TP53 mutation, as well as frequent alterations in PIK3CA-PTEN-AKT-mTOR pathway, SWI-SNF complex, histomethyltransferases, and mismatch repair genes. RAS-mutated PDTCs are commonly associated with a histologic phenotype defined by Turin proposal, high frequency of distant metastasis, high thyroid differentiation score, and a RAS-like gene expression profile, whereas BRAF-mutated PDTCs are usually defined solely by the Memorial Sloan Kettering Cancer Center (MSKCC) criteria with a propensity for nodal metastasis and are less differentiated with a BRAF-like expression signature. Such demarcation is largely lost in ATC which is characterized by genomic complexity, heavy mutation burden, and profound undifferentiation. Additionally, several molecular events, e.g., EIF1AX mutation, mutation burden, and chromosome 1q gain in PDTCs, as well as EIF1AX mutation, chromosome 13q loss, and 20q gains in ATCs, may serve as adverse prognostic markers predicting poor clinical outcome. PMID:27372303

  15. Bioinformatics analysis of differentially expressed pathways related to the metastatic characteristics of osteosarcoma

    PubMed Central

    Sun, Wei; Ma, Xiaojun; Shen, Jiakang; Yin, Fei; Wang, Chongren; Cai, Zhengdong

    2016-01-01

    In this study, gene expression data of osteosarcoma (OSA) were analyzed to identify metastasis-related biological pathways. Four gene expression data sets (GSE21257, GSE9508, GSE49003 and GSE66673) were downloaded from Gene Expression Omnibus (GEO). An analysis of differentially expressed genes (DEGs) was performed using the Significance Analysis of Microarray (SAM) method. Gene expression levels were converted into scores of pathways by the Functional Analysis of Individual Microarray Expression (FAIME) algorithm and the differentially expressed pathways (DEPs) were then disclosed by a t-test. The distinguishing and prediction ability of the DEPs for metastatic and non-metastatic OSA was further confirmed using the principal component analysis (PCA) method and 3 gene expression data sets (GSE9508, GSE49003 and GSE66673) based on the support vector machines (SVM) model. A total of 616 downregulated and 681 upregulated genes were identified in the data set, GSE21257. The DEGs could not be used to distinguish metastatic OSA from non-metastatic OSA, as shown by PCA. Thus, an analysis of DEPs was further performed, resulting in 14 DEPs, such as NRAS signaling, Toll-like receptor (TLR) signaling, matrix metalloproteinase (MMP) regulation of cytokines and tumor necrosis factor receptor-associated factor (TRAF)-mediated interferon regulatory factor 7 (IRF7) activation. Cluster analysis indicated that these pathways could be used to distinguish between metastatic OSA from non-metastatic OSA. The prediction accuracy was 91, 66.7 and 87.5% for the data sets, GSE9508, GSE49003 and GSE66673, respectively. The results of PCA further validated that the DEPs could be used to distinguish metastatic OSA from non-metastatic OSA. On the whole, several DEPs were identified in metastatic OSA compared with non-metastatic OSA. Further studies on these pathways and relevant genes may help to enhance our understanding of the molecular mechanisms underlying metastasis and may thus aid in

  16. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers

    PubMed Central

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  17. Genetic alterations in fatty acid transport and metabolism genes are associated with metastatic progression and poor prognosis of human cancers.

    PubMed

    Nath, Aritro; Chan, Christina

    2016-01-01

    Reprogramming of cellular metabolism is a hallmark feature of cancer cells. While a distinct set of processes drive metastasis when compared to tumorigenesis, it is yet unclear if genetic alterations in metabolic pathways are associated with metastatic progression of human cancers. Here, we analyzed the mutation, copy number variation and gene expression patterns of a literature-derived model of metabolic genes associated with glycolysis (Warburg effect), fatty acid metabolism (lipogenesis, oxidation, lipolysis, esterification) and fatty acid uptake in >9000 primary or metastatic tumor samples from the multi-cancer TCGA datasets. Our association analysis revealed a uniform pattern of Warburg effect mutations influencing prognosis across all tumor types, while copy number alterations in the electron transport chain gene SCO2, fatty acid uptake (CAV1, CD36) and lipogenesis (PPARA, PPARD, MLXIPL) genes were enriched in metastatic tumors. Using gene expression profiles, we established a gene-signature (CAV1, CD36, MLXIPL, CPT1C, CYP2E1) that strongly associated with epithelial-mesenchymal program across multiple cancers. Moreover, stratification of samples based on the copy number or expression profiles of the genes identified in our analysis revealed a significant effect on patient survival rates, thus confirming prominent roles of fatty acid uptake and metabolism in metastatic progression and poor prognosis of human cancers. PMID:26725848

  18. Adrenal Metastasis of a Poorly Differentiated Adenocarcinoma Mimicking a Pheochromocytoma on 18F-FDOPA PET/CT.

    PubMed

    Heimburger, Céline; Averous, Gerlinde; Charlin, Emmanuelle; Lang, Hervé; Kurtz, Jean-Emmanuel; Imperiale, Alessio

    2016-09-01

    We report the surprising intense uptake of F-FDOPA in a right adrenal metastasis of a poorly differentiated metastatic adenocarcinoma of unknown primary mimicking a pheochromocytoma in a hemodialyzed patient with the typical Menard's triad and increased serum catecholamines. Our observation emphasizes that F-FDOPA is not a specific radiotracer for pheochromocytoma and paraganglioma investigation, although it is currently and successfully used in this clinical setting. Moreover, we underline that kidney failure may be responsible for abnormally high serum catecholamines values even in subjects without pheochromocytoma, leading to erroneous diagnostic conclusions particularly in patients with adrenal masses. PMID:27355847

  19. Bioinformatics analysis of differentially expressed pathways related to the metastatic characteristics of osteosarcoma.

    PubMed

    Sun, Wei; Ma, Xiaojun; Shen, Jiakang; Yin, Fei; Wang, Chongren; Cai, Zhengdong

    2016-08-01

    In this study, gene expression data of osteosarcoma (OSA) were analyzed to identify metastasis-related biological pathways. Four gene expression data sets (GSE21257, GSE9508, GSE49003 and GSE66673) were downloaded from Gene Expression Omnibus (GEO). An analysis of differentially expressed genes (DEGs) was performed using the Significance Analysis of Microarray (SAM) method. Gene expression levels were converted into scores of pathways by the Functional Analysis of Individual Microarray Expression (FAIME) algorithm and the differentially expressed pathways (DEPs) were then disclosed by a t-test. The distinguishing and prediction ability of the DEPs for metastatic and non-metastatic OSA was further confirmed using the principal component analysis (PCA) method and 3 gene expression data sets (GSE9508, GSE49003 and GSE66673) based on the support vector machines (SVM) model. A total of 616 downregulated and 681 upregulated genes were identified in the data set, GSE21257. The DEGs could not be used to distinguish metastatic OSA from non-metastatic OSA, as shown by PCA. Thus, an analysis of DEPs was further performed, resulting in 14 DEPs, such as NRAS signaling, Toll-like receptor (TLR) signaling, matrix metalloproteinase (MMP) regulation of cytokines and tumor necrosis factor receptor-associated factor (TRAF)-mediated interferon regulatory factor 7 (IRF7) activation. Cluster analysis indicated that these pathways could be used to distinguish between metastatic OSA from non-metastatic OSA. The prediction accuracy was 91, 66.7 and 87.5% for the data sets, GSE9508, GSE49003 and GSE66673, respectively. The results of PCA further validated that the DEPs could be used to distinguish metastatic OSA from non-metastatic OSA. On the whole, several DEPs were identified in metastatic OSA compared with non-metastatic OSA. Further studies on these pathways and relevant genes may help to enhance our understanding of the molecular mechanisms underlying metastasis

  20. Identification of differentially expressed microRNAs in metastatic melanoma using next-generation sequencing technology

    PubMed Central

    QI, MIN; HUANG, XIAOYUAN; ZHOU, LEI; ZHANG, JIANGLIN

    2014-01-01

    In this study, we investigated differentially expressed microRNAs (miRNAs or miRs) and their functions in metastatic melanoma using next-generation sequencing technology. The GSE36236 data set was downloaded from the Gene Expression Omnibus (GEO) database and 4 primary cutaneous melanoma samples (used as controls) and 3 metastatic melanoma samples were selected from 31 samples for further analysis. Firstly, the differentially expressed miRNAs were screened by limma package in R language. Secondly, the target genes of the miRNAs were retrieved with TargetScanHuman 6.2, and the interactions among these genes were identified by String and an interaction network was established. Finally, functional and pathway analyses were performed for the genes in the network using Expression Analysis Systematic Explorer (EASE). A total of 4 differentially expressed miRNAs (hsa-miR-146, hsa-miR-27, hsa-miR-877 and hsa-miR-186) were obtained between the metastatic melanoma and primary cutaneous melanoma samples. We predicted 101 high-confidence target genes of hsa-miR-27 and obtained a network with 41 interactions. Finally, functional and pathway analyses revealed that the genes in the network were significantly enriched at the transcriptional level. Differentially expressed miRNAs were identified in the metastatic melanoma compared with the primary cutaneous melanoma samples and the target genes of hsa-miR-27 were found to be significantly enriched at the transcriptional level. The results presented in our study may prove helpful in the diagnosis and treatment of metastatic melanoma. PMID:24573402

  1. Energy substrate utilization in a poorly differentiated rat hepatoma

    SciTech Connect

    Mares-Perlman, J.A.

    1987-01-01

    Metabolism of energy substrates in a transplantable, poorly differentiated rat hepatoma and the effect of high fat total parenteral nutrition (TPN) on growth of this neoplasms and host were studied. Although high-fat TPN better maintained host weight and nitrogen balance than oral feeding and did not increase tumor growth, adverse consequences of high-fat TPN were found. These included liver lipid infiltration and indications of the possible development of insulin resistance. A method for isolating fresh hepatoma cells was designed to study the metabolism of energy substrates by this neoplasms. The metabolic viability of cells obtained by this procedure in sustained incubations was demonstrated by observations of linear rates of leucine and uridine incorporation into acid-insoluble material, retention of cellular ATP and ADP content and stable rates of oxygen consumption. Cells isolated by this procedure were used to determine whether this hepatoma was capable of oxidizing fatty acids and ketones and to estimate the contribution oxidation of these substrates made to ATP production relative to glucose and glutamine. Incorporation of radiolabel from both palmitate and ..beta..-hydroxybutyrate carbon into CO/sub 2/ was observed.

  2. Low skeletal muscle density is associated with poor survival in patients who receive chemotherapy for metastatic gastric cancer.

    PubMed

    Hayashi, Naomi; Ando, Yuichi; Gyawali, Bishal; Shimokata, Tomoya; Maeda, Osamu; Fukaya, Masahide; Goto, Hidemi; Nagino, Masato; Kodera, Yasuhiro

    2016-03-01

    Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [<33 Hounsfield units (HU) in obese and <41 HU in non-obese patients] and low SMI (<41 cm2/m2 in females, <43 cm2/m2 in non-obese males and <53 cm2/m2 in obese males) were referenced from a large population based study. The CT images of 53 patients were reviewed. The median SMD was 36.8 HU (range, 19.5-59.3 HU), and the median SMI was 39.8 cm2/m2 (range, 23.7-60.0 cm2/m2). Patients with low SMD had significantly shorter OS compared with patients having normal SMD (8.9 vs. 12.8 months, P=0.03). However, OS did not differ significantly between patients with low and normal SMI (11.1 and 14.3 months, P=0.18). Multivariate analyses confirmed that low SMD was an independent predictor of poor outcomes (P<0.01). SMD is an important prognosticator of survival in patients with metastatic gastric cancer receiving chemotherapy. PMID:26648321

  3. Differential characteristics of heart, liver, and brain metastatic subsets of murine breast carcinoma.

    PubMed

    Erin, Nuray; Kale, Sule; Tanrıöver, Gamze; Köksoy, Sadi; Duymuş, Ozlem; Korcum, Aylin F

    2013-06-01

    Breast carcinoma is comprised of heterogeneous groups of cells with different metastatic potential. To develop effective therapeutic strategies targeting metastatic disease, it is crucial to understand the characteristics of breast cancer cells that enable metastasis to distant organs. 4THM breast carcinoma cells are the cells of 4T1 primary tumors that metastasized to the heart. Cells of 4THM tumors which metastasized to liver (4TLM) were previously isolated. Recently macroscopic brain metastasis in 4THM injected animals, were isolated to obtain a brain metastatic cell line (4TBM). Using an orthotopic mouse model differential characteristic of cells metastasized to heart (4THM), liver (4TLM), and brain (4TBM) were compared for ability to metastasize and expression of stem cell markers. We found that 4TLM cells produced significantly more lung and liver metastasis compared to 4TBM and 4THM cells. In vitro, proliferation as well as migration rate of 4TLM cells was also significantly higher than the other cell lines. Remarkably primary tumors formed by 4TLM cells expressed significant amounts of CD34, a marker for mesenchymal malignancies. Markers of epithelial-mesenchymal transition were expressed in all metastatic cells, but the degree of expression differed. Majorities of 4TLM, 4THM, and 4TBM cells were CD44+ CD24- whereas, 12 % of 4TLM cells also expressed membranous CD24. Conditioned mediums of non-metastatic 67NR breast tumors and cancer-associated fibroblasts inhibited growth of highly metastatic 4TLM cells. Malignant cells metastasized to brain were distinguished by membranous E-cadherin expression that was markedly higher in 4TBM cells grown as spheroids suggesting E-cadherin is required for brain metastasis. Differential features of heart, brain, and liver metastatic cells in a syngenic model was shown in this study for the first time. These findings not only provide a model to explore new treatment modalities, but also demonstrate differential features of

  4. [Establishment and pathological study of a new poorly differentiated mucinous gastric cancer cell line].

    PubMed

    Uesugi, H; Atari, E

    1995-01-01

    We succeeded in establishing a human gastric carcinoma cell line (KE-97) from oncocytes obtained from the mesentery disseminated metastatic focus of a 52-year-old male stomach cancer patient. From a histopathological point of view the gastric carcinoma was clearly a mucin-producing mucinous carcinoma, portion of which were mixed with poorly differentiated adenocarcinoma and signet-ring cell carcinoma. The oncocytes were fused into a mass and exhibited a suspended proliferating system, with a doubling time of about 28.8 hours. Transplantation of the cancer cells into skid mice resulted in a tumor system in all cases, and histologically, mucinous vacuoles were found in the cell membranes. With immunological staining they were found to be positive for anti-CEA antibodies, anti-CA19-9 antibodies and anti-ICAM-1 antibodies. Autopsy found extensive hematogenous metastasis (lung, liver) and cancerous peritonitis. KE-97 is mucinous carcinoma, and it was reported with the belief that it is a useful cell line upon the investigation of its cancer metastasis mechanism and cytological characteristics. PMID:7861622

  5. Well Differentiated Neuroendocrine Tumors with a Morphologically Apparent High Grade Component: A Pathway Distinct from Poorly Differentiated Neuroendocrine Carcinomas

    PubMed Central

    Tang, Laura H.; Untch, Brian R.; Reidy, Diane L.; O'Reilly, Eileen; Dhall, Deepti; Jih, Lily; Basturk, Olca; Allen, Peter J.; Klimstra, David S.

    2016-01-01

    Purpose Most well-differentiated neuroendocrine tumors (WD-NETs) of the enteropancreatic system are low-intermediate grade (G1,G2). Elevated proliferation demonstrated by either a brisk mitotic rate (>20/10 high power fields) or high Ki67 index (>20%) defines a group of aggressive neoplasms designated as high grade (G3) neuroendocrine carcinoma (NEC). High grade NEC is equated with poorly-differentiated NEC (PD-NEC) and is associated with a dismal outcome. Progression of WD-NETs to a high grade neuroendocrine neoplasm very rarely occurs and their clinicopathologic and molecular features need to be characterized. Methods We investigated the 31 cases of WD-NETs with evidence of component of a high grade neoplasm. The primary sites included pancreas, small bowel, bile duct, and rectum. Histopathology of the cases was retrospectively reviewed and selected immunohistochemistry and gene mutation analyses performed. Results The high grade component occurred either within the primary tumor (48%) or at metastatic sites (52%). The clinical presentation, radiographic features, biomarkers, and the genotype of these WD-NETs with high grade component remained akin to those of G1-G2 WD-NETs. The median disease specific survival (DSS) was 55 months (16-119 months), and 2-year and 5-year DSS was 88% and 49%, respectively – significantly better than that of a comparison group of true PD-NEC (DSS 11 months). Conclusion Mixed grades can occur in WD-NETs, which are distinguished from PDNECs by their unique phenotype, proliferative indices, and the genotype. This phenomenon of mixed grade in WD-NET provides additional evidence to the growing recognition that the current WHO G3 category contains both WD-NETs as well as PDNECs. PMID:26482044

  6. Usefulness of Microvascular Ultrasonography in Differentiating Metastatic Lymphadenopathy from Tuberculous Lymphadenitis.

    PubMed

    Ryoo, Inseon; Suh, Sangil; You, Sung-Hye; Seol, Hae Young

    2016-09-01

    This study was undertaken to evaluate the usefulness of vascular pattern analysis on microvascular ultrasonography in distinguishing metastatic lymphadenopathy from tuberculous lymphadenitis, compared with conventional power Doppler ultrasonography, and to evaluate inter-observer agreement for microvascular ultrasonography. Thirty-four patients with metastatic lymphadenopathy and 27 patients with tuberculous lymphadenitis were included. The level of inter-observer agreement was excellent or good for all aspects of vascular pattern analysis on both ultrasonographic examinations. Vascular distribution, internal vascularity and internal vascular features of lymph nodes on microvascular ultrasonography differed significantly different (p ≤ 0.002) between metastatic lymphadenopathy and tuberculous lymphadenitis. A central vascular pattern with displacement was prevalent in metastasis, and an avascular pattern was more frequent in tuberculosis. Internal vascularity of metastasis was higher than that of tuberculosis. Vascular patterns on power Doppler ultrasonography did not differ significantly. Vascular pattern analysis using microvascular ultrasonography can be helpful in differentiating metastatic lymphadenopathy from tuberculous lymphadenitis with good inter-observer agreement. PMID:27353493

  7. Differentiating Metastatic and Non-metastatic Tumor Cells from Their Translocation Profile through Solid-State Micropores.

    PubMed

    Ali, Waqas; Ilyas, Azhar; Bui, Loan; Sayles, Bailey; Hur, Yeun; Kim, Young-Tae; Iqbal, Samir M

    2016-05-17

    Cancer treatment, care, and outcomes are much more effective if started at early stages of the disease. The presence of malignant cancer cells in human samples such as blood or biopsied tissue can be used to reduce overtreatment and underdiagnosis as well as for prognosis monitoring. Reliable quantification of metastatic tumor cells (MTCs) and non-metastatic tumor cells (NMTCs) from human samples can help in cancer staging as well. We report a simple, fast, and reliable approach to identify and quantify metastatic and non-metastatic cancer cells from whole biological samples in a point-of-care manner. The metastatic (MDA MB-231) and non-metastatic (MCF7) breast cancer cells were pushed through a solid-state micropore made in a 200 nm thin SiO2 membrane while measuring current across the micropore. The cells generated very distinctive translocation profiles. The translocation differences stemmed from their peculiar mechanophysical properties. The detection efficiency of the device for each type of tumor cells was ∼75%. MTCs showed faster translocation (36%) and 34% less pore blockage than NMTCs. The micropore approach is simple, exact, and quantitative for metastatic cell detection in a lab-on-a chip setting, without the need for any preprocessing of the sample. PMID:27035212

  8. Neuroendocrine Differentiation Is a Prognostic Factor for Stage II Poorly Differentiated Colorectal Cancer

    PubMed Central

    Liu, Yue; Xu, Jinghong; Jiao, Yurong; Hu, Yeting; Yi, Chenghao; Li, Qiong; Tong, Zhou; Wang, Xiaowei; Hu, Lifeng; Li, Jun; Ding, Kefeng

    2014-01-01

    Neuroendocrine differentiation (NED) in colorectal cancer is an indistinct phenomenon and may define a new cancer subtype, especially in the poorly differentiated colorectal cancer (PDCRC). The clinical features of PDCRC with NED remain controversial, thus confusing the implementation of individualized treatment. This study included 171 patients who underwent surgery from 2000 to 2011 and had pathology-confirmed PDCRC. Each sample was examined by immunohistochemistry for the biological markers of NED, synaptophysin (Syn), and chromogranin (CgA). Patients with Syn(+) and/or CgA(+) cells were classified as NED(+); otherwise, they were NED(−). Data were collected for patients who were followed up for at least two years. NED(+) staining was present in 71 (41.5%) patients. The median survival time was 36.9 months. No survival differences existed between the NED(−) and NED(+) groups (P > 0.05). However, stage II NED(+) patients had a significantly worse prognosis than NED(−) patients (P = 0.018). For the NED(+) group, the median survival was 38.56 months, and the 5-year survival was 65%. For the NED(−) group, the median survival was 53.18 months, and the 5-year survival was 90%. NED is a common event in primary PDCRC. For stage II PDCRC, NED(+) indicates a poor prognosis. PMID:25093184

  9. Complete remission with sunitinib in a poor-risk patient with metastatic renal cell carcinoma: the fine balance between toxicity and efficacy.

    PubMed

    Massari, Francesco; Ciccarese, Chiara; Bimbatti, Davide; Fantinel, Emanuela; Modena, Alessandra; Simbolo, Michele; Brunelli, Matteo; Artibani, Walter; Martignoni, Guido; Scarpa, Aldo; Tortora, Giampaolo

    2015-04-01

    Sunitinib represents a reasonable therapeutic option for first-line treatment of poor-risk metastatic renal cell carcinoma and the treatment should aim at the delicate balance between managing side effects to improve the toxicity profile and patient compliance to treatment while maintaining anticancer efficacy. Achievement of a complete response, although rare, is possible, even in poor-risk patients. Treatment discontinuation represents a viable alternative for both tumour biology and patients' quality of life. To date, no molecular markers have been identified with prognostic and/or predictive value for guiding therapeutic decisions. Further research should aim at gaining in-depth knowledge of renal cell carcinoma biology for a tailored personalized therapy. We report a case of poor-risk metastatic renal cell carcinoma, with Von Hippel-Lindau loss of function, which achieved and maintained a complete remission after first-line therapy with sunitinib by using a reduced dosage and a modified schedule of treatment. PMID:25569703

  10. Differential Expression of Prognostic Proteomic Markers in Primary Tumour, Venous Tumour Thrombus and Metastatic Renal Cell Cancer Tissue and Correlation with Patient Outcome

    PubMed Central

    Laird, Alexander; O’Mahony, Fiach C.; Nanda, Jyoti; Riddick, Antony C. P.; O’Donnell, Marie; Harrison, David J.; Stewart, Grant D.

    2013-01-01

    Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ensures predicting metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been shown to have prognostic significance, including Ki67, p53, vascular endothelial growth factor receptor 1 (VEGFR1) and ligand D (VEGFD), SNAIL and SLUG. Previous pathway analysis has been from study of the primary tumour, with little attention to the metastatic tumours which are the focus of targeted molecular therapies. As such, in this study a tissue microarray from 177 patients with primary renal tumour, renal vein tumour thrombus and/or RCC metastasis has been created and used with Automated Quantitative Analysis (AQUA) of immunofluorescence to study the prognostic significance of these markers in locally advanced and metastatic disease. Furthermore, this has allowed assessment of differential protein expression between the primary tumours, renal vein tumour thrombi and metastases. The results demonstrate that clinico-pathological parameters remain the most significant predictors of cancer specific survival; however, high VEGFR1 or VEGFD can predict poor cancer specific survival on univariate analysis for locally advanced and metastatic disease. There was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared with the primary tumours and renal vein tumour thrombi. With the exception of p53, these differences in protein expression have not been shown previously in RCC. This confirms the importance of proliferation, angiogenesis and epithelial to mesenchymal transition in the pathogenesis and metastasis of RCC. Importantly

  11. Carcinoembryonic Antigen Cell Adhesion Molecule 1 long isoform modulates malignancy of poorly differentiated colon cancer cells

    PubMed Central

    Arabzadeh, Azadeh; Dupaul-Chicoine, Jeremy; Breton, Valérie; Haftchenary, Sina; Yumeen, Sara; Turbide, Claire; Saleh, Maya; McGregor, Kevin; Greenwood, Celia M T; Akavia, Uri David; Blumberg, Richard S; Gunning, Patrick T; Beauchemin, Nicole

    2015-01-01

    Objective Nearly 20%–29% of patients with colorectal cancer (CRC) succumb to liver or lung metastasis and there is a dire need for novel targets to improve the survival of patients with metastasis. The long isoform of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1-L or CC1-L) is a key regulator of immune surveillance in primary CRC, but its role in metastasis remains largely unexplored. We have examined how CC1-L expression impacts on colon cancer liver metastasis. Design Murine MC38 transfected with CC1-L were evaluated in vitro for proliferation, migration and invasion, and for in vivo experimental liver metastasis. Using shRNA silencing or pharmacological inhibition, we delineated the role in liver metastasis of Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) downstream of CC1-L. We further assessed the clinical relevance of these findings in a cohort of patients with CRC. Results MC38-CC1-L-expressing cells exhibited significantly reduced in vivo liver metastasis and displayed decreased CCL2 chemokine secretion and reduced STAT3 activity. Down-modulation of CCL2 expression and pharmacological inhibition of STAT3 activity in MC38 cells led to reduced cell invasion capacity and decreased liver metastasis. The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival. Conclusions CC1-L regulates inflammation and STAT3 signalling and contributes to the maintenance of a less-invasive CRC metastatic phenotype of poorly differentiated carcinomas. PMID:25666195

  12. Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer

    PubMed Central

    McFarland, Daniel C; Misiukiewicz, Krzysztof J

    2014-01-01

    Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials. PMID:25053887

  13. EGFR mutations are more frequent in well-differentiated than in poor-differentiated lung adenocarcinomas.

    PubMed

    Liu, Yan; Xu, Mei Lin; Zhong, Hao Hao; Heng, Wan Jie; Wu, Bing Quan

    2008-12-01

    Somatic mutations in epidermal growth factor receptor (EGFR) tyrosine kinase domain, particularly deletions in exon 19 and point mutation in exon 21, are associated with clinical outcome in patients with lung adenocarcinoma, suggesting that EGFR mutation would have an important role in clinical decision making. DNA was extracted from the excised specimens of 60 lung adenocarcinoma patients with phenol-chloroform and ethanol precipitation. Exon 19 and 21 were amplified by PCR, and direct sequenced from both sense and antisense directions. EGFR somatic mutations were present in 13 of 60 patients (21.67%), including seven cases of in-frame deletion in exon 19 around codon 746 and six cases of amino acid substitution in exon 21. Exon 21 mutation is more frequent in adenocarcinomas with bronchi-alveolar component than exon 19 deletions. Mutations were more prevalent in well-differentiated adenocarcinomas (9/27, 33.33%) than in moderate to poor-differentiated adenocarcinomas (4/33, 12.12%) (P < 0.05). Adenocarcinomas with bronchi-alveolar components had higher mutation frequency (8/22,36. 36%) than those without bronchi-alveolar components (5/38, 13.16%) (P < 0.05). In this study, female patients had more mutation rate than male patients. This trend was also observed in the patients with pathologic stage I-II compared with stage III-IV, but neither of them was statistically significant. Patients with cisplatin-based adjuvant chemotherapy had no significantly prolonged survival compared with single radical resection. But patients with EGFR mutation had relative longer survival. In conclusion, our study suggest that EGFR mutations may be a valuable prognostic factor for disease free survival of surgically treated lung adenocarcinoma patients independently from adjuvant chemotherapy. PMID:18985444

  14. Upregulation of RNA Processing Factors in Poorly Differentiated Lung Cancer Cells.

    PubMed

    Geles, Kenneth G; Zhong, Wenyan; O'Brien, Siobhan K; Baxter, Michelle; Loreth, Christine; Pallares, Diego; Damelin, Marc

    2016-04-01

    Intratumoral heterogeneity in non-small cell lung cancer (NSCLC) has been appreciated at the histological and cellular levels, but the association of less differentiated pathology with poor clinical outcome is not understood at the molecular level. Gene expression profiling of intact human tumors fails to reveal the molecular nature of functionally distinct epithelial cell subpopulations, in particular the tumor cells that fuel tumor growth, metastasis, and disease relapse. We generated primary serum-free cultures of NSCLC and then exposed them to conditions known to promote differentiation: the air-liquid interface (ALI) and serum. The transcriptional network of the primary cultures was associated with stem cells, indicating a poorly differentiated state, and worse overall survival of NSCLC patients. Strikingly, the overexpression of RNA splicing and processing factors was a prominent feature of the poorly differentiated cells and was also observed in clinical datasets. A genome-wide analysis of splice isoform expression revealed many alternative splicing events that were specific to the differentiation state of the cells, including an unexpectedly high frequency of events on chromosome 19. The poorly differentiated cells exhibited alternative splicing in many genes associated with tumor progression, as exemplified by the preferential expression of the short isoform of telomeric repeat-binding factor 1 (TERF1), also known as Pin2. Our findings demonstrate the utility of the ALI method for probing the molecular mechanisms that underlie NSCLC pathogenesis and provide novel insight into posttranscriptional mechanisms in poorly differentiated lung cancer cells. PMID:27084424

  15. Identification of differentially expressed proteins from primary versus metastatic pancreatic cancer cells using subcellular proteomics.

    PubMed

    McKinney, Kimberly Q; Lee, Jin-Gyun; Sindram, David; Russo, Mark W; Han, David K; Bonkovsky, Herbert L; Hwang, Sun-Il

    2012-01-01

    Pancreatic cancer is an aggressive disease with nearly equal yearly rates of diagnosis and death. Current therapies have failed to improve outcomes due to rapid disease progression and late stage at presentation. Recently, pathways involved in progression and metastasis have been elucidated; however, new knowledge has not generated more effective therapies. We report on the use of subcellular fractionation and liquid chromatography (LC)-mass spectrometry to identify 3,907 proteins in four pancreatic cancer cell lines, 540 of which are unique to primary cancer cells, and 487 unique to cells derived from metastatic sites. Statistical analysis identified 134 proteins significantly differentially expressed between the two populations. The subcellular localization of these proteins was determined and expression levels for four targets were validated using western blot techniques. These identified proteins can be further investigated to determine their roles in progression and metastasis and may serve as therapeutic targets in the development of more effective treatments for pancreatic cancer. PMID:22990105

  16. Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM- Lung Cancer-Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis.

    PubMed

    Bertolini, Giulia; D'Amico, Lucia; Moro, Massimo; Landoni, Elena; Perego, Paola; Miceli, Rosalba; Gatti, Laura; Andriani, Francesca; Wong, Donald; Caserini, Roberto; Tortoreto, Monica; Milione, Massimo; Ferracini, Riccardo; Mariani, Luigi; Pastorino, Ugo; Roato, Ilaria; Sozzi, Gabriella; Roz, Luca

    2015-09-01

    Metastasis is the main reason for lung cancer-related mortality, but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here, we show that CD133(+)/CXCR4(+) cancer-initiating cells (CIC) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133(+)/CXCR4(+) cells in residual tumors and their metastatization. Immunophenotypic analysis of lung tumor cells intravenously injected or spontaneously disseminated to murine lungs demonstrated the survival advantage and increased colonization ability of a specific subset of CD133(+)/CXCR4(+) with reduced expression of epithelial cell adhesion molecule (EpCAM(-)), which also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cells from lungs of PDX-bearing mice enriched for CD133(+)/CXCR4(+)/EpCAM(-) CICs are highly tumorigenic and metastatic. Importantly, microenvironment stimuli eliciting epithelial-to-mesenchymal transition, including signals from cancer-associated fibroblasts, are able to increase the dissemination potential of lung cancer cells through the generation of the CD133(+)/CXCR4(+)/EpCAM(-) subset. These findings also have correlates in patient samples where disseminating CICs are enriched in metastatic lymph nodes (20-fold, P = 0.006) and their detection in primary tumors is correlated with poor clinical outcome (disease-free survival: P = 0.03; overall survival: P = 0.05). Overall, these results highlight the importance of specific cellular subsets in the metastatic process, the need for in-depth characterization of disseminating tumor cells, and the potential of therapeutic strategies targeting both primary tumor and tumor-microenvironment interactions. PMID:26141860

  17. Association Between Expression of Cancer Stem Cell Markers and Poor Differentiation of Hepatocellular Carcinoma

    PubMed Central

    Liu, Rui; Shen, Yuan; Nan, Kejun; Mi, Baibing; Wu, Tao; Guo, Jinyue; Li, Miaojing; Lv, Yi; Guo, Hui

    2015-01-01

    Abstract The role of cancer stem cell (CSC) markers in differentiation of hepatocellular carcinoma (HCC) remains uncertain. We conducted a meta-analysis to first investigate the association between expression of CSC markers (CD133, CD90, CD44, and EpCAM) and poor differentiation of HCC, and second, to determine if these CSC markers can be classified as biomarkers for patient classification and HCC differentiated therapy. The relevant literature was searched using PubMed, EMBASE, Elsevier, and Chinese Biological Medicine databases for association between CSC markers and HCC from January 1, 2000 to June 30, 2014. Data were synthesized using random-effect or fixed-effect models. The effect sizes were estimated by measuring odds ratios (OR) with 95% confidence interval (CI). The meta-analysis included 27 studies consisting of 2897 patients with HCC. The positive expression of CSC markers was associated with poor differentiation (OR = 2.37, 95% CI = 2.03–2.77, P < 0.00001). Similarly, the positive expression of CSC markers was only associated with HCC tissues compared with noncancerous liver tissues (OR = 9.26, 95% CI = 3.10–27.65, P < 0.0001). CD90 has a specificity of 91.9% for HCC and a sensitivity of 48.22% in predicting poor differentiation. The positive expression of CSC markers is associated with poor differentiation and aggressive phenotype of patients with HCC. The CD90 marker might be a promising target for patient with HCC classification and differentiation therapy. PMID:26252310

  18. Progression of Intravesical Condyloma Acuminata to Locally Advanced Poorly Differentiated Squamous Cell Carcinoma.

    PubMed

    Khambati, A; Bhanji, Y; Oberlin, D T; Yang, X J; Nadler, R B; Perry, K T; Kundu, S D

    2016-07-01

    Condyloma acuminata (CA) is a common sexually transmitted disease caused by Human Papilloma Virus (HPV) infection. CA of the bladder, however, is an exceedingly rare lesion. We present a rare case of poorly differentiated locally invasive squamous cell carcinoma (SCC) arising from recurrent CA of the bladder in an immunocompetent patient and discuss pathophysiology and management of this unusual condition. PMID:27335797

  19. Poorly differentiated sinonasal tract malignancies: A review focusing on recently described entities.

    PubMed

    Agaimy, Abbas

    2016-01-01

    Sinonasal tract malignancies are uncommon, representing no more than 5% of all head and neck neoplasms. However, in contrast to other head and neck sites, a significant proportion of sinonasal neoplasms tend to display a poorly/ undifferentiated significantly overlapping morphology and a highly aggressive clinical course, despite being of diverse histogenetic and molecular pathogenesis. The wide spectrum of poorly differentiated sinonasal epithelial neoplasms with small "basaloid" blue cell morphology includes basaloid squamous cell carcinoma (both HPV+ and HPV-unrelated), nasopharyngeal-type lymphoepithelial carcinoma (EBV+), small/large cell neuroendocrine carcinoma, esthesioneuroblastoma, poorly differentiated carcinoma of salivary type (myoepithelial carcinoma and solid adenoid cystic carcinoma), NUT midline carcinoma, the recently described SMARCB1-deficient sinonasal carcinoma, sinonasal teratocarcinosarcoma and, as a diagnosis of exclusion, sinonasal undifferentiated carcinoma (SNUC). On the other hand, a variety of sarcomas, melanoma and haematolymphoid malignancies have a predilection for the sinonasal cavities, and they occasionally display aberrant cytokeratin expression and show small round cell morphology thus closely mimicking poorly differentiated carcinomas. This review summarizes the clinicopathological features of the most recently described entities and discuss their differential diagnosis with emphasis on those aspects that represent pitfalls. PMID:27526015

  20. Primary Endometrial Yolk Sac Tumor With Endodermal-Intestinal Differentiation Masquerading as Metastatic Colorectal Adenocarcinoma.

    PubMed

    Damato, Stephen; Haldar, Krishnayan; McCluggage, W Glenn

    2016-07-01

    Yolk sac tumors (YSTs) with a somatic glandular pattern can be difficult to recognize histologically because they reproduce developing intestinal, hepatic, or lung tissue and can express markers such as CDX2 and TTF1. We report an unusual case of a primary endometrial YST showing florid endodermal-intestinal differentiation in a 63-yr-old woman with a history of colorectal adenocarcinoma. Histologically, the tumor exhibited a glandular and papillary architecture and showed widespread immunoreactivity for CDX2 and focal staining for CK20 and CEA, mimicking metastatic colorectal carcinoma on biopsy. The presence of subnuclear cytoplasmic clearing and positive staining for germ cell markers, however, pointed toward a diagnosis of primary endometrial YST, and this was supported by the radiologic and the subsequent pathologic finding of a primary endometrial-based lesion. YSTs in this age group usually arise in association with somatic tumors and in this case a small focus of coexistent endometrioid adenocarcinoma was identified within the uterus. Despite surgery and adjuvant chemotherapy, the patient showed disease progression with liver and lung metastases 6 mo postoperatively. PMID:26598980

  1. Efficacy of Immunohistochemical Staining in Differentiating a Squamous Cell Carcinoma in Poorly Differentiated Rectal Cancer: Two Case Reports

    PubMed Central

    Rami, Sairafi; Han, Yoon Dae; Jang, Mi; Cho, Min Soo; Hur, Hyuk; Min, Byung Soh; Lee, Kang Young

    2016-01-01

    A rectal carcinoma, including primary an adenosquamous and a squamous cell carcinoma (SCC), is a very rare disease, accounting for 0.025% to 0.20% of all large-bowel malignant tumors. Because SCCs have a higher mortality than adenosquamous carcinomas, determining whether the primary rectal cancer exhibits an adenomatous component or a squamous component is important. While differentiating between these 2 components, especially in poorly differentiated rectal cancer, is difficult, specific immunohistochemical stains enable accurate diagnoses. Here, we report the use of immunohistochemical stains to distinguish between the adenomatous and the squamous components in 2 patients with low rectal cancer, a 58-year-old man and a 73-year-old woman, who were initially diagnosed using the histopathologic results for a poorly differentiated carcinoma. These data suggest that using these immunohistochemical stains will help to accurately diagnose the type of rectal cancer, especially for poorly differentiated carcinomas, and will provide important information to determine the proper treatment for the patient. PMID:27626026

  2. Utility of FNAC in Conjunction with Cell Block for Diagnosing Space-Occupying Lesion (SOL) of Liver with Emphasis on Differentiating Hepatocellular Carcinoma from Metastatic SOL: Analysis of 61 Cases

    PubMed Central

    Sheefa, Haq; Lata, Jadhav; Basharat, Mubeen; Rumana, Makhdoomi; Veena, Malhotra

    2016-01-01

    Objectives To study the cytological patterns of fine-needle aspiration cytology (FNAC) obtained from space-occupying lesions (SOLs) of the liver with an aim to differentiate primary hepatocellular carcinoma from metastatic deposits and to evaluate the added advantage and efficacy of studying cell blocks in conjunction with smears for enhancing diagnostic accuracy.   Methods This prospective study took place over two years (September 2007 to 2009) and included 61 patients with cases of liver SOLs that were clinically or radiologically suspicious for malignancy and who were referred for computed tomography or ultrasonography-guided FNAC. Smears were prepared from the aspirated material, and any remainder was used to make the cell block (n = 55). A final diagnosis was made after evaluating the smears and cell block sections.   Results On cytomorphology, a diagnosis of moderately differentiated hepatocellular carcinoma (HCC) and metastatic carcinoma was made in 10 (18.2%) and 25 (45.5%) cases, respectively, and were confirmed using cell block sections. In cases where it was difficult to differentiate between well-differentiated HCC and regenerative nodules, and between poorly differentiated HCC and poorly differentiated metastatic carcinoma, a final diagnosis was made with the help of cell blocks sections. Cell blocks assisted in reaching a final diagnosis in 16 (29.1%) cases. Cases that were diagnosed using cytomorphology were confirmed by the cell block method. In these 39 (70.9%) cases we were able to render a diagnosis with much more confidence.   Conclusion In our experience, difficulties in diagnosing SOL liver are attributed to differentiation of the tumor. Cell block preparation gives an additional advantage as architectural details can be studied that help to reach an accurate diagnosis in problematic and challenging cases. Thus, we strongly recommend the use of the cell block technique in conjunction with cytosmears for the purpose of diagnosis. PMID

  3. Feasibility study on expanded indication for endoscopic submucosal dissection of intramucosal poorly differentiated early gastric cancer

    PubMed Central

    Li, Hua; Huo, Zhi-Bin; Chen, Shu-Bo; Li, Hui; Wu, Dian-Chao; Zhai, Tong-Shan; Xiao, Qi-Hai; Wang, Shu-Xia; Zhang, Li-Li

    2016-01-01

    AIM: To identify clinicopathological factors predictive of lymph node metastasis (LNM) in intramucosal poorly differentiated early gastric cancer (EGC), and further to expand the possibility of using endoscopic submucosal dissection (ESD) for the treatment of intramucosal poorly differentiated EGC. METHODS: Data for 81 surgically treated patients with intramucosal poorly differentiated EGC were collected, and the association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Several clinicopathologic factors were investigated to identify predictive factors for lymph nodes metastasis, including gender, age, family history of gastric cancer, number of tumors, tumor location, ulceration, tumor size, macroscopic type, lymphatic vessel involvement, and signet-ring-cell component. RESULTS: Tumor size (OR = 7.273, 95%CI: 1.246-29.918, P = 0.042), lymphatic vessel involvement (OR = 42.219, 95%CI: 1.923-97.052, P = 0.018) and signet-ring-cell component (OR = 17.513, 95%CI: 1.647-77.469, P = 0.034) that were significantly associated with LNM by univariate analysis, were found to be significant and independent risk factors for LNM by multivariate analysis. However, gender, age, family history of gastric cancer, number, location, ulceration and macroscopic type of tumor were found not to be associated with LNM. Of these 81 patients diagnosed with intramucosal poorly differentiated EGC, 7 (8.6%) had LNM. The LNM rates were 9.1%, 22.2% and 57.1%, respectively, in cases with one, two and three of the risk factors. There was no LNM in 54 patients without the three risk clinicopathological factors. CONCLUSION: Tumor size, lymphatic vessel involvement and signet-ring-cell component are independently associated with the presence of LNM in intramucosal poorly differentiated EGC. Thus, these three risk factors may

  4. Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma

    PubMed Central

    Liu, Weisi; Liu, Yidong; Fu, Qiang; Zhou, Lin; Chang, Yuan; Xu, Le; Zhang, Weijuan; Xu, Jiejie

    2016-01-01

    IFN-inducible CXCR3 ligands (ICL), namely CXCL9, CXCL10 and CXCL11, exhibit pleiotropic roles in orchestrating immunity and angiogenesis. However, the prognosis value of them in renal cell carcinoma (RCC) was still obscure. Thus, we retrospectively used immunohistochemistry approach to evaluate the impact of these ligands on recurrence and survival of non-metastatic clear cell RCC (ccRCC) patients after nephrectomy. We systemically built a prespecified ICL score based on these ligands, and found specimens with high ICL score were prone to possess high Fuhrman grade, necrosis, and high-risk level of SSIGN. Moreover, ICL score stratified patients into different risk subgroups, and remained an independent adverse prognosticator for overall survival (OS) and recurrence-free survival (RFS). Meanwhile, in TCGA database, the increasing ICL mRNA predicted poor survival and early recurrence. Furthermore, after adding ICL score into SSIGN, the C-index for OS and RFS increased from 0.705 to 0.746 and 0.712 to 0.765, respectively. In conclusion, the ICL score based on expression of CXCL9, CXCL10 and CXCL11 stratified non-metastatic ccRCC patients into different risk subgroups of recurrence and death, which might benefit preoperative risk stratification and guide immune therapy in the future. PMID:26910919

  5. Elevated expression of IFN-inducible CXCR3 ligands predicts poor prognosis in patients with non-metastatic clear-cell renal cell carcinoma.

    PubMed

    Liu, Weisi; Liu, Yidong; Fu, Qiang; Zhou, Lin; Chang, Yuan; Xu, Le; Zhang, Weijuan; Xu, Jiejie

    2016-03-22

    IFN-inducible CXCR3 ligands (ICL), namely CXCL9, CXCL10 and CXCL11, exhibit pleiotropic roles in orchestrating immunity and angiogenesis. However, the prognosis value of them in renal cell carcinoma (RCC) was still obscure. Thus, we retrospectively used immunohistochemistry approach to evaluate the impact of these ligands on recurrence and survival of non-metastatic clear cell RCC (ccRCC) patients after nephrectomy. We systemically built a prespecified ICL score based on these ligands, and found specimens with high ICL score were prone to possess high Fuhrman grade, necrosis, and high-risk level of SSIGN. Moreover, ICL score stratified patients into different risk subgroups, and remained an independent adverse prognosticator for overall survival (OS) and recurrence-free survival (RFS). Meanwhile, in TCGA database, the increasing ICL mRNA predicted poor survival and early recurrence. Furthermore, after adding ICL score into SSIGN, the C-index for OS and RFS increased from 0.705 to 0.746 and 0.712 to 0.765, respectively. In conclusion, the ICL score based on expression of CXCL9, CXCL10 and CXCL11 stratified non-metastatic ccRCC patients into different risk subgroups of recurrence and death, which might benefit preoperative risk stratification and guide immune therapy in the future. PMID:26910919

  6. Progressive dysphagia in a dog caused by a scirrhous, poorly differentiated perioesophageal carcinoma.

    PubMed

    Wray, J D; Blunden, A S

    2006-01-01

    Investigation of canine dysphagia is performed by a combination of diagnostic imaging, direct visualisation of the upper gastrointestinal tract, and ancillary diagnostic testing to differentiate between structural and functional causes. Video fluoroscopy may be especially helpful. The case of a seven-year-old Border collie that presented with a history of progressive pharyngeal dysphagia is described. Fluoroscopic investigation was initially suggestive of functional pharyngeal disease, but magnetic resonance imaging and surgical exploration demonstrated the presence of a diffuse, scirrhous, poorly differentiated carcinoma with extensive oesophageal involvement. This case highlights that, in some circumstances, fluoroscopy may occasionally be of limited use in the investigation of dysphagia in the dog. PMID:16417607

  7. Molecular profiling of peripheral blood is associated with circulating tumor cells content and poor survival in metastatic castration-resistant prostate cancer.

    PubMed

    Marín-Aguilera, Mercedes; Reig, Òscar; Lozano, Juan José; Jiménez, Natalia; García-Recio, Susana; Erill, Nadina; Gaba, Lydia; Tagliapietra, Andrea; Ortega, Vanesa; Carrera, Gemma; Colomer, Anna; Gascón, Pedro; Mellado, Begoña

    2015-04-30

    The enumeration of circulating tumor cells (CTCs) in peripheral blood correlates with clinical outcome in castration-resistant prostate cancer (CRPC). We analyzed the molecular profiling of peripheral blood from 43 metastatic CRPC patients with known CTC content in order to identify genes that may be related to prostate cancer progression. Global gene expression analysis identified the differential expression of 282 genes between samples with ≥5 CTCs vs <5 CTCs, 58.6% of which were previously described as over-expressed in prostate cancer (18.9% in primary tumors and 56.1% in metastasis). Those genes were involved in survival functions such as metabolism, signal transduction, gene expression, cell growth, death, and movement. The expression of selected genes was evaluated by quantitative RT-PCR. This analysis revealed a two-gene model (SELENBP1 and MMP9) with a high significant prognostic ability (HR 6; 95% CI 2.61 - 13.79; P<0.0001). The combination of the two-gene signature plus the CTCs count showed a higher prognostic ability than CTCs enumeration or gene expression alone (P<0.05). This study shows a gene expression profile in PBMNC associated with CTCs count and clinical outcome in metastatic CRPC, describing genes and pathways potentially associated with CRPC progression. PMID:25871394

  8. Poorly Differentiated Neuroendocrine Tumor of the Esophagus with Hypertrophic Osteoarthropathy and Brain Metastasis: A Success Story.

    PubMed

    Saif, Muhammad W; Vethody, Chandra

    2016-01-01

    Neuroendocrine carcinomas (NECs) of the esophagus are very rare. The majority of the patients with NECs present with metastasis. Paraneoplastic syndromes, such as syndrome of inappropriate secretion of anti-diuretic hormone and watery diarrhea-hypokalemia-achlorhydria syndrome, have been reported in previous reports. Esophageal NECs are related to a poor prognosis. A 38-year-old male with the histologic diagnosis of esophageal NEC, which initially manifested as hypertrophic osteoarthropathy (HOA), later developed brain metastases. He was initially treated with neoadjuvant chemotherapy consisting of cisplatin and etoposide followed by a partial esophagectomy in November 2009. At follow-up in February 2010, he complained of a headache that prompted imaging. MRI of the brain revealed a left frontal lobe lesion. Subsequently, he underwent a craniotomy and resection of the lesion. Pathological analysis revealed that the lesion was consistent with metastatic disease from the primary esophageal NEC. The patient underwent 40 Gy whole brain radiotherapy (WBRT), followed by two weeks of stereotactic radiation (SRS) to the tumor bed for an additional 12 Gy. During this time, his tumor marker neuron-specific enolase (NSE) initially dropped but later increased, which led us to offer him radiotherapy to the remaining esophagus to be followed by localized radiation to areas immediately adjacent to the surgical site, followed by six cycles of systemic chemotherapy consisting of cisplatin and irinotecan. Finally, his NSE normalized around the end of systemic chemotherapy. Surveillance imaging in 2015 - six years from initial diagnosis - showed no evidence of cancer. Of interest, treatment of the esophageal NEC also led to clinical resolution of his musculoskeletal symptoms, including his HOA. High-grade esophageal NECs are rare, aggressive, and have a poor prognosis. HOA can be a presenting sign associated with a high-grade esophageal NEC. The predominant site of metastatic

  9. Poorly Differentiated Neuroendocrine Tumor of the Esophagus with Hypertrophic Osteoarthropathy and Brain Metastasis: A Success Story

    PubMed Central

    Vethody, Chandra

    2016-01-01

    Neuroendocrine carcinomas (NECs) of the esophagus are very rare. The majority of the patients with NECs present with metastasis. Paraneoplastic syndromes, such as syndrome of inappropriate secretion of anti-diuretic hormone and watery diarrhea-hypokalemia-achlorhydria syndrome, have been reported in previous reports. Esophageal NECs are related to a poor prognosis. A 38-year-old male with the histologic diagnosis of esophageal NEC, which initially manifested as hypertrophic osteoarthropathy (HOA), later developed brain metastases. He was initially treated with neoadjuvant chemotherapy consisting of cisplatin and etoposide followed by a partial esophagectomy in November 2009. At follow-up in February 2010, he complained of a headache that prompted imaging. MRI of the brain revealed a left frontal lobe lesion. Subsequently, he underwent a craniotomy and resection of the lesion. Pathological analysis revealed that the lesion was consistent with metastatic disease from the primary esophageal NEC. The patient underwent 40 Gy whole brain radiotherapy (WBRT), followed by two weeks of stereotactic radiation (SRS) to the tumor bed for an additional 12 Gy. During this time, his tumor marker neuron-specific enolase (NSE) initially dropped but later increased, which led us to offer him radiotherapy to the remaining esophagus to be followed by localized radiation to areas immediately adjacent to the surgical site, followed by six cycles of systemic chemotherapy consisting of cisplatin and irinotecan. Finally, his NSE normalized around the end of systemic chemotherapy. Surveillance imaging in 2015 - six years from initial diagnosis - showed no evidence of cancer. Of interest, treatment of the esophageal NEC also led to clinical resolution of his musculoskeletal symptoms, including his HOA. High-grade esophageal NECs are rare, aggressive, and have a poor prognosis. HOA can be a presenting sign associated with a high-grade esophageal NEC. The predominant site of metastatic

  10. Well-Differentiated Grade 2, Type 3 Gastrointestinal Neuroendocrine Tumour with Bilateral Metastatic Ovarian Involvement: Report of an Unusual Case

    PubMed Central

    Manneh, Ray; Castellano, Daniel; Caso, Oscar; Loinaz, Carmelo; Jiménez, Jesús; Estenoz, Juana; Calatayud, Maria; Sepúlveda, Juan M.; García-Carbonero, Rocio

    2016-01-01

    Treatment of metastatic gastric neuroendocrine tumours (NETs) is challenging. In oligometastatic cases, surgical resection is recommended whenever possible. Somatostatin analogues have been used to decrease gastrin levels, and available evidence suggests that these drugs can also reduce recurrences. Here we present a highly unusual case involving a patient with a well-differentiated grade 2, type 3 gastric NET with exclusive metastatic bilateral ovarian involvement. To our knowledge, this is the first such case reported in the literature, as the cause of ovarian involvement is usually due to local invasion rather than metastasis. We believe this case is of interest not only due to the unusual presentation, but also because it makes us consider adjuvant treatment with somatostatin analogues in patients with low-grade tumours and a positive postoperative octreoscan. PMID:27239181

  11. Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

    PubMed Central

    Strosberg, Jonathan R; Fisher, George A; Benson, Al B; Anthony, Lowell B; Arslan, Bulent; Gibbs, John F; Greeno, Edward; Iyer, Renuka V; Kim, Michelle K; Maples, William J; Philip, Philip A; Wolin, Edward M; Cherepanov, Dasha; Broder, Michael S

    2015-01-01

    AIM: To evaluate systemic treatment choices in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors (PNETs) and provide consensus treatment recommendations. METHODS: Systemic treatment options for pancreatic neuroendocrine tumors have expanded in recent years to include somatostatin analogs, angiogenesis inhibitors, inhibitors of mammalian target of rapamycin and cytotoxic agents. At this time, there is little data to guide treatment selection and sequence. We therefore assembled a panel of expert physicians to evaluate systemic treatment choices and provide consensus treatment recommendations. Treatment appropriateness ratings were collected using the RAND/UCLA modified Delphi process. After studying the literature, a multidisciplinary panel of 10 physicians assessed the appropriateness of various medical treatment scenarios on a 1-9 scale. Ratings were done both before and after an extended discussion of the evidence. Quantitative measurements of agreement were made and consensus statements developed from the second round ratings. RESULTS: Specialties represented were medical and surgical oncology, interventional radiology, and gastroenterology. Panelists had practiced for a mean of 15.5 years (range: 6-33). Among 202 rated scenarios, disagreement decreased from 13.2% (26 scenarios) before the face-to-face discussion of evidence to 1% (2) after. In the final ratings, 46.5% (94 scenarios) were rated inappropriate, 21.8% (44) were uncertain, and 30.7% (62) were appropriate. Consensus statements from the scenarios included: (1) it is appropriate to use somatostatin analogs as first line therapy in patients with hormonally functional tumors and may be appropriate in patients who are asymptomatic; (2) it is appropriate to use everolimus, sunitinib, or cytotoxic chemotherapy therapy as first line therapy in patients with symptomatic or progressive tumors; and (3) beyond first line, these same agents can be used. In patients with uncontrolled

  12. Tyrosine-kinase inhibitors to treat radioiodine-refracted, metastatic, or recurred and progressive differentiated thyroid carcinoma [Review].

    PubMed

    Ito, Yasuhiro; Suzuki, Shinichi; Ito, Ken-Ichi; Imai, Tsuneo; Okamoto, Takahiro; Kitano, Hiroya; Sugitani, Iwao; Sugino, Kiminori; Tsutsui, Hidemitsu; Hara, Hisato; Yoshida, Akira; Shimizu, Kazuo

    2016-07-30

    Differentiated thyroid carcinoma (DTC) is generally indolent in nature and, even though it metastasizes to distant organs, the prognosis is normally excellent. In contrast, the overall survival (OS) of patients with radioactive iodine (RAI)-refractory and progressive metastases is dire, because no effective therapies have been available to control the metastatic lesions. However, recently, administration of tyrosine-kinase inhibitors (TKIs) has become a new line of therapy for RAI-refractory and progressive metastases. Previous studies have reported significant improvement regarding the progression-free survival rates of patients with metastatic lesions. However, TKIs cause various severe adverse events (AEs) that damage patients' quality of life and can even be life-threatening. Additionally, metastatic lesions may progress significantly after stopping TKI therapy. Therefore, it is difficult to determine who is a candidate for TKI therapy, as well as how and when physicians start and stop the therapy. The present review, created by Committee of pharmacological therapy for thyroid cancer of the Japanese Society of Thyroid Surgery (JSTS) and the Japan Association of Endocrine Surgeons (JAES) describes how to appropriately use TKIs by describing what we do and do not know about treatment using TKIs. PMID:27210070

  13. Internalization of Vectored Liposomes in a Culture of Poorly Differentiated Tumor Cells.

    PubMed

    Mel'nikov, P A; Baklaushev, V P; Gabashvili, A N; Nukolova, N V; Levinsky, A B; Chehonin, V P

    2016-08-01

    Internalization of liposomal nanocontainers conjugated with monoclonal antibodies to VEGF, VEGFR2 (KDR), and proteins overproduced in the tumor tissue was studied in vitro on cultures of poorly differentiated tumor cells. Comparative analysis of accumulation of vectored liposomes in the tumor cells was performed by evaluating co-localization of labeled containers and cell organelles by laser scanning confocal microscopy. We observed nearly 2 times more active penetration and accumulation of liposomes vectored with antibodies in the tumor cells in comparison with non-vectored liposomes. Selective clathrin-dependent penetration of vectored liposomes into tumor cells was demonstrated by using pharmacological agents inhibiting endocytosis. PMID:27590766

  14. First high-precision differential abundance analysis of extremely metal-poor stars

    NASA Astrophysics Data System (ADS)

    Reggiani, Henrique; Meléndez, Jorge; Yong, David; Ramírez, Ivan; Asplund, Martin

    2016-02-01

    Context. Studies of extremely metal-poor stars indicate that chemical abundance ratios [X/Fe] have a root mean square scatter as low as 0.05 dex (12%). It remains unclear whether this reflects observational uncertainties or intrinsic astrophysical scatter arising from physical conditions in the interstellar medium at early times. Aims: We measure differential chemical abundance ratios in extremely metal-poor stars to investigate the limits of precision and to understand whether cosmic scatter or observational errors are dominant. Methods: We used high-resolution (R ~ 95 000) and high signal-to-noise (S/N = 700 at 5000 Å) HIRES/Keck spectra to determine high-precision differential abundances between two extremely metal-poor stars through a line-by-line differential approach. We determined stellar parameters for the star G64-37 with respect to the standard star G64-12. We performed EW measurements for the two stars for the lines recognized in both stars and performed spectral synthesis to study the carbon abundances. Results: The differential approach allowed us to obtain errors of σ(Teff) = 27 K, σ(log g) = 0.06 dex, σ( [Fe/H] ) = 0.02 dex and σ(vt) = 0.06 km s-1. We estimated relative chemical abundances with a precision as low as σ([X/Fe]) ≈ 0.01 dex. The small uncertainties demonstrate that there are genuine abundance differences larger than the measurement errors. The observed Li difference cannot be explained by the difference in mass because the less massive star has more Li. Conclusions: It is possible to achieve an abundance precision around ≈ 0.01-0.05 dex for extremely metal-poor stars, which opens new windows on the study of the early chemical evolution of the Galaxy. Table A.1 is also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/586/A67

  15. Enhanced reactive oxygen species overexpression by CuO nanoparticles in poorly differentiated hepatocellular carcinoma cells

    NASA Astrophysics Data System (ADS)

    Kung, Mei-Lang; Hsieh, Shu-Ling; Wu, Chih-Chung; Chu, Tian-Huei; Lin, Yu-Chun; Yeh, Bi-Wen; Hsieh, Shuchen

    2015-01-01

    Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively. Cellular fluorescence intensity using DCFH-DA staining analysis revealed significant intracellular reactive oxygen species (ROS) generation of up to 242% in SK-Hep-1 cells, compared with 86% in HepG2 cells. HPLC analysis demonstrated that a CuO NP treatment caused cellular GSH depletion of 58% and a GSH/GSSG ratio decrease to ~0.1 in SK-Hep-1 cells. The oxidative stress caused by enhanced superoxide anion production was observed in both HepG2 (146%) and SK-Hep-1 (192%) cells. The Griess assay verified that CuO NPs induced NO production (170%) in SK-Hep-1 cells. Comet assay and western blot further demonstrated that CuO NPs induced severe DNA strand breakage (70%) in SK-Hep-1 cells and caused DNA damage via increased γ-H2AX levels. These results suggest that well-differentiated HepG2 cells possess a robust antioxidant defense system against CuO NP-induced ROS stress and exhibit more tolerance to oxidative stress. Conversely, poorly differentiated SK-Hep-1 cells exhibited a deregulated antioxidant defense system that allowed accumulation of CuO NP-induced ROS and resulted in severe cytotoxicity.Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 μg ml-1 and 85 μg ml-1, respectively

  16. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics.

    PubMed Central

    Rüschoff, J.; Dietmaier, W.; Lüttges, J.; Seitz, G.; Bocker, T.; Zirngibl, H.; Schlegel, J.; Schackert, H. K.; Jauch, K. W.; Hofstaedter, F.

    1997-01-01

    Clinicopathological evidence has accumulated that colorectal adenocarcinoma with minimal or no glandular differentiation constitutes two entities with different prognosis. In a series of 20 predominantly nonglandular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatellite instability were analyzed and correlated to the biology of the tumors. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated by nested polymerase chain reaction. Histologically, 13 tumors showed small uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly an expansive growth pattern (69.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltrate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpart, solid or medullary carcinoma. These tumors showed less frequent lymph node as well as hematogeneous metastases than pleomorphic carcinomas. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.05) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0.05). No significant difference between the medullary and the pleomorphic tumor type was found with respect to bcl2 expression and the occurrence of Ki-ras mutations at codon 12. In contrast, microsatellite instability was almost totally restricted to poorly differentiated adenocarcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finally, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, which was, however, restricted to the peritumor lymphoid infiltrate as shown by in situ hybridization. Correlation with the biology of the tumors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months), which was the case in five of the seven patients with the pleomorphic-type carcinoma (P < 0.025). Our

  17. Maxilla Osteonecrosis: a differential diagnosis in patients with metastatic cancer on bisphosphonates

    PubMed Central

    Smith, Joshua; Birkeland, Andrew C.; McHugh, Jonathan B.; Spector, Matthew E.

    2016-01-01

    Bisphosphonate-induced osteonecrosis of the mandible and/or maxilla is an increasingly recognized, though still rare complication of bisphosphonate therapy. In the present case, the patient presented with a seven-month history of maxillary sinusitis and pain, and was originally diagnosed with a bony metastasis from her primary breast cancer. However, surgical excision and biopsy led to a diagnosis of bisphosphonate-induced osteonecrosis of the maxilla. As bisphosphonates are often prescribed for patients with metastatic disease, it is important to recognize that bisphosphonate-induced osteonecrosis may present similarly to bony metastases. PMID:27347432

  18. Poorly differentiated salivary gland carcinoma with prominent squamous metaplasia in a pregnant Wistar Hannover rat.

    PubMed

    Shimada, Yuko; Yoshida, Toshinori; Takahashi, Naofumi; Akema, Satoshi; Soma, Katsumi; Ohnuma-Koyama, Aya; Sato, Akira; Kuwahara, Maki; Harada, Takanori

    2016-06-01

    A subcutaneous pale brown-colored mass was observed macroscopically in the ventral neck of a 16-week-old Wistar rat on day 18 of gestation. The mass was well demarcated from the adjacent tissues with partial invasion into connective tissues. Necrosis and hemorrhage were evident throughout the mass. The mass comprised a diffuse sheet and a nest-like structure of epithelial cells with prominent squamous metaplasia. The neoplastic cells tested immunopositive for keratin, vimentin, glial fibrillary acidic protein and p63. A portion of the neoplastic cells exhibited a similar immunoreaction of prominin-1 to the ductal and acinar cells in normal submandibular and parotid glands. Collectively, the tumor was diagnosed as a poorly differentiated carcinoma derived from epithelial/myoepithelial lineages in the submandibular and/or parotid glands. PMID:26782134

  19. Poorly differentiated salivary gland carcinoma with prominent squamous metaplasia in a pregnant Wistar Hannover rat

    PubMed Central

    SHIMADA, Yuko; YOSHIDA, Toshinori; TAKAHASHI, Naofumi; AKEMA, Satoshi; SOMA, Katsumi; OHNUMA-KOYAMA, Aya; SATO, Akira; KUWAHARA, Maki; HARADA, Takanori

    2016-01-01

    A subcutaneous pale brown-colored mass was observed macroscopically in the ventral neck of a 16-week-old Wistar rat on day 18 of gestation. The mass was well demarcated from the adjacent tissues with partial invasion into connective tissues. Necrosis and hemorrhage were evident throughout the mass. The mass comprised a diffuse sheet and a nest-like structure of epithelial cells with prominent squamous metaplasia. The neoplastic cells tested immunopositive for keratin, vimentin, glial fibrillary acidic protein and p63. A portion of the neoplastic cells exhibited a similar immunoreaction of prominin-1 to the ductal and acinar cells in normal submandibular and parotid glands. Collectively, the tumor was diagnosed as a poorly differentiated carcinoma derived from epithelial/myoepithelial lineages in the submandibular and/or parotid glands. PMID:26782134

  20. Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): Novel gene therapeutic for metastatic melanoma

    SciTech Connect

    Fisher, Paul B. Sarkar, Devanand; Lebedeva, Irina V.; Emdad, Luni; Gupta, Pankaj; Sauane, Moira; Su Zaozhong; Grant, Steven; Dent, Paul; Curiel, David T.; Senzer, Neil; Nemunaitis, John

    2007-11-01

    A potentially less toxic approach for cancer therapy comprises induction of tumor cells to lose growth potential irreversibly and terminally differentiate. Combining this scheme termed 'differentiation therapy of cancer' with subtraction hybridization to human melanoma cells resulted in the cloning of melanoma differentiation associated (mda) genes displaying elevated expression as a consequence of induction of terminal differentiation. One originally novel gene, mda-7, was found to display elevated expression in normal melanocytes and nevi with progressive loss of expression as a consequence of melanoma development and progression to metastasis. Based on structure, biochemical properties and chromosomal location, mda-7 has now been reclassified as interleukin (IL)-24, a member of the expanding IL-10 family of cytokines. In vitro cell culture and in vivo animal studies indicate that mda-7/IL-24 selectively induces programmed cell death (apoptosis) in multiple human cancers (including melanomas), without harming normal cells, and promotes profound anti-tumor activity in nude mice containing human tumor xenografts. Based on these remarkable properties, a Phase I clinical trial was conducted to test the safety of administration of mda-7/IL-24 by a replication incompetent adenovirus (Ad.mda-7; INGN 241) in patients with advanced solid cancers including melanoma. mda-7/IL-24 was found to be safe and to promote significant clinical activity, particularly in the context of patients with metastatic melanoma. These results provide an impetus for further clinical studies and document a central paradigm of cancer therapy, namely translation of basic science from the 'bench to the bedside.'.

  1. Phospholipid hydroperoxide glutathione peroxidase (PHGPx) expression is downregulated in poorly differentiated breast invasive ductal carcinoma.

    PubMed

    Cejas, P; García-Cabezas, M A; Casado, E; Belda-Iniesta, C; De Castro, J; Fresno, J A; Sereno, M; Barriuso, J; Espinosa, E; Zamora, P; Feliu, J; Redondo, A; Hardisson, D A; Renart, J; González-Barón, M

    2007-06-01

    Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPx) is the only known enzyme able to reduce lipid peroxides bound to cell membranes. Moreover it has been involved in apoptosis and can influence intracellular signaling. To investigate the possible relationship between PHGPx and human cancer we have quantified PHGPx expression levels by real-time quantitative PCR and immunohistochemistry in tissue samples of human breast invasive ductal carcinoma from 34 patients compared with their own controls of benign breast tissue. PHGPx expression levels were compared with the clinical and pathological data of these patients. The results showed that PHGPx expression levels are downregulated in poorly differentiated (grade 3) breast invasive ductal carcinoma (P = 0.0043). PHGPx expression levels decreased gradually with tumor grade from grade 1 to grade 3. We also found a downregulation of PHGPx in cases that showed p53 accumulation compared with cases without p53 immunostaining (P = 0.0011). PHGPx was also downregulated in cases without progesterone receptors (PR) immunostaining compared with cases with PR immunostaining (P = 0.0165). Grade 3, p53 immunostaining and absence of PR immunostaining are poor prognostic factors. These results suggest that PHGPx downregulation could be related with a poorer prognosis in breast invasive ductal carcinoma. PMID:17516241

  2. A DIFFERENTIAL CHEMICAL ELEMENT ANALYSIS OF THE METAL-POOR GLOBULAR CLUSTER NGC 6397

    SciTech Connect

    Koch, Andreas; McWilliam, Andrew E-mail: andy@obs.carnegiescience.edu

    2011-08-15

    We present chemical abundances in three red giants and two turnoff (TO) stars in the metal-poor Galactic globular cluster (GC) NGC 6397 based on spectroscopy obtained with the Magellan Inamori Kyocera Echelle high-resolution spectrograph on the Magellan 6.5 m Clay telescope. Our results are based on a line-by-line differential abundance analysis relative to the well-studied red giant Arcturus and the Galactic halo field star Hip 66815. At a mean of -2.10 {+-} 0.02 (stat.) {+-}0.07 (sys.), the differential iron abundance is in good agreement with other studies in the literature based on gf-values. As in previous differential works we find a distinct departure from ionization equilibrium in that the abundances of Fe I and Fe II differ by {approx}0.1 dex, with opposite signs for the red giant branch (RGB) and TO stars. The {alpha}-element ratios are enhanced to 0.4 (RGB) and 0.3 dex (TO), respectively, and we also confirm strong variations in the O, Na, and Al/Fe abundance ratios. Accordingly, the light-element abundance patterns in one of the red giants can be attributed to pollution by an early generation of massive Type II supernovae. TO and RGB abundances are not significantly different, with the possible exception of Mg and Ti, which are, however, amplified by the patterns in one TO star additionally belonging to this early generation of GC stars. We discuss interrelations of these light elements as a function of the GC metallicity.

  3. ACR appropriateness criteria on metastatic bone disease.

    PubMed

    Roberts, Catherine C; Daffner, Richard H; Weissman, Barbara N; Bancroft, Laura; Bennett, D Lee; Blebea, Judy S; Bruno, Michael A; Fries, Ian Blair; Germano, Isabelle M; Holly, Langston; Jacobson, Jon A; Luchs, Jonathan S; Morrison, William B; Olson, Jeffrey J; Payne, William K; Resnik, Charles S; Schweitzer, Mark E; Seeger, Leanne L; Taljanovic, Mihra; Wise, James N; Lutz, Stephen T

    2010-06-01

    Appropriate imaging modalities for screening, staging, and surveillance of patients with suspected and documented metastatic disease to bone include (99m)Tc bone scanning, MRI, CT, radiography, and 2-[(18)F]fluoro-2-deoxyglucose-PET. Clinical scenarios reviewed include asymptomatic stage 1 breast carcinoma, symptomatic stage 2 breast carcinoma, abnormal bone scan results with breast carcinoma, pathologic fracture with known metastatic breast carcinoma, asymptomatic well-differentiated and poorly differentiated prostate carcinoma, vertebral fracture with history of malignancy, non-small-cell lung carcinoma staging, symptomatic multiple myeloma, osteosarcoma staging and surveillance, and suspected bone metastasis in a pregnant patient. No single imaging modality is consistently best for the assessment of metastatic bone disease across all tumor types and clinical situations. In some cases, no imaging is indicated. The recommendations contained herein are the result of evidence-based consensus by the ACR Appropriateness Criteria((R)) Expert Panel on Musculoskeletal Radiology. PMID:20522392

  4. Differential Diagnosis of Axillary Inflammatory and Metastatic Lymph Nodes in Rabbit Models by Using Diffusion-Weighted Imaging: Compared with Conventional Magnetic Resonance Imaging

    PubMed Central

    Liao, Qian; Zhang, Yunting; Yu, Chunshui; Bai, Renju; Sun, Haoran

    2012-01-01

    Objective This experiment aims to determine the diagnostic value of diffusion-weighted imaging (DWI) in the differentiation of axillary inflammatory lymph nodes from metastatic lymph nodes in rabbit models in comparison with conventional magnetic resonance imaging (MRI). Materials and Methods Conventional MRI and DWI were performed at 4 weeks after successful inoculation into the forty female New Zealand white rabbits' mammary glands. The size-based and signal-intensity-based criteria and the relative apparent diffusion coefficient (rADC) value were compared between the axillary inflammatory lymph nodes and metastatic lymph nodes, with histopathological findings as the reference standard. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of the aforementioned criteria and rADC value in differentiating the axillary inflammatory lymph nodes from metastatic lymph nodes. Results Thirty-two axillary inflammatory lymph nodes and 46 metastatic ones were successfully isolated and taken into pathological analysis. The differences of the aforementioned criteria between the two groups were not statistically significant (p > 0.05). However, the rADC value of the inflammatory lymph nodes (0.9 ± 0.14) was higher than that of metastatic ones (0.7 ± 0.18), with significant difference (p = 0.016). When the rADC value was chosen as 0.80, the area under the ROC curve is greater than all other criteria, and the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiating two groups were 86.2%, 79.3%, 81.2%, 84.2%, and 85.6%, respectively. Conclusion Diffusion-weighted imaging is a promising new technique for differentiating axillary inflammatory lymph nodes from metastatic lymph nodes. Compared with routine magnetic resonance sequences, DWI could provide more useful physiological and functional information for diagnosis. PMID:22778568

  5. 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

  6. Distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma using precontrast and gadoxetic acid-enhanced MRI

    PubMed Central

    Asayama, Yoshiki; Nishie, Akihiro; Ishigami, Kousei; Ushijima, Yasuhiro; Takayama, Yukihisa; Fujita, Nobuhiro; Kubo, Yuichiro; Aishima, Shinichi; Shirabe, Ken; Yoshiura, Takashi; Honda, Hiroshi

    2015-01-01

    PURPOSE We aimed to gain further insight in magnetic resonance imaging characteristics of mass-forming intrahepatic cholangiocarcinoma (mICC), its enhancement pattern with gadoxetic acid contrast agent, and distinction from poorly differentiated hepatocellular carcinoma (pHCC). METHODS Fourteen mICC and 22 pHCC nodules were included in this study. Two observers recorded the tumor shape, intratumoral hemorrhage, fat on chemical shift imaging, signal intensity at the center of the tumor on T2-weighted image, fibrous capsule, enhancement pattern on arterial phase of dynamic study, late enhancement three minutes after contrast injection (dynamic late phase), contrast uptake on hepatobiliary phase, apparent diffusion coefficient, vascular invasion, and intrahepatic metastasis. RESULTS Late enhancement was more common in mICC (n=10, 71%) than in pHCC (n=3, 14%) (P < 0.001). A fat component was observed in 11 pHCC cases (50%) versus none of mICC cases (P = 0.002). Fibrous capsule was observed in 13 pHCC cases (59%) versus none of mICC cases (P < 0.001). On T2-weighted images a hypointense area was seen at the center of the tumor in 43% of mICC (6/14) and 9% of pHCC (2/22) cases (P = 0.018). Other parameters were not significantly different between the two types of nodules. CONCLUSION The absence of fat and fibrous capsule, and presence of enhancement at three minutes appear to be most characteristic for mICC and may help its differentiation from pHCC. PMID:25698097

  7. Bradymyces gen. nov. (Chaetothyriales, Trichomeriaceae), a new ascomycete genus accommodating poorly differentiated melanized fungi.

    PubMed

    Hubka, Vit; Réblová, Martina; Rehulka, Jiří; Selbmann, Laura; Isola, Daniela; de Hoog, Sybren G; Kolařík, Miroslav

    2014-11-01

    Three slow growing, melanized and morphologically poorly differentiated fungal strains were isolated from a hyperaemic focus near the enlarged spleen of a farmed rainbow trout (Oncorhynchus mykiss) and from a rock collected at 3,200 m a. s. l. (Alps, Italy). Two phylogenetic analyses of the combined nuc18S and nuc28S rDNA and ITS rDNA and β-tubulin sequences showed that these isolates belong to the Trichomeriaceae, a family of the ascomycete order Chaetothyriales containing black yeasts that cause infections in humans and animals. The strains form a well-supported monophyletic clade. The new genus Bradymyces, with two new species, Bradymyces oncorhynchi and Bradymyces alpinus, is proposed based on phylogenetic, ecophysiological and morphological data. It is characterized by the presence of moniliform hyphae, blastic proliferation, endoconidia, multicellular and muriform bodies, and bodies with dark fragmented incrustations on the surface. Bradymyces most closely resembles members of Knufia. The ex-type isolate of B. oncorhynchi CCF 4369(T) ( = CBS 133066(T) = CCFEE 6134(T)) represents the first case of a Trichomeriaceae member isolated from cold-blooded water vertebrates. B. alpinus [ex-type strain CCFEE 5493(T) ( = CBS 138368(T) = CCF 4803(T))] is represented by two isolates from a single locality in the Alps and in contrast to B. oncorhynchi shows overall slower growth parameters and does not grow at 25 °C. PMID:25164483

  8. Sorafenib: a review of its use in patients with radioactive iodine-refractory, metastatic differentiated thyroid carcinoma.

    PubMed

    Blair, Hannah A; Plosker, Greg L

    2015-03-01

    Sorafenib (Nexavar®) is the first tyrosine kinase inhibitor to be approved for the treatment of radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). In the pivotal phase III DECISION trial in patients with RAI-refractory, locally advanced or metastatic DTC, oral sorafenib 400 mg twice daily significantly prolonged median progression-free survival (PFS) relative to placebo. The PFS benefit of sorafenib over placebo was evident in all pre-specified clinical and genetic biomarker subgroups, and neither BRAF nor RAS mutation status was predictive of sorafenib benefit for PFS. The objective response rate was significantly higher in patients receiving sorafenib than in those receiving placebo; all objective responses were partial responses. The overall survival benefit of sorafenib is as yet unclear, with no significant benefit observed at the time of primary analysis or at 9 months following the primary analysis. Overall survival was possibly confounded by the crossover of patients in the placebo group to sorafenib upon disease progression. The adverse events associated with sorafenib in the DECISION trial were consistent with the known tolerability profile of the drug, with hand-foot skin reaction, diarrhea, and alopecia reported most commonly. Most treatment-emergent adverse events were grade 1 or 2 in severity and occurred early in treatment. However, a high proportion of patients discontinued sorafenib therapy or required dose reductions or interruptions because of toxicity. Although final overall survival data are awaited, current evidence suggests that sorafenib is a promising new treatment option for patients with RAI-refractory, metastatic DTC. PMID:25742918

  9. An in vitro correlation of mechanical forces and metastatic capacity

    PubMed Central

    Indra, Indrajyoti; Undyala, Vishnu; Kandow, Casey; Thirumurthi, Umadevi; Dembo, Micah; Beningo, Karen A

    2013-01-01

    Mechanical forces have a major influence on cell migration and are predicted to significantly impact cancer metastasis, yet this idea is currently poorly defined. In this study we have asked if changes in traction stress and migratory properties correlate with the metastatic progression of tumor cells. For this purpose, four murine breast cancer cell lines derived from the same primary tumor, but possessing increasing metastatic capacity, were tested for adhesion strength, traction stress, focal adhesion organization and for differential migration rates in two-dimensional and three-dimensional environments. Using traction force microscopy (TFM), we were surprised to find an inverse relationship between traction stress and metastatic capacity, such that force production decreased as the metastatic capacity increased. Consistent with this observation, adhesion strength exhibited an identical profile to the traction data. A count of adhesions indicated a general reduction in the number as metastatic capacity increased but no difference in the maturation as determined by the ratio of nascent to mature adhesions. These changes correlated well with a reduction in active beta-1 integrin with increasing metastatic ability. Finally, in two dimensions, wound healing, migration and persistence were relatively low in the entire panel, maintaining a downward trend with increasing metastatic capacity. Why metastatic cells would migrate so poorly prompted us to ask if the loss of adhesive parameters in the most metastatic cells indicated a switch to a less adhesive mode of migration that would only be detected in a three-dimensional environment. Indeed, in three-dimensional migration assays, the most metastatic cells now showed the greatest linear speed. We conclude that traction stress, adhesion strength and rate of migration do indeed change as tumor cells progress in metastatic capacity and do so in a dimension-sensitive manner. PMID:21301068

  10. An in vitro correlation of mechanical forces and metastatic capacity

    NASA Astrophysics Data System (ADS)

    Indra, Indrajyoti; Undyala, Vishnu; Kandow, Casey; Thirumurthi, Umadevi; Dembo, Micah; Beningo, Karen A.

    2011-02-01

    Mechanical forces have a major influence on cell migration and are predicted to significantly impact cancer metastasis, yet this idea is currently poorly defined. In this study we have asked if changes in traction stress and migratory properties correlate with the metastatic progression of tumor cells. For this purpose, four murine breast cancer cell lines derived from the same primary tumor, but possessing increasing metastatic capacity, were tested for adhesion strength, traction stress, focal adhesion organization and for differential migration rates in two-dimensional and three-dimensional environments. Using traction force microscopy (TFM), we were surprised to find an inverse relationship between traction stress and metastatic capacity, such that force production decreased as the metastatic capacity increased. Consistent with this observation, adhesion strength exhibited an identical profile to the traction data. A count of adhesions indicated a general reduction in the number as metastatic capacity increased but no difference in the maturation as determined by the ratio of nascent to mature adhesions. These changes correlated well with a reduction in active beta-1 integrin with increasing metastatic ability. Finally, in two dimensions, wound healing, migration and persistence were relatively low in the entire panel, maintaining a downward trend with increasing metastatic capacity. Why metastatic cells would migrate so poorly prompted us to ask if the loss of adhesive parameters in the most metastatic cells indicated a switch to a less adhesive mode of migration that would only be detected in a three-dimensional environment. Indeed, in three-dimensional migration assays, the most metastatic cells now showed the greatest linear speed. We conclude that traction stress, adhesion strength and rate of migration do indeed change as tumor cells progress in metastatic capacity and do so in a dimension-sensitive manner.

  11. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

    PubMed Central

    Ibrahimpasic, Tihana; Boucai, Laura; Shah, Ronak H.; Dogan, Snjezana; Ricarte-Filho, Julio C.; Krishnamoorthy, Gnana P.; Schultz, Nikolaus; Berger, Michael F.; Sander, Chris; Taylor, Barry S.; Ghossein, Ronald; Ganly, Ian; Fagin, James A.

    2016-01-01

    BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS. Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation. CONCLUSIONS. These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality. FUNDING. This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family

  12. Comparison of Clinical and Ultrasonographic Features of Poorly Differentiated Thyroid Carcinoma and Papillary Thyroid Carcinoma

    PubMed Central

    Zhang, Bo; Niu, Hui-Min; Wu, Qiong; Zhou, Jiong; Jiang, Yu-Xin; Yang, Xiao; Li, Jian-Chu; Zhao, Rui-Na; Wang, Ming; Li, Kang-Ning; Zhu, Shen-Ling; Xia, Yu; Zhong, Ding-Rong

    2016-01-01

    Background: The clinical behavior and management of poorly differentiated thyroid carcinoma (PDTC) are very different from papillary thyroid carcinoma (PTC). By comparing the clinical and ultrasonographic features between the two tumors, we proposed to provide more possibilities for recognizing PDTC before treatment. Methods: The data of 13 PDTCs and 39 age- and gender-matched PTCs in Peking Union Medical College Hospital between December 2003 and September 2013 were retrospectively reviewed. The clinical and ultrasonic features between the two groups were compared. Results: The frequencies of family history of carcinoma, complication with other thyroid lesions, lymph node metastases, recurrent laryngeal nerve injuries, and distant metastases were higher in PDTCs (30.8%, 61.6%, 69.2%, 23.1%, and 46.2%, respectively) than those in PTCs (2.6%, 23.1%, 25.6%, 2.6%, and 2.6%, respectively) (P < 0.05). The mortality rate of PDTCs was greatly higher than PTCs (P < 0.01). Conventional ultrasound showed that the size of PDTCs was larger than that of PTCs (3.1 ± 1.9 cm vs. 1.7 ± 1.0 cm). Clear margins and rich and/or irregular blood flow were found in 92.3% of PDTCs, which differed substantially from PTCs (51.7% and 53.8%, respectively) (P < 0.05). Conclusions: PDTC is more aggressive and its mortality rate is higher than PTCs. Accordingly, more attention should be given to suspicious thyroid cancer nodules that show large size, regular shape, and rich blood flow signals on ultrasound to exclude the possibility of PDTCs. PMID:26830987

  13. Sorafenib in locally advanced or metastatic, radioactive iodine-refractory, differentiated thyroid cancer: a randomized, double-blind, phase 3 trial

    PubMed Central

    Brose, Marcia S; Nutting, Christopher M; Jarzab, Barbara; Elisei, Rossella; Siena, Salvatore; Bastholt, Lars; de la Fouchardiere, Christelle; Pacini, Furio; Paschke, Ralf; KeeShong, Young; Sherman, Steven I; Smit, Johannes WA; Chung, John; Kappeler, Christian; Pena, Carol; Molnár, István; Schlumberger, Martin J

    2015-01-01

    Background Patients with radioactive iodine (131I, RAI)-refractory locally advanced or metastatic differentiated thyroid cancer (DTC) have a poor prognosis due to the lack of effective treatment options. Methods This multicentre, randomized (1:1), double-blind, placebo-controlled, phase 3 study (DECISION; NCT00984282) investigated sorafenib (400 mg orally twice-daily) in patients with RAI-refractory locally advanced or metastatic DTC progressing within the past 14 months. The primary endpoint was progression-free survival (PFS) by central independent review. Patients receiving placebo could crossover to open-label sorafenib upon progression. Archival tumour tissue was examined for BRAF and RAS mutations. Serum thyroglobulin was measured at baseline and each visit. Findings A total of 417 patients were randomized to sorafenib (n=207) or placebo (n=210). Sorafenib treatment significantly improved PFS compared with placebo (hazard ratio, 0·59; 95% confidence interval, 0·45–0·76; P<0·0001; median 10·8 vs. 5·8 months, respectively). PFS improvement was seen in all pre-specified clinical and genetic biomarker subgroups irrespective of mutation status. There was no statistically significant difference in overall survival (hazard ratio, 0·80; 95% confidence interval, 0·54–1·19; P=0·14); median overall survival had not been reached and 150 (71%) patients receiving placebo crossed over to sorafenib upon progression. Response rates (all partial responses) were 12·2% (24/196; sorafenib) and 0·5% (1/201; placebo; p<0·0001). Median thyroglobulin levels increased in the placebo group, and decreased, then paralleled treatment responses in the sorafenib group. Most adverse events were grade 1 or 2. The most common treatment-emergent adverse events in the sorafenib arm were hand–foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash/desquamation (50·2%). Interpretation Sorafenib significantly improved PFS compared with placebo in patients

  14. Multidetector CT Findings and Differential Diagnoses of Malignant Pleural Mesothelioma and Metastatic Pleural Diseases in Korea

    PubMed Central

    Kim, Yoon Kyung; Lee, Kyung Won; Yi, Chin A; Koo, Jin Mo; Jung, Soon-Hee

    2016-01-01

    Objective To compare the multidetector CT (MDCT) features of malignant pleural mesothelioma (MPM) and metastatic pleural disease (MPD). Materials and Methods The authors reviewed the MDCT images of 167 patients, 103 patients with MPM and 64 patients with MPD. All 167 cases were pathologically confirmed by sonography-guided needle biopsy of pleura, thoracoscopic pleural biopsy, or open thoracotomy. CT features were evaluated with respect to pleural effusion, pleural thickening, invasion of other organs, lung abnormality, lymphadenopathy, mediastinal shifting, thoracic volume decrease, asbestosis, and the presence of pleural plaque. Results Pleural thickening was the most common CT finding in MPM (96.1%) and MPD (93.8%). Circumferential pleural thickening (31.1% vs. 10.9%, odds ratio [OR] 3.670), thickening of fissural pleura (83.5% vs. 67.2%, OR 2.471), thickening of diaphragmatic pleura (90.3% vs. 73.4%, OR 3.364), pleural mass (38.8% vs. 23.4%, OR 2.074), pericardial involvement (56.3% vs. 20.3%, OR 5.056), and pleural plaque (66.0% vs. 21.9%, OR 6.939) were more frequently seen in MPM than in MPD. On the other hand, nodular pleural thickening (59.2% vs. 76.6%, OR 0.445), hilar lymph node metastasis (5.8% vs. 20.3%, OR 0.243), mediastinal lymph node metastasis (10.7% vs. 37.5%, OR 0.199), and hematogenous lung metastasis (9.7% vs. 29.2%, OR 0.261) were less frequent in MPM than in MPD. When we analyzed MPD from extrathoracic malignancy (EMPD) separately and compared them to MPM, circumferential pleural thickening, thickening of interlobar fissure, pericardial involvement and presence of pleural plaque were significant findings indicating MPM than EMPD. MPM had significantly lower occurrence of hematogenous lung metastasis, as compared with EMPD. Conclusion Awareness of frequent and infrequent CT findings could aid in distinguishing MPM from MPD. PMID:27390546

  15. The Differential Contributions of Auditory-Verbal and Visuospatial Working Memory on Decoding Skills in Children Who Are Poor Decoders

    ERIC Educational Resources Information Center

    Squires, Katie Ellen

    2013-01-01

    This study investigated the differential contribution of auditory-verbal and visuospatial working memory (WM) on decoding skills in second- and fifth-grade children identified with poor decoding. Thirty-two second-grade students and 22 fifth-grade students completed measures that assessed simple and complex auditory-verbal and visuospatial memory,…

  16. Resolution of Hepatic Encephalopathy Following Hepatic Artery Embolization in a Patient with Well-Differentiated Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Erinjeri, Joseph P. Deodhar, Ajita; Thornton, Raymond H.; Allen, Peter J.; Getrajdman, George I.; Brown, Karen T.; Sofocleous, Constantinos T.; Reidy, Diane L.

    2010-06-15

    Hepatic encephalopathy is considered a contraindication to hepatic artery embolization. We describe a patient with a well-differentiated neuroendocrine tumor metastatic to the liver with refractory hepatic encephalopathy and normal liver function tests. The encephalopathy was refractory to standard medical therapy with lactulose. The patient's mental status returned to baseline after three hepatic artery embolization procedures. Arteriography and ultrasound imaging before and after embolization suggest that the encephalopathy was due to arterioportal shunting causing hepatofugal portal venous flow and portosystemic shunting. In patients with a primary or metastatic well-differentiated neuroendocrine tumor whose refractory hepatic encephalopathy is due to portosystemic shunting (rather than global hepatic dysfunction secondary to tumor burden), hepatic artery embolization can be performed safely and effectively.

  17. The value of SATB2 in the differential diagnosis of intestinal-type mucinous tumors of the ovary: primary vs metastatic.

    PubMed

    Perez Montiel, Delia; Arispe Angulo, Karen; Cantú-de León, David; Bornstein Quevedo, Leticia; Chanona Vilchis, José; Herrera Montalvo, Luis

    2015-08-01

    Primary mucinous adenocarcinomas of the ovary are a diagnostic challenge because their histologic and immunohistochemical features usually overlap with metastatic tumors. SATB2 is a recently identified protein with restricted expression in the glandular cells lining the lower gastrointestinal tract. The aim of this study is to examine the differential expression of SATB2 in primary and metastatic tumors of the ovary. Mucinous ovarian tumors of intestinal type were retrieved from the pathology files of the Instituto Nacional de Cancerología de México. A double reading of the hematoxylin and eosin-stained slides was performed to confirm the diagnosis, and a detailed review of the clinical chart was performed to define the primary origin of the tumor (ovarian vs metastatic). Immunohistochemical staining for CK20, CDX2, and SATB2 was performed and evaluated by 2 gynecopathologists. A total of 106 mucinous tumors were identified, 26 of which were considered to be metastatic, and 80 of which were primary ovarian tumors. All of the primary tumors that were not associated with cystic teratomas were negative for SATB2, and the 4 that were associated with a teratoma were positive for SATB2. All 20 of the metastatic tumors of the colon and appendix were positive for CK20, and 4 were positive for CK7. In addition, all 20 of these tumors were positive for SATB2, and 19 were positive for CDX2. SATB2 appears to be a useful marker for the diagnosis of primary vs metastatic mucinous intestinal-type neoplasms and is highly sensitive in detecting lower gastrointestinal tract metastasis. PMID:26059401

  18. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study

    PubMed Central

    Bible, Keith C; Suman, Vera J; Molina, Julian R; Smallridge, Robert C; Maples, William J; Menefee, Michael E; Rubin, Joseph; Sideras, Kostandinos; Morris, John C; McIver, Bryan; Burton, Jill K; Webster, Kevin P; Bieber, Carolyn; Traynor, Anne M; Flynn, Patrick J; Goh, Boon Cher; Tang, Hui; Ivy, Susan Percy; Erlichman, Charles

    2011-01-01

    Summary Background Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. Methods This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. Findings 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders

  19. 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. PMID:26427663

  20. Development of poorly differentiated invasive squamous cell carcinoma in giant Bowen’s disease: a case report with dermatoscopy

    PubMed Central

    Akay, Bengu Nisa; Maden, Aysenur; Kocak, Oguzhan; Bostanci, Seher; Boyvat, Ayşe; Kocyigit, Pelin; Heper, Aylin Okcu

    2016-01-01

    Bowen’s disease (BD) is an in situ form of squamous cell carcinoma (SCC), often occurring in the chronically UV-damaged skin of elderly people. The risk of progression of BD to invasive SCC varies between 3% and 5%, and one-third of invasive tumors may metastasize. Herein we discuss the dermatoscopic findings of a case of giant Bowen’s disease, which progressed to poorly differentiated invasive SCC. PMID:27222765

  1. The Differentiation of Giant Right Atrial Myxoma from Metastatic Cancer with the Use of Multiple Imaging Modalities.

    PubMed

    Nakabayashi, Keisuke; Murata, Satoru; Kato, Hiroko; Oka, Toshiaki

    2016-01-01

    Whether a cardiac tumor is primary or metastatic strongly influences the therapeutic strategy. We herein present a case of a cardiac tumor that occupied most of the right atrium which required immediate treatment in a patient with breast cancer. Multiple imaging modalities, especially computed tomography and cardiac magnetic resonance imaging, provided a precise preoperative diagnosis. We performed cardiac surgery prior to breast cancer surgery because the cardiac tumor was thought to be a myxoma rather than a metastatic cancer. PMID:27086806

  2. Yes associated protein is a poor prognostic factor in well-differentiated lung adenocarcinoma

    PubMed Central

    Kim, Mi Hyun; Kim, Young Keum; Shin, Dong Hoon; Lee, Hyun Jeong; Shin, Nari; Kim, Arong; Lee, Jung Hee; Choi, Kyung Un; Kim, Jee Yeon; Lee, Chang Hun; Sol, Mee Young

    2015-01-01

    The Hippo pathway is a highly conserved potent regulator of cell growth and apoptosis including large tumor suppressor (LATS) and Yes-associated protein (YAP). LATS has been regarded as a tumor suppressor gene and YAP as either of a tumor suppressor gene or an oncogene. We investigated their expression in lung adenocarcinoma. YAP and LATS protein expression was assessed in 167 surgically resected lung adenocarcinomas and compared with clinicopathologic factors. Disease free survival and overall survival were also evaluated. YAP expression was noted in cytoplasm (48 cases; 28.7%), nuclear (34; 20.4%) and both locations (4; 2.4%). The nuclear expression was typically observed in well differentiated adenocarcinoma. LATS was expressed in cytoplasm when its signal is weak. Perinuclear expression of LATS was observed when it is strongly expressed. While cytoplasmic and nuclear YAP expressions were inversely related. In well differentiated adenocarcinoma patients, YAP nuclear expression was related with more frequent relapse. Both of nuclear YAP and LATS expression were more frequently observed in well differentiated adenocarcinoma. Furthermore, YAP expression exhibited more frequent relapse in well differentiated adenocarcinoma group. We suggest that YAP may act as an oncogene and predict poorer prognosis in well differentiated lung adenocarcinoma. PMID:26884866

  3. Microtubule-Associated Protein 2, a Marker of Neuronal Differentiation, Induces Mitotic Defects, Inhibits Growth of Melanoma Cells, and Predicts Metastatic Potential of Cutaneous Melanoma

    PubMed Central

    Soltani, Mohammad H.; Pichardo, Rita; Song, Ziqui; Sangha, Namrata; Camacho, Fabian; Satyamoorthy, Kapaettu; Sangueza, Omar P.; Setaluri, Vijayasaradhi

    2005-01-01

    Dynamic instability of microtubules is critical for mitotic spindle assembly and disassembly during cell division, especially in rapidly dividing tumor cells. Microtubule-associated proteins (MAPs) are a family of proteins that influence this property. We showed previously that MAP2, a neuron-specific protein that stabilizes microtubules in the dendrites of postmitotic neurons, is induced in primary cutaneous melanoma but is absent in metastatic melanomas. We proposed that induction of a microtubule-stabilizing protein in primary melanoma could disrupt the dynamic instability of microtubules, inhibit cell division and prevent or delay tumor progression. Here we show, by Kaplan-Meier survival and multivariate Cox regression analysis, that patients diagnosed with MAP2+ primary melanomas have significantly better metastatic disease-free survival than those with MAP2− disease. Investigation of the mechanisms that underlie the effect of MAP2 on melanoma progression showed that MAP2 expression in metastatic melanoma cell lines leads to microtubule stabilization, cell cycle arrest in G2-M phase and growth inhibition. Disruption of microtubule dynamics by MAP2 resulted in multipolar mitotic spindles, defects in cytokinesis and accumulation of cells with large nuclei, similar to those seen in vivo in MAP2+ primary melanomas cells. These data suggest that ectopic activation of a neuronal differentiation gene in melanoma during early tumor progression inhibits cell division and correlates with inhibition or delay of metastasis. PMID:15920168

  4. Pneumobilia Resulting From Choledochoduodenal Fistula Secondary to Metastatic Colon Adenocarcinoma

    PubMed Central

    Kramer, Scott; Tzimas, Demetrios; Saitta, Patrick

    2016-01-01

    Pneumobilia, or air within the biliary tree, is a poor prognostic indicator in a patient without prior biliary sphincterotomy. Differential diagnosis includes infection with gas-forming organisms, choledochoenteric fistula in the setting of gallstones or penetrating ulcer disease, malignant invasion from a primary liver or biliary tract tumor, or metastatic disease. Treatment depends on etiology and patient factors, but often requires surgical intervention. We report a patient with gastrointestinal bleeding in whom pneumobilia was incidentally noted on abdominal plain film. Computed tomography and endoscopy revealed the biliary-enteric fistula to be caused by metastatic colon adenocarcinoma invading the biliary tree. PMID:26958563

  5. Loss of CRABP-II Characterizes Human Skin Poorly Differentiated Squamous Cell Carcinomas and Favors DMBA/TPA-Induced Carcinogenesis.

    PubMed

    Passeri, Daniela; Doldo, Elena; Tarquini, Chiara; Costanza, Gaetana; Mazzaglia, Donatella; Agostinelli, Sara; Campione, Elena; Di Stefani, Alessandro; Giunta, Alessandro; Bianchi, Luca; Orlandi, Augusto

    2016-06-01

    Retinol and its derivatives play an important role in epidermal growth and differentiation and represent chemopreventive agents in nonmelanoma skin cancer. Retinoic acid binding protein II (CRABP-II) is a cytoplasmic receptor that critically regulates all-trans-retinoic acid (ATRA) trafficking. We documented the marked reduced expression of CRABP-II and its promoter methylation in human poorly differentiated squamous cell carcinomas. To investigate the role of CRABP-II in skin carcinogenesis we used skin lesion induction by dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate in CRABP-II-knockout C57BL/6 mice. We observed earlier and more diffuse epidermal dysplasia, greater incidence and severity of tumors, reduced expression of cytokeratin 1/cytokeratin 10 and involucrin, increased proliferation, and impaired ATRA inhibition of tumor promotion compared with wild-type animals. CRABP-II-transfected HaCaT, FaDu, and A431 cells showed expression of differentiation markers, retinoic acid receptor-β/-γ signaling, ATRA sensitivity, and suppression of EGFR/v-akt murine thymoma viral oncogene homolog 1 (AKT) pathways in a fatty acid binding protein 5/peroxisome proliferator-activated receptor-β/-δ-independent manner. The opposite was true in keratinocytes isolated from CRABP-II-knockout mice. Finally, CRABP-II accumulation induced ubiquitination-associated reduction of EGFR. Our results showed reduced CRABP-II expression in human poorly differentiated squamous cell carcinomas, and its gene deletion favored experimental skin carcinogenesis and impaired ATRA antitumor efficacy, likely modulating EGFR/AKT pathways and retinoic acid receptor-β/-γ signaling. Therapeutic interventions aimed at restoring CRABP-II-mediated signaling may amplify therapeutic retinoid efficacy in nonmelanoma skin cancer. PMID:26945879

  6. [Prevalence and differentiating aspects related to gender with regard to the bullying phenomenon in poor countries].

    PubMed

    Romera Félix, Eva M; Del Rey Alamillo, Rosario; Ortega Ruiz, Rosario

    2011-11-01

    There is a large body of scientific knowledge about school violence and bullying in Europe and some other regions of the so-called developed world. However, improvement is scarce in poor and developing regions, as in the case of Latin America and, in particular, Nicaragua. The goal of this work was to determine the prevalence of the bullying phenomenon in Nicaraguan primary schools, to analyze the eventual relationships between the different forms of violence used by the students and to explore, in relation to these aspects, the similarities and differences between boys and girls. For this purpose, we surveyed 3042 pupils of primary school (50.3% girls) using the "Cuestionario sobre Convivencia, Violencia y Experiencias de Riesgo" (COVER, in English, Questionnaire about Living Together, Violence and Risk Experiences). We found that the level of involvement in bullying is significantly higher than in developed countries, that boys are more involved than girls in verbal, physical and psychological bullying, and that there are no differences with regard to social exclusion. The results are discussed, comparing them with studies conducted in different countries but with similar methodologies. PMID:22047849

  7. Cripto-1 vaccination elicits protective immunity against metastatic melanoma

    PubMed Central

    Ligtenberg, M. A.; Witt, K.; Galvez-Cancino, F.; Sette, A.; Lundqvist, A.; Lladser, A.; Kiessling, R.

    2016-01-01

    ABSTRACT Metastatic melanoma is a fatal disease that responds poorly to classical treatments but can be targeted by T cell-based immunotherapy. Cancer vaccines have the potential to generate long-lasting cytotoxic CD8+ T cell responses able to eradicate established and disseminated tumors. Vaccination against antigens expressed by tumor cells with enhanced metastatic potential represents a highly attractive strategy to efficiently target deadly metastatic disease. Cripto-1 is frequently over-expressed in human carcinomas and melanomas, but is expressed only at low levels on normal differentiated tissues. Cripto-1 is particularly upregulated in cancer-initiating cells and is involved in cellular processes such as cell migration, invasion and epithelial–mesenchymal transition, which are hallmarks of aggressive cancer cells able to initiate metastatic disease. Here, we explored the potential of Cripto-1 vaccination to target metastatic melanoma in a preclinical model. Cripto-1 was overexpressed in highly metastatic B16F10 cells as compared to poorly metastatic B16F1 cells. Moreover, B16F10 cells grown in sphere conditions to enrich for cancer stem cells (CSC) progressively upregulated cripto1 expression. Vaccination of C57Bl/6 mice with a DNA vaccine encoding mouse Cripto-1 elicited a readily detectable/strong cytotoxic CD8+ T cell response specific for a H-2 Kb-restricted epitope identified based on its ability to bind H-2b molecules. Remarkably, Cripto-1 vaccination elicited a protective response against lung metastasis and subcutaneous challenges with highly metastatic B16F10 melanoma cells. Our data indicate that vaccination against Cripto-1 represents a novel strategy to be tested in the clinic.

  8. Accretion timescales and style of asteroidal differentiation in an 26Al-poor protoplanetary disk

    PubMed Central

    Larsen, K.K.; Schiller, M.; Bizzarro, M.

    2016-01-01

    The decay of radioactive 26Al to 26Mg (half-life of 730,000 years) is postulated to have been the main energy source promoting asteroidal melting and differentiation in the nascent solar system. High-resolution chronological information provided by the 26Al−26Mg decay system is, therefore, intrinsically linked to the thermal evolution of early-formed planetesimals. In this paper, we explore the timing and style of asteroidal differentiation by combining high-precision Mg isotope measurements of meteorites with thermal evolution models for planetesimals. In detail, we report Mg isotope data for a suite of olivine-rich [Al/Mg ~ 0] achondritic meteorites, as well as a few chondrites. Main Group, pyroxene and the Zinder pallasites as well as the lodranite all record deficits in the mass-independent component of μ26Mg (μ26Mg*) relative to chondrites and Earth. This isotope signal is expected for the retarded ingrowth of radiogenic 26Mg* in olivine-rich residues produced through partial silicate melting during 26Al decay and consistent with their marginally heavy Mg isotope composition relative to ordinary chondrites, which may reflect the early extraction of isotopically light partial melts from the source rock. We propose that their parent planetesimals started forming within ~250,000 years of solar system formation from a hot (>~500 K) inner protoplanetary disk region characterized by a reduced initial (26Al/27Al)0 abundance (~1–2 × 10−5) relative to the (26Al/27Al)0 value in CAIs of 5.25 × 10−5. This effectively reduced the total heat production and allowed for the preservation of solid residues produced through progressive silicate melting with depth within the planetesimals. These ‘non-carbonaceous’ planetesimals acquired their mass throughout an extended period (>3 Myr) of continuous accretion, thereby generating onion-shell structures of incompletely differentiated zones, consisting of olivine-rich residues, overlaid by metachondrites and

  9. Accretion timescales and style of asteroidal differentiation in an 26Al-poor protoplanetary disk

    NASA Astrophysics Data System (ADS)

    Larsen, K. K.; Schiller, M.; Bizzarro, M.

    2016-03-01

    The decay of radioactive 26Al to 26Mg (half-life of 730,000 years) is postulated to have been the main energy source promoting asteroidal melting and differentiation in the nascent solar system. High-resolution chronological information provided by the 26Al-26Mg decay system is, therefore, intrinsically linked to the thermal evolution of early-formed planetesimals. In this paper, we explore the timing and style of asteroidal differentiation by combining high-precision Mg isotope measurements of meteorites with thermal evolution models for planetesimals. In detail, we report Mg isotope data for a suite of olivine-rich [Al/Mg ∼ 0] achondritic meteorites, as well as a few chondrites. Main Group, pyroxene and the Zinder pallasites as well as the lodranite all record deficits in the mass-independent component of μ26Mg (μ26Mg∗) relative to chondrites and Earth. This isotope signal is expected for the retarded ingrowth of radiogenic 26Mg∗ in olivine-rich residues produced through partial silicate melting during 26Al decay and consistent with their marginally heavy Mg isotope composition relative to ordinary chondrites, which may reflect the early extraction of isotopically light partial melts from the source rock. We propose that their parent planetesimals started forming within ∼250,000 years of solar system formation from a hot (>∼500 K) inner protoplanetary disk region characterized by a reduced initial (26Al/27Al)0 abundance (∼1-2 × 10-5) relative to the (26Al/27Al)0 value in CAIs of 5.25 × 10-5. This effectively reduced the total heat production and allowed for the preservation of solid residues produced through progressive silicate melting with depth within the planetesimals. These 'non-carbonaceous' planetesimals acquired their mass throughout an extended period (>3 Myr) of continuous accretion, thereby generating onion-shell structures of incompletely differentiated zones, consisting of olivine-rich residues, overlaid by metachondrites and

  10. The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts

    PubMed Central

    Dragoo, Jason L.

    2016-01-01

    Objectives: Platelet-rich plasma (PRP) has been has been used to augment tissue repair and regeneration after musculoskeletal injury. However, there is increasing clinical evidence that PRP, and related blood products, do not show a consistent clinical effect. The purpose of this study is to compare the effects of non-neutrophil containing PRP (LP-PRP), modified LP-PRP (Mod LP-PRP) where TGF-β1 and myostatin (MSTN) were depleted, and platelet poor plasma (PPP) on human skeletal muscle myoblast (HSMM) differentiation. Our hypothesis was that LP-PRP would lead to myoblast proliferation, not differentiation, while modifications of PRP preparations will increase myoblast differentiation, which is necessary for skeletal muscle regeneration. Methods: Blood was simultaneously processed from eight healthy human donors to create LP-PRP, Mod-LP-PRP, PPP and second spin (ss) PRP and Mod-PRP groups. Mod-PRP was created using antibodies attached to sterile beads to remove TGF- β1 and MSTN. The biologics were then individually added to human skeletal muscle myoblasts (HSMM) and were analyzed over four days. Analysis for induction into myoblast proliferation and differentiation pathways included Western blot and RT-PCR, as well as confocal microscopy to assess for polynucleated myotubule formation. Results: LP-PRP treatment lead to increased myoblast proliferation compared to PPP (1.01 x 106 vs 5.1 x 105 cells), but showed no evidence differentiation into muscle cells either by myotubule formation or via inducing myosin heavy chain (MHC) RNA compared to negative controls (0.1x fold change; p>0.05). TGF- β1 and MSTN were successfully depleted in Mod-PRP, but this modification did little to improve myoblast differentiation (0.2x fold change MHC RNA vs control; p>0.05). Application of PPP to cultures induced myoblast differentiation that included visible multinucleated myotubule formation and MHC induction compared to negative controls (9.8x fold change; p<0.05). A second

  11. Myeloid Clusters Are Associated with a Pro-Metastatic Environment and Poor Prognosis in Smoking-Related Early Stage Non-Small Cell Lung Cancer

    PubMed Central

    Zhang, Wang; Pal, Sumanta K.; Liu, Xueli; Yang, Chunmei; Allahabadi, Sachin; Bhanji, Shaira; Figlin, Robert A.; Yu, Hua; Reckamp, Karen L.

    2013-01-01

    Background This study aimed to understand the role of myeloid cell clusters in uninvolved regional lymph nodes from early stage non-small cell lung cancer patients. Methods Uninvolved regional lymph node sections from 67 patients with stage I–III resected non-small cell lung cancer were immunostained to detect myeloid clusters, STAT3 activity and occult metastasis. Anthracosis intensity, myeloid cluster infiltration associated with anthracosis and pSTAT3 level were scored and correlated with patient survival. Multivariate Cox regression analysis was performed with prognostic variables. Human macrophages were used for in vitro nicotine treatment. Results CD68+ myeloid clusters associated with anthracosis and with an immunosuppressive and metastasis-promoting phenotype and elevated overall STAT3 activity were observed in uninvolved lymph nodes. In patients with a smoking history, myeloid cluster score significantly correlated with anthracosis intensity and pSTAT3 level (P<0.01). Nicotine activated STAT3 in macrophages in long-term culture. CD68+ myeloid clusters correlated and colocalized with occult metastasis. Myeloid cluster score was an independent prognostic factor (P = 0.049) and was associated with survival by Kaplan-Maier estimate in patients with a history of smoking (P = 0.055). The combination of myeloid cluster score with either lymph node stage or pSTAT3 level defined two populations with a significant difference in survival (P = 0.024 and P = 0.004, respectively). Conclusions Myeloid clusters facilitate a pro-metastatic microenvironment in uninvolved regional lymph nodes and associate with occult metastasis in early stage non-small cell lung cancer. Myeloid cluster score is an independent prognostic factor for survival in patients with a history of smoking, and may present a novel method to inform therapy choices in the adjuvant setting. Further validation studies are warranted. PMID:23717691

  12. Differential pathways to adult metabolic dysfunction following poor nutrition at two critical developmental periods in sheep.

    PubMed

    Poore, Kirsten R; Hollis, Lisa J; Murray, Robert J S; Warlow, Anna; Brewin, Andrew; Fulford, Laurence; Cleal, Jane K; Lillycrop, Karen A; Burdge, Graham C; Hanson, Mark A; Green, Lucy R

    2014-01-01

    Epidemiological and experimental studies suggest early nutrition has long-term effects on susceptibility to obesity, cardiovascular and metabolic diseases. Small and large animal models confirm the influence of different windows of sensitivity, from fetal to early postnatal life, on offspring phenotype. We showed previously that undernutrition in sheep either during the first month of gestation or immediately after weaning induces differential, sex-specific changes in adult metabolic and cardiovascular systems. The current study aims to determine metabolic and molecular changes that underlie differences in lipid and glucose metabolism induced by undernutrition during specific developmental periods in male and female sheep. Ewes received 100% (C) or 50% nutritional requirements (U) from 1-31 days gestation, and 100% thereafter. From weaning (12 weeks) to 25 weeks, offspring were then fed either ad libitum (CC, UC) or were undernourished (CU, UU) to reduce body weight to 85% of their individual target. From 25 weeks, all offspring were fed ad libitum. A cohort of late gestation fetuses were studied after receiving either 40% nutritional requirements (1-31 days gestation) or 50% nutritional requirements (104-127 days gestation). Post-weaning undernutrition increased in vivo insulin sensitivity, insulin receptor and glucose transporter 4 expression in muscle, and lowered hepatic methylation at the delta-like homolog 1/maternally expressed gene 3 imprinted cluster in adult females, but not males. Early gestational undernutrition induced lower hepatic expression of gluconeogenic factors in fetuses and reduced in vivo adipose tissue insulin sensitivity in adulthood. In males, undernutrition in early gestation increased adipose tissue lipid handling mechanisms (lipoprotein lipase, glucocorticoid receptor expression) and hepatic methylation within the imprinted control region of insulin-like growth factor 2 receptor in adulthood. Therefore, undernutrition during development

  13. Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948)

    PubMed Central

    Fosså, S D; Paluchowska, B; Horwich, A; Kaiser, G; de Mulder, P H M; Koriakine, O; van Oosterom, A T; de Prijck, L; Collette, L; de Wit, R

    2005-01-01

    New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP. PMID:16251877

  14. Metastatic pancreatic cancer presenting as linitis plastica of the stomach.

    PubMed

    Garg, Shivani; Mulki, Ramzi; Sher, Daniel

    2016-01-01

    Metastatic disease from pancreatic carcinoma involving the stomach is an unusual event, and the pattern of spread in the form of linitis plastica, to our knowledge, has not been reported previously. Local recurrence after curative resection for pancreatic cancer is the most common pattern of disease. We report a case of metastatic pancreatic adenocarcinoma presenting as linitis plastica of the stomach 4 years after curative resection. A 52-year-old man presented with epigastric pain and melaena 4 years after undergoing a Whipple's procedure for a poorly-differentiated pancreatic adenocarcinoma, stage IB; T2N0M0. CT imaging of the abdomen revealed thickening of the gastric wall, and subsequent oesophagogastroduodenoscopy (OGD) revealed diffuse friable erythaematous tissue. The biopsy specimen obtained during the OGD revealed a poorly differentiated adenocarcinoma, with similar appearance to the prior specimen obtained from the pancreas. PMID:26957034

  15. Differentiating between Difficult-to-Remediate and Readily Remediated Poor Readers: More Evidence against the IQ-Achievement Discrepancy Definition of Reading Disability.

    ERIC Educational Resources Information Center

    Vellutino, Frank R.; Scanlon, Donna M.; Lyon, G. Reid

    2000-01-01

    This article discusses research on the traditional use of the IQ-achievement discrepancy to define specific reading disability. It highlights results from a study which found that IQ scores did not differentiate between poor readers who were found to be readily remediated and poor readers who were difficult to remediate. (Contains references.)…

  16. 249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients

    PubMed Central

    2009-01-01

    Background Ser-249 TP53 mutation (249Ser) is a molecular evidence for aflatoxin-related carcinogenesis in Hepatocellular Carcinoma (HCC) and it is frequent in some African and Asian regions, but it is unusual in Western countries. HBV has been claimed to add a synergic effect on genesis of this particular mutation with aflatoxin. The aim of this study was to investigate the frequency of 249Ser mutation in HCC from patients in Brazil. Methods We studied 74 HCC formalin fixed paraffin blocks samples of patients whom underwent surgical resection in Brazil. 249Ser mutation was analyzed by RFLP and DNA sequencing. HBV DNA presence was determined by Real-Time PCR. Results 249Ser mutation was found in 21/74 (28%) samples while HBV DNA was detected in 13/74 (16%). 249Ser mutation was detected in 21/74 samples by RFLP assay, of which 14 were confirmed by 249Ser mutant-specific PCR, and 12 by nucleic acid sequencing. All HCC cases with p53-249ser mutation displayed also wild-type p53 sequences. Poorly differentiated HCC was more likely to have 249Ser mutation (OR = 2.415, 95% CI = 1.001 – 5.824, p = 0.05). The mean size of 249Ser HCC tumor was 9.4 cm versus 5.5 cm on wild type HCC (p = 0.012). HBV DNA detection was not related to 249Ser mutation. Conclusion Our results indicate that 249Ser mutation is a HCC important factor of carcinogenesis in Brazil and it is associated to large and poorly differentiated tumors. PMID:19558663

  17. Application of two oriented partial differential equation filtering models on speckle fringes with poor quality and their numerically fast algorithms.

    PubMed

    Zhu, Xinjun; Chen, Zhanqing; Tang, Chen; Mi, Qinghua; Yan, Xiusheng

    2013-03-20

    In this paper, we are concerned with denoising in experimentally obtained electronic speckle pattern interferometry (ESPI) speckle fringe patterns with poor quality. We extend the application of two existing oriented partial differential equation (PDE) filters, including the second-order single oriented PDE filter and the double oriented PDE filter, to two experimentally obtained ESPI speckle fringe patterns with very poor quality, and compare them with other efficient filtering methods, including the adaptive weighted filter, the improved nonlinear complex diffusion PDE, and the windowed Fourier transform method. All of the five filters have been illustrated to be efficient denoising methods through previous comparative analyses in published papers. The experimental results have demonstrated that the two oriented PDE models are applicable to low-quality ESPI speckle fringe patterns. Then for solving the main shortcoming of the two oriented PDE models, we develop the numerically fast algorithms based on Gauss-Seidel strategy for the two oriented PDE models. The proposed numerical algorithms are capable of accelerating the convergence greatly, and perform significantly better in terms of computational efficiency. Our numerically fast algorithms are extended automatically to some other PDE filtering models. PMID:23518722

  18. Sorafenib for Metastatic Thyroid Cancer

    Cancer.gov

    A summary of results from an international phase III trial that compared sorafenib (Nexavar®) and a placebo for the treatment of locally advanced or metastatic differentiated thyroid cancer that is no longer responding to treatment with radioactive iodine

  19. Lung Metastasis in a Case of Recurrent Poorly Differentiated Leiomyosarcoma of the Bartholin Gland: A Case Report and Review of the Literature

    PubMed Central

    Alfieri, Joanne

    2016-01-01

    Vulvar neoplasms represent four percent of all gynecological cancers. While most cases of vulvar neoplasms are benign, two percent of patients present with malignant disease. We present the case of a 37-year-old premenopausal female who presented to an outside institution with a lump in her left vulva, which had progressively enlarged to the size of an egg. A wide local excision of the left vulva was performed, and the pathology revealed a high-grade sarcoma, not otherwise specified (NOS), with negative margins. Imaging showed enlarged bilateral external iliac lymph nodes, likely metastatic. After discussion at a multidisciplinary gynecology oncology tumor board, she was treated with gemcitabine/docetaxel chemotherapy, followed by a left inguinal lymph node dissection and a left radical vulvectomy after being referred to our centre. The final pathology at that time showed a residual sarcoma of 3.5 mm in the left vulva with no lympho-vascular invasion (LVI) and negative margins, with the closest, laterally, at 2 mm. A total of three lymph nodes were negative. She received additional chemotherapy postoperatively. Approximately one year later, she returned to her gynecologist with a 1 cm mass on the left vulva. She underwent a left hemi-vulvectomy and lymph node dissection, and pathology confirmed the presence of a high-grade sarcoma with close margins. She received adjuvant radiotherapy. Three months later, she presented with persistent cough and pneumonia. Imaging revealed a 10 cm lung mass, which was believed to be metastasis from the vulva. This was confirmed with biopsy and was completely resected. Any mass in the Bartholin gland area should be investigated carefully. Poorly differentiated vulvar leiomyosarcoma in the Bartholin gland can recur locally but may also lead to distant metastasis. Despite surgical and systemic treatment, as well as adjuvant radiation, the tumor recurred. Due to the rarity of this condition, there are no clear recommendations for

  20. Lung Metastasis in a Case of Recurrent Poorly Differentiated Leiomyosarcoma of the Bartholin Gland: A Case Report and Review of the Literature.

    PubMed

    Alnafisah, Fatimah; Alfieri, Joanne

    2016-01-01

    Vulvar neoplasms represent four percent of all gynecological cancers. While most cases of vulvar neoplasms are benign, two percent of patients present with malignant disease. We present the case of a 37-year-old premenopausal female who presented to an outside institution with a lump in her left vulva, which had progressively enlarged to the size of an egg. A wide local excision of the left vulva was performed, and the pathology revealed a high-grade sarcoma, not otherwise specified (NOS), with negative margins. Imaging showed enlarged bilateral external iliac lymph nodes, likely metastatic. After discussion at a multidisciplinary gynecology oncology tumor board, she was treated with gemcitabine/docetaxel chemotherapy, followed by a left inguinal lymph node dissection and a left radical vulvectomy after being referred to our centre. The final pathology at that time showed a residual sarcoma of 3.5 mm in the left vulva with no lympho-vascular invasion (LVI) and negative margins, with the closest, laterally, at 2 mm. A total of three lymph nodes were negative. She received additional chemotherapy postoperatively. Approximately one year later, she returned to her gynecologist with a 1 cm mass on the left vulva. She underwent a left hemi-vulvectomy and lymph node dissection, and pathology confirmed the presence of a high-grade sarcoma with close margins. She received adjuvant radiotherapy. Three months later, she presented with persistent cough and pneumonia. Imaging revealed a 10 cm lung mass, which was believed to be metastasis from the vulva. This was confirmed with biopsy and was completely resected. Any mass in the Bartholin gland area should be investigated carefully. Poorly differentiated vulvar leiomyosarcoma in the Bartholin gland can recur locally but may also lead to distant metastasis. Despite surgical and systemic treatment, as well as adjuvant radiation, the tumor recurred. Due to the rarity of this condition, there are no clear recommendations for

  1. Poor interoperability of the Adams-Harbertson method for analysis of anthocyanins: comparison with AOAC pH differential method.

    PubMed

    Brooks, Larry M; Kuhlman, Benjamin J; McKesson, Doug W; McCloskey, Leo

    2013-01-01

    The poor interoperability of anthocyanin glycosides measurements by two pH differential methods is documented. Adams-Harbertson, which was proposed for commercial winemaking, was compared to AOAC Official Method 2005.02 for wine. California bottled wines (Pinot Noir, Merlot, and Cabernet Sauvignon) were assayed in a collaborative study (n=105), which found mean precision of Adams-Harbertson winery versus reference measurements to be 77 +/- 20%. Maximum error is expected to be 48% for Pinot Noir, 42% for Merlot, and 34% for Cabernet Sauvignon from reproducibility RSD. Range of measurements was actually 30 to 91% for Pinot Noir. An interoperability study (n=30) found Adams-Harbertson produces measurements that are nominally 150% of the AOAC pH differential method. Large analytical chemistry differences are: AOAC method uses Beer-Lambert equation and measures absorbance at pH 1.0 and 4.5, proposed a priori by Flueki and Francis; whereas Adams-Harbertson uses "universal" standard curve and measures absorbance ad hoc at pH 1.8 and 4.9 to reduce the effects of so-called co-pigmentation. Errors relative to AOAC are produced by Adams-Harbertson standard curve over Beer-Lambert and pH 1.8 over pH 1.0. The study recommends using AOAC Official Method 2005.02 for analysis of wine anthocyanin glycosides. PMID:23513962

  2. Recombinant Human Thyroid Stimulating Hormone versus Thyroid Hormone Withdrawal for Radioactive Iodine Treatment of Differentiated Thyroid Cancer with Nodal Metastatic Disease

    PubMed Central

    Wolfson, Robert M.; Rachinsky, Irina; Morrison, Deric; Driedger, Al; Spaic, Tamara; Van Uum, Stan H. M.

    2016-01-01

    Introduction. Recombinant human thyroid stimulating hormone (rhTSH) is approved for preparation of thyroid remnant ablation with radioactive iodine (RAI) in low risk patients with well differentiated thyroid cancer (DTC). We studied the safety and efficacy of rhTSH preparation for RAI treatment of thyroid cancer patients with nodal metastatic disease. Methods. A retrospective analysis was performed on 108 patients with histopathologically confirmed nodal metastatic DTC, treated with initial RAI between January 1, 2000, and December 31, 2007. Within this selected group, 31 and 42 patients were prepared for initial and all subsequent RAI treatments by either thyroid hormone withdrawal (THW) or rhTSH protocols and were followed up for at least 3 years. Results. The response to initial treatment, classified as excellent, acceptable, or incomplete, was not different between the rhTSH group (57%, 21%, and 21%, resp.) and the THW group (39%, 13%, and 48%, resp.; P = 0.052). There was no significant difference in the final clinical outcome between the groups. The rhTSH group received significantly fewer additional doses of RAI than the THW group (P = 0.03). Conclusion. In patients with nodal-positive DTC, preparation for RAI with rhTSH is a safe and efficacious alternative to THW protocol. PMID:26977148

  3. Ki-67 cytological index can distinguish well-differentiated from poorly differentiated pancreatic neuroendocrine tumors: a comparative cytohistological study of 53 cases.

    PubMed

    Carlinfante, Gabriele; Baccarini, Paola; Berretti, Debora; Cassetti, Tiziana; Cavina, Maurizio; Conigliaro, Rita; De Pellegrin, Alessandro; Di Tommaso, Luca; Fabbri, Carlo; Fornelli, Adele; Frasoldati, Andrea; Gardini, Giorgio; Losi, Luisa; Maccio, Livia; Manta, Raffaele; Pagano, Nico; Sassatelli, Romano; Serra, Silvia; Camellini, Lorenzo

    2014-07-01

    The Ki-67 labeling index has been found to bear prognostic significance in gastrointestinal neuroendocrine tumors (NETs), and it was recently incorporated in NET histological grading. Nevertheless, a reliable preoperative determination of NET grading could be useful in clinical practice. The aim of this study is to compare the results of Ki-67 labeling index, as measured on cytological samples and on surgical specimens of patients with pancreatic NETs (P-NETs). We also investigated whether concordance might be improved, using a 5 % (instead of 2 %) cutoff value for defining G2 tumors. We retrospectively identified 48 consecutive patients with 53 P-NETs, from our five institutions, and we measured Ki-67 labeling index on their cytological samples and surgical specimens. The traditional 2 % and the alternative 5 % cutoff values were used to classify G2 tumors. The concordance rate between cytological and histological grading was 46/53 (86.8 %; weighted κ statistic 0.77; 95 % confidence interval (95 % CI) 0.60-0.94). No cases of cytological G1-G2 NETs were upgraded to G3 neuroendocrine carcinoma (NEC) at histological grading. Cytology was found to be highly specific in the diagnosis of both G2 (94.1 %; 95 % CI 80.3-99.3) and G3 tumors (100.0 %; 95 % CI 92.8-100), but the sensitivity was poor for G2 NETs (66.7 %; 95 % CI 38.4-88.2) and high for the prediction of G3 NECs (100 %; 95 % CI 39.8-100.0). When the 5 % cutoff value was adopted, concordance rate was 49/53 (92.4 %; weighted κ 0.82; 95 % CI 0.64-1.00). In conclusion, Ki-67 cytological expression can distinguish well-differentiated (both G1 and G2) from poorly differentiated P-NETs, and it may be useful for their preoperative classification. PMID:24807732

  4. [Metastatic prostate cancer complicated with chronic disseminated intravascular coagulopathy causing acute renal failure, mimicking thrombotic thrombocytopenic purpura and hemolytic uremic syndrome: pathomechanism, differential diagnosis and therapy related to a case].

    PubMed

    Deme, Dániel; Ragán, Márton; Kalmár, Katalin; Kovács, Lajos; Varga, Erzsébet; Varga, Tünde; Rakonczai, Ervin

    2010-12-01

    Disseminated intravascular coagulopathy (DIC) is characterized as activation of the clotting system resulting in fibrin thrombi, gradually diminishing levels of clotting factors with increased risk of bleeding. Basically two types of DIC are distinguished: (1) chronic (compensated) - with alteration of laboratory values and (2) acute (non-compensated) - with severe clinical manifestations: bleeding, shock, acute renal failure (ARF), transient focal neurologic deficit, delirium or coma. Chronic DIC related to metastatic neoplasia is caused by pancreatic, gastric or prostatic carcinoma in most of the cases. Incidence rate of DIC is 13-30% in prostate cancer, among those only 0.4-1.65% of patients had clinical signs and symptoms of DIC. In other words, chronic DIC is developed in one of eight patients with prostate cancer. DIC is considered as a poor prognostic factor in prostatic carcinoma. The similar clinical and laboratory findings of TTP-HUS (thrombotic thrombocytopenic purpura - hemolytic uremic syndrome) and DIC makes it difficult to differentiate between them. A 71 years old male patient with known chronic obstructive pulmonary disease, benign prostatic hyperplasia, significant carotid artery stenosis, gastric ulcer and alcoholic liver disease was admitted to another hospital with melena. Gastroscopy revealed intact gastric mucosa and actually non-bleeding duodenal ulcer covered by clots. Laboratory results showed hyperkalemia, elevated kidney function tests, indirect hyperbilirubinemia, increased liver function tests, leukocytosis, anemia, thrombocytopenia and elevated international normalized ratio (INR). He was treated with saline infusions, four units of red blood cells and one unit of fresh frozen plasma transfusions. Four days later he was transported to our Institution with ARF. Physical examination revealed dyspnoe, petechiae, hemoptoe, oliguria, chest-wall pain and aggressive behavior. Thrombocytopenia, signs of MAHA (fragmentocytes and helmet cells

  5. A clinical and radiological objective tumor response with somatostatin analogs (SSA) in well-differentiated neuroendocrine metastatic tumor of the ileum: a case report

    PubMed Central

    De Divitiis, Chiara; von Arx, Claudia; Carbone, Roberto; Tatangelo, Fabiana; Di Girolamo, Elena; Romano, Giovanni Maria; Ottaiano, Alessandro; de Lutio di Castelguidone, Elisabetta; Iaffaioli, Rosario Vincenzo; Tafuto, Salvatore

    2015-01-01

    Somatostatin analogs (SSAs) are typically used to treat the symptoms caused by neuroendocrine tumors (NETs), but they are not used as the primary treatment to induce tumor shrinkage. We report a case of a 63-year-old woman with a symptomatic metastatic NET of the ileum. Complete symptomatic response was achieved after 1 month of treatment with SSAs. In addition, there was an objective response in the liver, with the disappearance of secondary lesions noted on computed tomography scan after 3 months of octreotide treatment. Our experience suggests that SSAs could be useful for downstaging and/or downsizing well-differentiated NETs, and they could allow surgery to be performed. Such presurgery therapy could be a promising tool in the management of patients with initially inoperable NETs. PMID:25878507

  6. Prognostic Impact of Microsatellite Instability in Colorectal Cancer Presenting With Mucinous, Signet-Ring, and Poorly Differentiated Cells

    PubMed Central

    Jung, Sang Hun; Kim, Jae Hwang

    2016-01-01

    Purpose Mucinous cells (MUCs), signet-ring cells (SRCs), and poorly differentiated cells (PDCs) are uncommon histologic types and have been associated with advanced tumor stage and poor prognosis. However, MUCs, SRCs, and PDCs are commonly observed in cancers with high microsatellite instability (MSI), which have favorable outcomes compared with cancers with microsatellite stability (MSS). The purpose of this study was to evaluate the prognostic impact of high-MSI in patients with sporadic colorectal cancer presenting with MUCs, SRCs, and/or PDCs. Methods Between January 2006 and December 2012, 176 with proven microsatellite status who also presented with MUCs, SRCs, and PDCs were selected for this study and were divided into 2 groups, high-MSI and MSS; their outcomes were analyzed. Results Of the 176 patients, 56 and 120, respectively, had high-MSI and MSS cancers. High-MSI cancers had larger tumors, proximal tumor location, and a lower TNM stage. The recurrence rate was lower in the high-MSI group (13.7% vs. 35.4%, P = 0.006). Common patterns of distant metastasis for MUC, SRC, PDC cancers were peritoneal spread (46.9%) and hematogenous metastasis (46.4%). The 5-year CSS rates were 88.2% and 61.2% for patients with high-MSI and MSS cancers, respectively (P < 0.0001). In the multivariate analysis, except for stage-IV cancer, MSI status was an independent risk factor for cancer-specific survival (MSS: hazard ratio, 4.34; 95% confidence interval, 1.68-11.21). Conclusion In patients with colorectal cancer presenting with MUCs, SRCs, and/or PDCs, those with high-MSI cancers had better outcomes. PMID:27218096

  7. Prolonged Response to an IGF-1 Receptor Antibody in a Patient with Metastatic Castration Prostate Cancer with Neuroendocrine Differentiation

    PubMed Central

    Thomas, George V; Higano, Celestia S; Beer, Tomasz M

    2015-01-01

    The androgen receptor is the main therapeutic target that has been successfully exploited through direct inhibition to extend survival of patients with metastatic castration-resistant prostate cancer (mCRPC). We present a patient who participated in a Phase II study of an antagonist antibody to insulin-like growth factor 1 receptor (IGF-1R) in men with mCRPC and experienced over five years of stable disease. His disease was rapidly progressing before exposure to the antibody and resumed its aggressive behavior following discontinuation of therapy, strongly supporting the attribution of his stable disease to IGF-1R inhibition. His pre-treatment biopsy exhibited increased protein expression of IGF-1R (and its downstream effector, phosphorylated-S6). Consequently, agents that target IGF-1R may provide profound and durable responses in a subset of patients and upfront molecular selection may enable us to identify those most likely to benefit. PMID:26848415

  8. High RhoA expression at the tumor front in clinically localized prostate cancer and association with poor tumor differentiation

    PubMed Central

    CHEN, WEIHUA; DELONGCHAMPS, NICOLAS BARRY; MAO, KAILI; BEUVON, FRÉDÉRIC; PEYROMAURE, MICHAËL; LIU, ZHONGMIN; DINH-XUAN, ANH TUAN

    2016-01-01

    Ras homolog gene family, member A (RhoA) has been reported as essential to the invasion process and aggressiveness of numerous cancers. However, there are only sparse data on the expression and activity of RhoA in clinically localised prostate cancer. In numerous cancers, tumour cells at the invasive front demonstrate more aggressive behaviour in comparison with the cells in the central regions. In the present study, the expression and activity of RhoA was evaluated in 34 paraffin-embedded and 20 frozen prostate tissue specimens obtained from 45 patients treated with radical prostatectomy for clinically localised cancer. The expression patterns of RhoA were assessed by immunohistochemical staining and western blotting. Additional comparisons were performed between the tumour centre, tumour front and distant peritumoural tissue. RhoA activity was assessed by G-LISA. Associations between RhoA expression and the clinical features and outcome of the patients were also analysed. The present study found an increasing gradient of expression from the centre to the periphery of index tumour foci. RhoA expression was significantly increased at the tumour front compared to the tumour centre, which was determined using immunohistochemistry (P=0.001). Increased RhoA expression was associated with poor tumour differentiation in the tumour front (P=0.044) and tumour centre (P=0.039). Subsequent to a median follow-up period of 52 months, the rate of prostate-specific antigen (PSA) relapse was increased in patients with higher RhoA expression at the tumour front when compared with patients with lower RhoA expression (62.5 vs. 35.0%), although the difference was not significant (P=0.09). There was no association between RhoA expression and the PSA level or pathological stage in the present study. In conclusion, RhoA expression was increased at the tumour front and was associated with poor tumour differentiation in the tumour front and tumour centre, indicating the potential role of

  9. Differential expression of PD-L1 between primary and metastatic sites in clear cell Renal Cell Carcinoma

    PubMed Central

    Callea, Marcella; Albiges, Laurence; Gupta, Mamta; Cheng, Su-Chun; Genega, Elizabeth M.; Fay, André P.; Song, Jiaxi; Carvo, Ingrid; Bhatt, Rupal S.; Atkins, Michael B.; Hodi, F. Stephen; Choueiri, Toni K.; McDermott, David F.; Freeman, Gordon J.; Signoretti, Sabina

    2015-01-01

    PD-L1 expression in primary clear cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti-PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti-PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11/53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (p=0.51). Tumor cell PD-L1 positivity was associated with higher T stage (p=0.03) and higher Fuhrman Nuclear Grade (FNG) (p<0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (p<0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (p=0.82). Heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, since PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false negative results, these areas should be specifically selected for assessment. PMID:26014095

  10. Metastatic Cancer

    MedlinePlus

    ... cancers, including cancers of the blood and the lymphatic system ( leukemia , multiple myeloma , and lymphoma ), can form metastatic tumors. Although rare, the metastasis of blood and lymphatic system cancers to the lung, heart, central nervous system , ...

  11. The treatment of metastatic thyroid disease

    SciTech Connect

    Lee, K.Y.; Lore, J.M. Jr. )

    1990-06-01

    Removal of all resectable disease commensurate with reasonable morbidity and mortality is the initial treatment of all thyroid carcinoma. Patients with no evidence of recurrent metastatic well-differentiated thyroid carcinoma should be placed on suppressive doses of Synthroid. {sup 131}I is utilized for nonresectable and for distant metastatic well-differentiated thyroid carcinoma. External radiation therapy and chemotherapy are utilized in recurrent or metastatic thyroid carcinomas that do not concentrate {sup 131}I. 49 references.

  12. Interlaboratory Performance of a Microarray-Based Gene Expression Test to Determine Tissue of Origin in Poorly Differentiated and Undifferentiated Cancers

    PubMed Central

    Dumur, Catherine I.; Lyons-Weiler, Maureen; Sciulli, Christin; Garrett, Carleton T.; Schrijver, Iris; Holley, Tara K.; Rodriguez-Paris, Juan; Pollack, Jonathan R.; Zehnder, James L.; Price, Melissa; Hagenkord, Jill M.; Rigl, C. Ted; Buturovic, Ljubomir J.; Anderson, Glenda G.; Monzon, Federico A.

    2008-01-01

    Clinical workup of metastatic malignancies of unknown origin is often arduous and expensive and is reported to be unsuccessful in 30 to 60% of cases. Accurate classification of uncertain primary cancers may improve with microarray-based gene expression testing. We evaluated the analytical performance characteristics of the Pathwork tissue of origin test, which uses expression signals from 1668 probe sets in a gene expression microarray, to quantify the similarity of tumor specimens to 15 known tissues of origin. Sixty archived tissue specimens from poorly and undifferentiated tumors (metastatic and primary) were analyzed at four laboratories representing a wide range of preanalytical conditions (eg, personnel, reagents, instrumentation, and protocols). Cross-laboratory comparisons showed highly reproducible results between laboratories, with correlation coefficients between 0.95 to 0.97 for measurements of similarity scores, and an average 93.8% overall concordance between laboratories in terms of final tissue calls. Bland-Altman plots (mean coefficients of reproducibility of 32.48 ± 3.97) and κ statistics (κ > 0.86) also indicated a high level of agreement between laboratories. We conclude that the Pathwork tissue of origin test is a robust assay that produces consistent results in diverse laboratory conditions reflecting the preanalytical variations found in the everyday clinical practice of molecular diagnostics laboratories. PMID:18083688

  13. Undetectable Thyroglobulin Levels in Poorly Differentiated Thyroid Carcinoma Patients Free of Macroscopic Disease After Initial Treatment: Are They Useful?

    PubMed Central

    Ibrahimpasic, Tihana; Ghossein, Ronald; Carlson, Diane L.; Nixon, Iain J.; Palmer, Frank L.; Patel, Snehal G.; Tuttle, Robert M.; Shaha, Ashok; Shah, Jatin P.; Ganly, Ian

    2016-01-01

    Background Predictive role of undetectable thyroglobulin (Tg) in patients with poorly differentiated thyroid carcinoma (PDTC) is unclear. Our goal was to report on Tg levels following total thyroidectomy and adjuvant RAI in PDTC patients and to correlate Tg levels with recurrence. Methods Forty patients with PDTC with no distant metastases at presentation (M0) and managed by total thyroidectomy and adjuvant RAI were identified from a database of 91 PDTC patients. Of these, 31 patients had Tg values recorded and formed the basis of our analysis. A nonstimulated Tg level <1 ng/ml was used as a cutoff point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ2 test. Recurrence-free survival (RFS) stratified by postop Tg level was calculated by Kaplan–Meier method and compared by log-rank test. Results Twenty patients had undetectable Tg (<1 ng/ml) and 11 had detectable Tg (≥1 ng/ml; range 2–129 ng/ml) following surgery. After adjuvant RAI, 24 patients had undetectable Tg (<1 ng/ml) and 7 had detectable Tg (≥1 ng/ml; range 1–57 ng/ml). Patients with undetectable Tg were less likely to have pathologically positive margins compared to those with detectable Tg (33 vs. 72 % respectively; p = 0.03). Patients with undetectable Tg levels had better 5-year regional control and distant control than patients with detectable Tg level (5-year regional recurrence- free survival 96 vs. 69 %; p = 0.03; 5-year distant recurrence-free survival 96 vs. 46 %, p = 0.11). Conclusion Postoperative thyroglobulin levels in subset of patients with PDTC appear to have predictive value for recurrence. Patients with undetectable Tg have a low rate of recurrence. PMID:25893415

  14. Site-specific tumor grading system in colorectal cancer: multicenter pathologic review of the value of quantifying poorly differentiated clusters.

    PubMed

    Ueno, Hideki; Hase, Kazuo; Hashiguchi, Yojiro; Shimazaki, Hideyuki; Tanaka, Masafumi; Miyake, Ohki; Masaki, Tadahiko; Shimada, Yoshifumi; Kinugasa, Yusuke; Mori, Yoshiyuki; Kishimoto, Mitsuo; Kameoka, Shingo; Sato, Yu; Matsuda, Keiji; Nakadoi, Koichi; Shinto, Eiji; Nakamura, Takahiro; Sugihara, Kenichi

    2014-02-01

    The study aimed to determine the value of a novel site-specific grading system based on quantifying poorly differentiated clusters (PDC; Grade(PDC)) in colorectal cancer (CRC). A multicenter pathologic review involving 12 institutions was performed on 3243 CRC cases (stage I, 583; II, 1331; III, 1329). Cancer clusters of ≥5 cancer cells and lacking a gland-like structure (PDCs) were counted under a ×20 objective lens in a field containing the maximum clusters. Tumors with <5, 5 to 9, and ≥10 PDCs were classified as grades G1, G2, and G3, respectively. According to Grade(PDC), 1594, 1005, and 644 tumors were classified as G1, G2, and G3 and had 5-year recurrence-free survival rates of 91.6%, 75.4%, and 59.6%, respectively (P<0.0001). Multivariate analysis showed that Grade exerted an influence on prognostic outcome independently of TNM staging; approximately 20% and 46% of stage I and II patients, respectively, were selected by Grade(PDC) as a population whose survival estimate was comparable to or even worse than that of stage III patients. Grade(PDC) surpassed TNM staging in the ability to stratify patients by recurrence-free survival (Akaike information criterion, 2915.6 vs. 2994.0) and had a higher prognostic value than American Joint Committee on Cancer (AJCC) grading (Grade(AJCC)) at all stages. Regarding judgment reproducibility of grading tumors, weighted κ among the 12 institutions was 0.40 for Grade(AJCC) and 0.52 for Grade(PDC). Grade(PDC) has a robust prognostic power and promises to be of sufficient clinical value to merit implementation as a site-specific grading system in CRC. PMID:24418853

  15. Metastatic Paraganglioma

    PubMed Central

    Fliedner, Stephanie M. J.; Lehnert, Hendrik; Pacak, Karel

    2010-01-01

    Paragangliomas (PGLs) are rare chromaffin cell tumors that can often be cured by resection. Although described for the first time in 1886 1, the diagnosis of PGL remains a challenge, because patients do not present with characteristic signs and symptoms. If untreated, PGL can have a devastating outcome due to myocardial infarction, severe hypertension, stroke and/or arrhytmia caused by catecholamine excess. Even after proper diagnosis, the risk of metastatic disease remains. In recent years the opinion that metastatic disease is rare in PGL had to be revised, particularly in patients presenting with extra-adrenal PGL, with a PGL exceeding a size of 5 cm and/or carrying an SDHB germline mutation (especially for children and adolescents). In up to 10 % of patients, metastases are already present at diagnosis of PGL. Measurement of plasma and urinary metanephrine levels has long been used effectively in the diagnosis of PGL. Recently, a dopaminergic phenotype (excess dopamine, L-3,4-dihydroxyphenylalanine and or methoxytyramine) was recognized as a good indicator for metastatic disease. Vast progress in targeted PET imaging (e.g. 18F-FDA, 18F-FDOPA, 18F-FDG) now allows for reliable early detection of metastatic disease. However, once metastatses are present, treatment options are limited. Survival of patients with metastatic PGL is variable. Depending on the study population the overall 5 year survival is 35–60 %, 2. Here we review recent advances involving findings about the genetic background, the molecular pathogenesis, new diagnostic indicators, pathologic markers and emerging treatment options for metastatic PGL. PMID:21167381

  16. Silent subtype 3 pituitary adenomas are not always silent and represent poorly differentiated monomorphous plurihormonal Pit-1 lineage adenomas.

    PubMed

    Mete, Ozgur; Gomez-Hernandez, Karen; Kucharczyk, Walter; Ridout, Rowena; Zadeh, Gelareh; Gentili, Fred; Ezzat, Shereen; Asa, Sylvia L

    2016-02-01

    findings argue against the use of the nomenclature 'silent' for these tumors. To better reflect the characteristics of these tumors, we propose that they be classified as 'poorly differentiated Pit-1 lineage adenomas'. PMID:26743473

  17. Differential effects of retinoic acid on the growth of isogenic metastatic and non-metastatic breast cancer cell lines and their association with distinct expression of retinoic acid receptor beta isoforms 2 and 4.

    PubMed

    Hayashi, Ken; Goodison, Steven; Urquidi, Virginia; Tarin, David; Lotan, Reuben; Tahara, Eiichi

    2003-03-01

    The human retinoic acid receptor beta (RARbeta) has three isoforms (beta1, beta2, and beta4), which play important, distinct roles in mediating the effects of retinoic acid on cell growth and apoptosis. Whereas RARbeta2 is a potent inhibitor of breast cancer cell proliferation, RARbeta4 can act as a dominant-negative repressor of RARbeta2-mediated growth suppression. In this study we investigated the effects of all-trans-retinoic acid (ATRA) on two clones derived from the breast cancer cell line MDA-MB-435: a non-metastatic clone (NM-2C5) and a metastatic clone (M-4A4). ATRA treatment of the NM-2C5 cells resulted in growth inhibition and apoptosis, whereas the M-4A4 cells were resistant to ATRA. Analyses of the expression of RARbeta isoforms revealed that the sensitive NM-2C5 clone expressed only RARbeta2, whereas the resistant M-4A4 cells expressed both RARbeta2 and RARbeta4 mRNA and protein. ATRA treatment increased RARbeta2 mRNA level in NM-2C5 cells, whereas the same treatment of the M-4A4 cells resulted in an increase in RARbeta4 and a decrease in RARbeta2 mRNA. ATRA treatment of NM-2C5 cells increased the protein levels of the histone acetyl transferases p300 and CBP, suppressed the level of histone deacetylase and increased the level of acetylated histone H4. ATRA also decreased Bcl-2 and increased Bax and decreased VEGF. In contrast, the same treatment of the M-4A4 cells resulted in opposite effects. These results suggest that the effects of ATRA on the growth of the metastatic and non-metastatic breast cancer cell lines depend on the expression of RARbeta isoforms and that the expression of RARbeta4 may contribute to metastatic properties. PMID:12579317

  18. Cutaneous PEComas Express CD10: Implications for the Classification of PEComas and the Differential Diagnosis With Metastatic Renal Cell Carcinoma.

    PubMed

    Fernandez-Flores, Angel; Nguyen, Catherine M; Cassarino, David S

    2016-09-01

    Cutaneous perivascular epithelioid cell tumors (PEComas) are peculiar, rare mesenchymal tumors of uncertain lineage. They show a characteristic epithelioid morphology, and they are usually composed of monomorphous clear-to-granular appearing perivascular cells. One of the main differential diagnoses with PEComas is a cutaneous metastasis from renal cell carcinoma (RCC). CD10 has been emphasized to be a crucial marker in the diagnosis of metastasis from RCC. Although visceral PEComas have been studied for CD10 expression, primary cutaneous PEComas have not. Although it could be assumed a priori that cutaneous PEComas would stain as their visceral counterpart, there is increasing evidence that cutaneous PEComas could actually be unrelated to PEComas from other organs. In this report, the author's studied three primary cutaneous PEComas, and included CD10 in our immunohistochemical studies. All three PEComas expressed the marker. They conclude that a CD10 clear-cell dermal tumor is not necessarily equivalent to a metastasis from RCC and that additional stains should be added to rule out PEComa, even if the biopsy or the panel of antibodies is limited. PMID:26909587

  19. Enhanced viability and neural differential potential in poor post-thaw hADSCs by agarose multi-well dishes and spheroid culture.

    PubMed

    Guo, Xiaoling; Li, Shanyi; Ji, Qingshan; Lian, Ruiling; Chen, Jiansu

    2015-10-01

    Human adipose-derived stem cells (hADSCs) are potential adult stem cells source for cell therapy. But hADSCs with multi-passage or cryopreservation often revealed poor growth performance. The aim of our work was to improve the activity of poor post-thaw hADSCs by simple and effective means. We describe here a simple method based on commercially available silicone micro-wells for creating hADSCs spheroids to improve viability and neural differentiation potential on poor post-thaw hADSCs. The isolated hADSCs positively expresse d CD29, CD44, CD105, and negatively expressed CD34, CD45, HLA-DR by flow cytometry. Meanwhile, they had adipogenic and osteogenic differentiation capacity. The post-thaw and post-spheroid hADSCs from poor growth status hADSCs showed a marked increase in cell proliferation by CKK-8 analysis, cell cycle analysis and Ki67/P27 quantitative polymerase chain reaction (qPCR) analysis. They also displayed an increase viability of anti-apoptosis by annexin v and propidium iodide assays and mitochondrial membrane potential assays. After 3 days of neural induction, the neural differentiation potential of post-thaw and post-spheroid hADSCs could be enhanced by qPCR analysis and western blotting analysis. These results suggested that the spheroid formation could improve the viability and neural differentiation potential of bad growth status hADSCs, which is conducive to ADSCs research and cell therapy. PMID:26054839

  20. A retrospective study of six patients with mandibular metastatic carcinoma

    PubMed Central

    CAI, ZHEN; ZHU, CHAO; WANG, LIZHEN; ZHU, LING; ZHANG, ZHIYUAN; ZHU, HANGUANG; WANG, YAN'AN

    2016-01-01

    Mandibular metastatic carcinoma is a rare lesion that accounts for <1% of all oral malignancies. To provide greater experience in this field, the present study was conducted in which 6 cases of mandibular metastatic carcinoma were retrospectively reviewed. The origin of the lesions was the prostate in 2 cases, the lungs in 2 cases, the breast in 1 case and the thyroid gland in 1 case. The clinical and computed tomography features, surgical management and follow-up outcomes were investigated. The study indicated that surgeons should include the suspicion of metastasis in the differential diagnosis for mandibular tumor, particularly in patients who have a history of malignancy. A poor prognosis was associated with the examined patients. To extend the survival time as long as possible, a treatment strategy using multiple therapies, including segmental mandibulectomy, radiotherapy and chemotherapy, is recommended. PMID:27284368

  1. Metastatic brain tumor

    MedlinePlus

    Brain tumor - metastatic (secondary); Cancer - brain tumor (metastatic) ... For many people with metastatic brain tumors, the cancer is not curable. It will eventually spread to other areas of the body. Prognosis depends on the type of tumor ...

  2. The Number of Pathologically Positive Lymph Nodes and Pathological Tumor Depth Predicts Prognosis in Patients With Poorly Differentiated Squamous Cell Carcinoma of the Oral Cavity

    SciTech Connect

    Kang, Chung-Jan; Lin, Chien-Yu; Wang, Hung-Ming; Fan, Kang-Hsing; Ng, Shu-Hang; Lee, Li-Yu; Chen, I-How; Huang, Shiang-Fu; and others

    2011-11-15

    Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions. Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures. Results: The 5-year rates were as follows: local control (79%), neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes ({>=}4 vs. {<=}3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of {>=}11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates. Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth {>=}11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches.

  3. Poor prognostic value of lymphovascular invasion for pT1 urothelial carcinoma with squamous differentiation in bladder cancer.

    PubMed

    Li, Gang; Song, Hualin; Wang, Jiaxin; Bao, Yali; Niu, Yuanjie

    2016-01-01

    Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (-) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation. PMID:27279531

  4. Poor prognostic value of lymphovascular invasion for pT1 urothelial carcinoma with squamous differentiation in bladder cancer

    PubMed Central

    Li, Gang; Song, Hualin; Wang, Jiaxin; Bao, Yali; Niu, Yuanjie

    2016-01-01

    Lymphovascular invasion (LVI) is the primary and essential step in the systemic dissemination of cancer cells. The aim of our study was to assess the independent prognostic role of LVI for pT1 urothelial carcinoma with squamous differentiation in bladder cancer. We retrospectively analyzed the clinical and pathological information of 206 patients diagnosed pT1 urothelial carcinoma with squamous differentiation. Of the 206 patients, LVI was detected in 57 (27.6%) patients. The 5 year cancer specific survival (CSS) rates were 87.2% in LVI (−) and 52.4% in LVI (+) (p < 0.001). According to univariate analysis, tumor multiplicity, tumor size, recurrence and LVI were the prognostic factors associated with CSS. Additionally, tumor size and LVI significantly influenced the CSS in multivariate analysis. TURBT had shorter median CSS than RC in recurred patients with LVI (+). Our study suggested that LVI is an important predictor for survival of pT1 urothelial carcinoma with squamous differentiation. LVI positive status and tumor size ≥3 cm led to a higher risk of death. RC should be routinely performed in recurred LVI (+) bladder cancer patients of pT1 urothelial carcinoma with squamous differentiation. PMID:27279531

  5. Do count-based differential expression methods perform poorly when genes are expressed in only one condition?

    PubMed

    Zhou, Xiaobei; Robinson, Mark D

    2015-01-01

    A response to 'Comprehensive evaluation of differential gene expression analysis methods for RNA-seq data' by Rapaport F, Khanin R, Liang Y, Pirun M, Krek A, Zumbo P, Mason CE, Socci ND and Betel D in Genome Biology, 2013, 14:R95. PMID:26450178

  6. 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

  7. Monosomy 22 and partial loss of INI1 expression in a biphasic synovial sarcoma with an Ewing sarcoma-like poorly differentiated component: Report of a case.

    PubMed

    Bruyneel, Jasper; Van Dorpe, Jo; Praet, Marleen; Matthys, Bart; Van Roy, Nadine; Ferdinande, Liesbeth; Creytens, David

    2016-07-01

    Poorly differentiated synovial sarcoma (PDSS) is a less common subtype of synovial sarcoma (SS) associated with a poor prognosis. We present a case of a SS with a poorly differentiated component that resembles Ewing sarcoma (ES). Initial immunohistochemical staining revealed a characteristic and strong expression of transducin-like enhancer of split 1 (TLE1) and weak to absent expression of integrase integrator 1 (INI1) staining. Stainings for keratin and epithelial membrane antigen (EMA) were negative in the tumoral lesion. Fluorescence In Situ Hybridization (FISH) analysis showed a rearrangement of the synaptotagmin (SYT) gene, confirming the diagnosis of SS. FISH analysis for the EWS RNA-binding protein 1 (EWSR1) gene revealed monoallelic loss of EWSR1. This finding was confirmed by an array comparative genomic hybridization (aCGH), showing complete loss of chromosome 22. Based on literature review, showing only a handful of cases of cytogenetically studied SS with loss of chromosome 22, this is probably a rare event in SS. Therefore, we assume that monoallelic loss of chromosome 22 cannot fully elaborate the underlying mechanism of the INI1 staining pattern in all SS, but it could account for the weak to absent INI1 staining in at least some cases. PMID:27118264

  8. Vagal Tone and Children's Delay of Gratification: Differential Sensitivity in Resource-Poor and Resource-Rich Environments.

    PubMed

    Sturge-Apple, Melissa L; Suor, Jennifer H; Davies, Patrick T; Cicchetti, Dante; Skibo, Michael A; Rogosch, Fred A

    2016-06-01

    Children from different socioeconomic backgrounds have differing abilities to delay gratification, and impoverished children have the greatest difficulties in doing so. In the present study, we examined the role of vagal tone in predicting the ability to delay gratification in both resource-rich and resource-poor environments. We derived hypotheses from evolutionary models of children's conditional adaptation to proximal rearing contexts. In Study 1, we tested whether elevated vagal tone was associated with shorter delay of gratification in impoverished children. In Study 2, we compared the relative role of vagal tone across two groups of children, one that had experienced greater impoverishment and one that was relatively middle-class. Results indicated that in resource-rich environments, higher vagal tone was associated with longer delay of gratification. In contrast, high vagal tone in children living in resource-poor environments was associated with reduced delay of gratification. We interpret the results with an eye to evolutionary-developmental models of the function of children's stress-response system and adaptive behavior across varying contexts of economic risk. PMID:27117276

  9. Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study

    ClinicalTrials.gov

    2016-03-18

    Poorly Differentiated Neuroendocrine Carcinoma,; Neuroendocrine Carcinoma, Grade 3; Neuroendocrine Carcinoma, Grade 1 [Well-differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Carcinoma, Grade 2 [Moderately Differentiated Neuroendocrine Carcinoma] That Switched to G3; Neuroendocrine Tumor, Grade 3 and Disease Progression as Measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1.)

  10. Trop-2 overexpression in poorly differentiated endometrial endometrioid adenocarcinoma: Implications for immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody

    PubMed Central

    Bignotti, Eliana; Ravaggi, Antonella; Romani, Chiara; Falchetti, Marcella; Lonardi, Silvia; Facchetti, Fabio; Pecorelli, Sergio; Varughese, Joyce; Cocco, Emiliano; Bellone, Stefania; Schwartz, Peter E.; Rutherford, Thomas J.; Santin, Alessandro D.

    2011-01-01

    Objective We evaluated the expression of human trophoblast cell-surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti-Trop-2 antibody, as a therapeutic agent against poorly-differentiated EEC. Methods Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by real-time polymerase-chain-reaction (qRT-PCR) and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly-differentiated EEC. Finally, sensitivity of G3 EEC cell lines to hRS7 antibody-dependent cellular-cytotoxicity (ADCC) was tested in standard 5-hours 51Cr-release assays. Results Trop-2 expression was detected in 126 of 131 (96.2%) EEC samples. Tumor tissues showed markedly increased Trop-2 positivity as compared to NEC (p=0.001). Trop-2 expression was significantly higher in all grades of EEC vs. NEC. G3 tumors displayed significantly stronger Trop-2 immunostaining compared to G1 EEC (p=0.01). High Trop-2 expression by qRT-PCR and flow cytometry was found in one G3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2-negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated ADCC in vitro (range of killing: 33.9% to 50.6%) (p=0.004). Human serum did not significantly inhibit hRS7-mediated-cytotoxicity against EEC-ARK-1 (p= 0.773). Conclusions Trop-2 is highly expressed in EEC and its expression is significantly higher in poorly-differentiated EEC when compared to well-differentiated EEC. Primary G3 EEC overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities. PMID:21892093

  11. Differentially expressed microRNA cohorts in seed development may contribute to poor grain filling of inferior spikelets in rice

    PubMed Central

    2014-01-01

    Background The inferior spikelets are defined to be those at portions where the grains receive less photosynthetic products during the seed development. The typical inferior spikelets are physically located on the proximal secondary branches in a rice panicle and traditionally characterized by a later flowering time and a slower grain-filling rate, compared to those so-called superior spikelets. Grains produced on the inferior spikelets are consequently under-developed and lighter in weight than those formed on the superior spikelets. MicroRNAs (miRNAs) are recognized as key players in regulating plant development through post-transcriptional gene regulations. We previously presented the evidence that miRNAs may influence grain-filling rate and played a role in determining the grain weight and yield in rice. Results In this study, further analyses of the expressed small RNAs in superior and inferior spikelets were conducted at five distinct developmental stages of grain development. Totally, 457 known miRNAs and 13 novel miRNAs were analyzed, showing a differential expression of 141 known miRNAs between superior and inferior spikelets with higher expression levels of most miRNAs associated with the superior than the inferior spikelets during the early stage of grain filling. Genes targeted by those differentially expressed miRNAs (i.e. miR156, miR164, miR167, miR397, miR1861, and miR1867) were recognized to play roles in multiple developmental and signaling pathways related to plant hormone homeostasis and starch accumulation. Conclusions Our data established a complicated link between miRNA dynamics and the traditional role of hormones in grain filling and development, providing new insights into the widely accepted concepts of the so-called superior and inferior spikelets in rice production. PMID:25052585

  12. Metastatic Malignant Melanoma With Complete Loss of Differentiation Markers (Undifferentiated/Dedifferentiated Melanoma): Analysis of 14 Patients Emphasizing Phenotypic Plasticity and the Value of Molecular Testing as Surrogate Diagnostic Marker.

    PubMed

    Agaimy, Abbas; Specht, Katja; Stoehr, Robert; Lorey, Thomas; Märkl, Bruno; Niedobitek, Gerald; Straub, Melanie; Hager, Thomas; Reis, Anna-Carinna; Schilling, Bastian; Schneider-Stock, Regine; Hartmann, Arndt; Mentzel, Thomas

    2016-02-01

    Metastatic malignant melanoma is notorious for its phenotypic diversity and loss of differentiation markers. We herein summarized our experience with 14 metastatic melanomas showing complete loss of immunohistochemical melanocytic markers (with or without heterologous differentiation). Patients included 11 men and 3 women aged 24 to 78 years (median, 67 y). Thirteen patients had histologically confirmed primary skin melanoma, and 1 had metastatic melanoma of unknown primary. Undifferentiated metastasis was diagnosed synchronous to primary tumor (n=1), following skin melanoma by 3 months to 9 years (n=11) and preceding it by 1 year (n=1). Sites of undifferentiated metastases were axillary (3), inguinal (1), or submandibular (1) lymph nodes, digestive tract (2), bone/soft tissue (2), lung/pleura (2), and disseminated (n=3). Histology of metastases mimicked undifferentiated pleomorphic or spindle cell sarcoma with variable myxoid and giant cell areas (n=10) and cytokeratin-positive undifferentiated small cell sarcoma (n=1). Three cases showed heterologous dedifferentiation: pleomorphic rhabdomyosarcoma (n=1), teratocarcinosarcoma-like with prominent rhabdomyoblasts (n=1), and adenocarcinoma-like with metaplastic bone (n=1). All cases were negative for S100, melanoma cocktail, HMB45, Melan A, and SOX10. Other markers showed following results: smooth muscle actin (1/14), p16 (1/14), TP53 (2/12), pancytokeratin (4/14), desmin (5/14), h-caldesmon (0/9), and MDM2/CDK4 (0/5). SMARCB1 was intact in 8/8 cases. Genotyping showed BRAF(V600E) mutation (5/14), NRAS mutation (5/14), and BRAF/NRAS wild-type (4/14). In conclusion, undifferentiated/dedifferentiated metastatic melanoma is likely underrecognized and frequently mistaken for undifferentiated sarcoma or other neoplasms. Diagnosis of undifferentiated sarcoma at sites where melanoma metastasis are frequent (eg, inguinal and axillary region) should be made with great caution and warrants exploration of the remote history

  13. Tracing thalamo-cortical connections in tenrecA further attempt to characterize poorly differentiated neocortical regions, particularly the motor cortex.

    PubMed

    Künzle, Heinz

    2009-02-01

    The hedgehog tenrec (Afrosoricidae) has a very poorly differentiated neocortex. Previously its primary sensory regions have been characterized with hodological and electrophysiological techniques. Unlike the marsupial opossum the tenrec may also have a separate motor area as far as there are cortico-spinal cells located rostral to the primary somatosensory cortex. However, not knowing its thalamic input it may be premature to correlate this area with the true (mirror-image-like) primary motor cortex in higher mammals. For this reason the tenrec's thalamo-cortical connections were studied following tracer injections into various neocortical regions. The main sensory areas were confirmed by their afferents from the principal thalamic nuclei. The dorsal lateral geniculate nucleus, in addition, was connected with the retrosplenial area and a rostromedial visual region. Unlike the somatosensory cortex the presumed motor area did not receive afferents from the ventrobasal thalamus but fibers from the cerebello-thalamic target regions. These projections, however, were not restricted to the motor area, but involved the entire somatosensorimotor field as well as adjacent regions. The projections appeared similar to those arising in the rat thalamic ventromedial nucleus known to have a supporting function rather than a specific motor task. The question was raised whether the input from the basal ganglia might play a crucial role in the evolution of the mammalian motor cortex? Certainly, in the tenrec, the poor differentiation of the motor cortex coincides with the virtual absence of an entopeduncular projection to the ventrolateral thalamus. PMID:19084507

  14. Allelic loss of chromosome 16q in endometrial cancer: correlation with poor prognosis of patients and less differentiated histology.

    PubMed

    Kihana, T; Yano, N; Murao, S; Iketani, H; Hamada, K; Yano, J; Murao, S; Iketani, H; Hamada, K; Yano, J; Matsuura, S

    1996-11-01

    Deletion of certain chromosomal regions can be demonstrated in malignant cells. Chromosome 16q is one of the regions where allelic loss is frequently detected in carcinoma of the breast and many other tumors, suggesting that gene(s) which retard tumor growth may exist here. To elucidate the clinicopathological significance of chromosome 16q, loss of heterozygosity (LOH) was investigated using microsatellite polymorphism analysis in 58 patients with endometrial lesions (50 with endometrial carcinoma and 8 who had hyperplasia with or without atypia). When 11 regions of chromosome 16q were examined, LOH was found in 20 patients with carcinoma (40%) and none of the patients with hyperplasia. The tumors of 9 of the 20 patients (45%) showed total loss of 16q, while the others (55%) showed partial deletion. Tumors with LOH were histologically less differentiated than those without LOH (P = 0.038, chi2 test). Patients with tumors showing LOH of 16q had a worse prognosis than those without LOH according to Kaplan-Meier survival analysis (P=0.0158, log-rank test). In addition, LOH of 16q showed a significant relationship to prognosis by Cox regression analysis. Deletion mapping of 16q demonstrated that two regions (16q22.1 and 16q22.2-23.1) were frequently involved. Patients with 16q22.1 LOH had a poorer prognosis than those with intact 16q22.1 (P=0.0003, log-rank test). These findings suggest that gene(s) of which defect is possibly related to the aggressiveness of endometrial cancer are localized on a limited region of 16q that includes 16q22.1. PMID:9045949

  15. NUT midline carcinoma of the mediastinum showing two types of poorly differentiated tumor cells: a case report and a literature review.

    PubMed

    Nakamura, Harumi; Tsuta, Koji; Tsuda, Hitoshi; Katsuya, Yuki; Naka, Go; Iizuka, Toshihiko; Igari, Toru

    2015-01-01

    Nuclear protein in testis (NUT) midline carcinoma (NMC) is an extremely aggressive carcinoma that is genetically defined by rearrangement of the NUT gene. Herein, we describe a case of NMC in a young Japanese man, and review 31 cases of NMC in the literature. The present case was of a massive tumor of the anterior and middle mediastinum in a 26-year-old man. The tumor included 2 types of poorly differentiated tumor cells and was immunohistochemically positive for the NUT-specific antigen, epithelial membrane antigen (EMA), cluster of differentiation 99 (CD99) antigen, CD45RO antigen, keratins, p63, and p40. The patient died 2 months after the initial diagnosis. At least two-thirds of the 31 NMC cases in the literature were immunohistochemically positive for EMA, p63, and AE1/AE3. However, some exceptional NMC cases are keratins-negative/CD99-positive like Ewing sarcoma or CD45RO-positive like the present case. PMID:25433996

  16. Challenge in differential diagnosis of a liver mass histologically defined as a metastatic lesion from an occult primary intestinal tumour. The importance of clinical findings and the limitations of histology and molecular profiles. A case report.

    PubMed

    Gardini, A; Saragoni, L; La Barba, G; Serra, L; Calistri, D; Ulivi, P; Casadei, A; Frassineti, G L; Garcea, D

    2012-08-01

    Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases. PMID:23316620

  17. Differential regulation of HIF-1α and HIF-2α in neuroblastoma: Estrogen-related receptor alpha (ERRα) regulates HIF2A transcription and correlates to poor outcome

    SciTech Connect

    Hamidian, Arash; Stedingk, Kristoffer von; Munksgaard Thorén, Matilda; Mohlin, Sofie; Påhlman, Sven

    2015-06-05

    Hypoxia-inducible factors (HIFs) are differentially regulated in tumor cells. While the current paradigm supports post-translational regulation of the HIF-α subunits, we recently showed that hypoxic HIF-2α is also transcriptionally regulated via insulin-like growth factor (IGF)-II in the childhood tumor neuroblastoma. Here, we demonstrate that transcriptional regulation of HIF-2α seems to be restricted to neural cell-derived tumors, while HIF-1α is canonically regulated at the post-translational level uniformly across different tumor forms. Enhanced expression of HIF2A mRNA at hypoxia is due to de novo transcription rather than increased mRNA stability, and chemical stabilization of the HIF-α proteins at oxygen-rich conditions unexpectedly leads to increased HIF2A transcription. The enhanced HIF2A levels do not seem to be dependent on active HIF-1. Using a transcriptome array approach, we identified members of the Peroxisome proliferator-activated receptor gamma coactivator (PGC)/Estrogen-related receptor (ERR) complex families as potential regulators of HIF2A. Knockdown or inhibition of one of the members, ERRα, leads to decreased expression of HIF2A, and high expression of the ERRα gene ESRRA correlates with poor overall and progression-free survival in a clinical neuroblastoma material consisting of 88 tumors. Thus, targeting of ERRα and pathways regulating transcriptional HIF-2α are promising therapeutic avenues in neuroblastoma. - Highlights: • Transcriptional control of HIF-2α is restricted to neural cell-derived tumors. • Enhanced transcription of HIF2A is not due to increased mRNA stability. • Chemical stabilization of the HIF-α subunits leads to increased HIF2A transcription. • ERRα regulates HIF2A mRNA expression in neuroblastoma. • High expression of ESRRA correlates to poor outcome in neuroblastoma.

  18. Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis.

    PubMed

    Li, Yuchang; Lua, Ingrid; French, Samuel W; Asahina, Kinji

    2016-02-15

    Mesothelial cells (MCs) form a single layer of the mesothelium and cover the liver surface. A previous study demonstrated that, upon liver injury, MCs migrate inward from the liver surface and give rise to hepatic stellate cells (HSCs) in biliary fibrosis induced by bile duct ligation (BDL) or myofibroblasts in CCl4-induced fibrosis. The present study analyzed the role of transforming growth factor-β (TGF-β) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-β type II receptor (Tgfbr2) gene in cultured MCs suppressed TGF-β-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl4 models, respectively, indicating that the direct TGF-β signaling in MCs is responsible to MMT. After BDL and CCl4 treatment, MC-derived HSCs and myofibroblasts were distributed near the liver surface and the thickness of collagen was increased in Glisson's capsule beneath the liver surface. Fluorescence-activated cell sorting analysis revealed that MC-derived HSCs and myofibroblasts store little vitamin A lipids and have fibrogenic phenotype in the fibrotic livers. MCs contributed to 1.4 and 2.0% of activated HSCs in the BDL and CCl4 models, respectively. During regression of CCl4-induced fibrosis, 20% of MC-derived myofibroblasts survived in the liver and deactivated to vitamin A-poor HSCs. Our data indicate that MCs participate in capsular fibrosis by supplying vitamin A-poor HSCs during a process of liver fibrosis and regression. PMID:26702136

  19. Inhibition of miR-146b expression increases radioiodine-sensitivity in poorly differential thyroid carcinoma via positively regulating NIS expression

    SciTech Connect

    Li, Luchuan; Lv, Bin; Chen, Bo; Guan, Ming; Sun, Yongfeng; Li, Haipeng; Zhang, Binbin; Ding, Changyuan; He, Shan; Zeng, Qingdong

    2015-07-10

    Dedifferentiated thyroid carcinoma (DTC) with the loss of radioiodine uptake (RAIU) is often observed in clinical practice under radioiodine therapy, indicating the challenge for poor prognosis. MicroRNA (miRNA) has emerged as a promising therapeutic target in many diseases; yet, the role of miRNAs in RAIU has not been generally investigated. Based on recent studies about miRNA expression in papillary or follicular thyroid carcinomas, the expression profiles of several thyroid relative miRNAs were investigated in one DTC cell line, derived from normal DTC cells by radioiodine treatment. The top candidate miR-146b, with the most significant overexpression profiles in dedifferentiated cells, was picked up. Further research found that miR-146b could be negatively regulated by histone deacetylase 3 (HDAC3) in normal cells, indicating the correlation between miR-146b and Na{sup +}/I{sup −} symporter (NIS)-mediated RAIU. Fortunately, it was confirmed that miR-146b could regulate NIS expression/activity; what is more important, miR-146b interference would contribute to the recovery of radioiodine-sensitivity in dedifferentiated cells via positively regulating NIS. In the present study, it was concluded that NIS-mediated RAIU could be modulated by miR-146b; accordingly, miR-146b might serve as one of targets to enhance efficacy of radioactive therapy against poorly differential thyroid carcinoma (PDTC). - Highlights: • Significant upregulated miR-146b was picked up from thyroid relative miRNAs in DTC. • MiR-146b was negatively regulated by HDAC3 in normal thyroid carcinoma cells. • NIS activity and expression could be regulated by miR-146b in thyroid carcinoma. • MiR-146b inhibition could recover the decreased radioiodine-sensitivity of DTC cells.

  20. Tubulocystic renal cell carcinoma with poorly differentiated foci is indicative of aggressive behavior: clinicopathologic study of two cases and review of the literature

    PubMed Central

    Zhao, Ming; Teng, Xiaodong; Ru, Guoqing; Zhao, Zhongsheng; Hu, Qinqin; Han, Likai; He, Xianglei

    2015-01-01

    Tubulocystic renal cell carcinoma (TCRCC) is a rare, recently characterized RCC subtype with distinctive clinicopathologic and genetic characterizations as well as typical behaviors in an indolent fashion. However, sporadic case reports in the literature have indicated that TCRCC with sarcomatoid differentiation or poorly differentiated (PD) foci could behave aggressively. Herein, we reported two cases of TCRCC with PD foci indentified from our consultative service. Both patients were male and aged 66 y and 47 y, respectively. The first patient experienced radical nephrectomy while the other was treated by partial nephrectomy. Macroscopically, both tumors were described as partly cystic and solid with the greatest diameter measuring of 12-cm and 4.5-cm, respectively. Histologically, both lesions had classic areas of TCRCC occupying most part of the tumor with small papillary RCC component. In case one, PD foci were scatteredly distributed and mixed with TCRCC and papillary RCC components, while in the other case the PD foci were adjacent to the areas of TCRCC. In both tumors, the PD foci were composed of irregular, often angulated, small tubules lined by atypical eosinophilic cells and surrounded by desmoplastic stroma, resembling collecting duct carcinoma. Immunohistochemistry, in both tumors, both TCRCC component and PD foci showed the similar immunoprofiles, i.e., labeling strongly and diffusely with PAX8, AMACR and Vimentin, and focally with CK34βE12 but not with renal cell carcinoma marker or P63. In case one, the tumor invaded extensively into the adjacent renal parenchyma and focally into both renal sinusal and perirenal adipose tissues. The patient had metastasis in the pelvic cavity at the time of diagnosis and succumbed to the disease without further treatment 3 months later. The other case was organ confined but with focal positive renal parenchymal margin. The patient subsequently underwent radical nephrectomy and was in a good status without evidence

  1. Metastatic metaplastic breast carcinoma mimicking pulmonary squamous cell carcinoma on fine-needle aspiration.

    PubMed

    Nguyen, Doreen N; Kawamoto, Satomi; Cimino-Mathews, Ashley; Illei, Peter B; Rosenthal, Dorothy L; VandenBussche, Christopher J

    2015-10-01

    Metaplastic squamous cell carcinoma (SCC) of the breast is a rare type of breast cancer. Metastases to the lung, which can be a major site of second primary tumor development among breast cancer patients, are difficult to distinguish from primary SCC of the lung and present a unique challenge for pathologists. There are few available discriminating immunohistochemical markers as squamous differentiation typically leads to loss of expression of characteristic primary epithelial cell markers of both breast and lung origin. GATA protein binding 3 (GATA-3) is a useful marker of breast origin in metastatic ductal and lobular carcinomas including poorly differentiated triple-negative carcinomas and some metaplastic carcinomas. Here, we present a case of metastatic SCC presenting as a solitary lung mass with regional lymph node metastases and a single satellite lesion in a patient with a history of metaplastic SCC of the breast. In addition to the routine markers of squamous differentiation, the metastases were also positive for estrogen receptor (ER) and GATA-3 on cytologic material obtained by transbronchial FNA. This suggests that immunoreactivity for ER and GATA-3 may support a diagnosis of metastatic SCC in the context of a prior metaplastic SCC of the breast. PMID:26238413

  2. Fournier gangrene as a manifestation of undiagnosed metastatic perforated colorectal cancer.

    PubMed

    Chan, Cyrus C; Williams, Mallory

    2013-01-01

    Abstract Fournier gangrene is a necrotizing soft tissue infection involving the perineum. We present a case of Fournier gangrene as the clinical presentation of perforated metastatic rectal cancer. The patient is a 78-year-old man in a nursing home who presented to our institution with necrosis and ischemia of the scrotum. After wide debridement of necrotic tissue and bilateral orchiectomy, computed tomography was carried out to investigate abnormal findings seen on his chest X-ray, which revealed multiple pulmonary metastases as well as a mass highly suspicious for a perforated rectal mass. Once stable, a diverting colostomy and biopsies of the rectal mass were performed, confirming the presence of a metastatic, poorly differentiated rectal adenocarcinoma. Albeit an unusual etiology of Fournier gangrene, this case highlights the rare but important causes of this deadly condition and teaches us to be cognizant of the variations in the presentation of colorectal cancer. PMID:23438275

  3. Potential performance of dual-time-point 18F-FDG PET/CT compared with single-time-point imaging for differential diagnosis of metastatic lymph nodes: a meta-analysis.

    PubMed

    Shen, Guohua; Deng, Houfu; Hu, Shuang; Jia, Zhiyun

    2014-10-01

    In recent years, dual-time-point (DTP) fluorine-18 fluorodeoxyglucose PET/computed tomography (CT) has emerged as a new method for evaluating metastatic lymph nodes in cancer patients. We performed this meta-analysis to evaluate the performance of DTP PET/CT compared with single-time-point (STP) imaging for differential diagnosis of lymph nodes metastases. On the basis of data from included studies, pooled sensitivity, specificity, diagnostic odds ratio, positive likelihood ratio, and negative likelihood ratio were calculated. Summary receiver-operating characteristic curves were also constructed to assess the diagnostic value of DTP PET/CT and STP imaging in detecting metastatic lymph nodes. Totally, 17 articles were included in the analysis. On a per-patient basis, the pooled sensitivity and specificity were 0.74 [95% confidence interval (CI): 0.68-0.79] and 0.77 (95% CI: 0.72-0.81) for DTP PET/CT and 0.68 (95% CI: 0.61-0.73) and 0.81 (95% CI: 0.78-0.85) for STP PET/CT, respectively. On a per-lesion basis, the pooled sensitivity of DTP and STP PET/CT was 0.82 (95% CI: 0.79-0.84) and 0.80 (95% CI: 0.78-0.83), respectively. The pooled specificity was 0.88 (95% CI: 0.86-0.89) for DTP PET/CT and 0.82 (95% CI: 0.80-0.84) for STP PET/CT. Compared with STP imaging, DTP PET/CT has higher sensitivity but lower specificity in detecting lymph nodes metastases on a per-patient analysis, and DTP PET/CT performs only a little better than STP PET/CT on a per-lesion basis. The current results of our meta-analysis do not support the routine use of DTP imaging for the diagnosis of metastatic lymph nodes. Further prospective research with large samples is required to better define the potential benefits of DTP PET/CT imaging. PMID:25023998

  4. Risk of lymph node metastasis in mixed-type early gastric cancer determined by the extent of the poorly differentiated component

    PubMed Central

    Hwang, Chung-Su; Ahn, Sangjeong; Lee, Bong-Eun; Lee, So-Jeong; Kim, Ahrong; Choi, Chang In; Kim, Dae Hwan; Jeon, Tae-Yong; Kim, Gwang Ha; Song, Geum Am; Park, Do Youn

    2016-01-01

    AIM: To predict the rate of lymph node (LN) metastasis in diffuse- and mixed-type early gastric cancers (EGC) for guidelines of the treatment. METHODS: We reviewed 550 cases of EGC with diffuse- and mixed-type histology. We investigated the clinicopathological factors and histopathological components that influence the probability of LN metastasis, including sex, age, site, gross type, presence of ulceration, tumour size, depth of invasion, perineural invasion, lymphovascular invasion, and LN metastasis status. We reviewed all slides and estimated the proportions of each tumour component; pure diffuse type, mixed-predominantly diffuse type (diffuse > intestinal type), mixed-predominantly intestinal type (intestinal > diffuse type), and mixed diffuse = intestinal type. We calculated the extents of the respective components. RESULTS: LN metastasis was observed in 12.9% (71/550) of early gastric cancers cases [15/288 mucosal EGCs (5.2%) and 56/262 submucosal EGCs (21.4%)]. Of 550 cases, 302 were diffuse-type and 248 were mixed-type EGCs. Of 248 mixed-type EGCs, 163 were mixed-predominantly diffuse type, 82 were mixed-predominantly intestinal type, and 3 were mixed diffuse = intestinal type. Mixed-type cases with predominantly diffuse type histology showed a higher frequency of LN metastasis (20.2%) than cases of pure diffuse type (9.3%) and predominantly intestinal type (12.2%) histology. We measured the dimensions of each component (intestinal and diffuse type) to determine the association of the extent of each component with LN metastasis in mixed-type gastric carcinoma. The total tumour size and the extent of poorly differentiated components was associated with LN metastasis, while that of signet ring cell components was not. CONCLUSION: We recommend careful identification and quantitative evaluation of mixed-type early gastric cancer components after endoscopic resection to determine the intensity of the treatment. PMID:27099445

  5. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche

    PubMed Central

    Sánchez, Catherine A.; Andahur, Eliana I.; Valenzuela, Rodrigo; Castellón, Enrique A.; Fullá, Juan A.; Ramos, Christian G.; Triviño, Juan C.

    2016-01-01

    The different prostate cancer (PCa) cell populations (bulk and cancer stem cells, CSCs) release exosomes that contain miRNAs that could modify the local or premetastatic niche. The analysis of the differential expression of miRNAs in exosomes allows evaluating the differential biological effect of both populations on the niche, and the identification of potential biomarkers and therapeutic targets. Five PCa primary cell cultures were established to originate bulk and CSCs cultures. From them, exosomes were purified by precipitation for miRNAs extraction to perform a comparative profile of miRNAs by next generation sequencing in an Illumina platform. 1839 miRNAs were identified in the exosomes. Of these 990 were known miRNAs, from which only 19 were significantly differentially expressed: 6 were overexpressed in CSCs and 13 in bulk cells exosomes. miR-100-5p and miR-21-5p were the most abundant miRNAs. Bioinformatics analysis indicated that differentially expressed miRNAs are highly related with PCa carcinogenesis, fibroblast proliferation, differentiation and migration, and angiogenesis. Besides, miRNAs from bulk cells affects osteoblast differentiation. Later, their effect was evaluated in normal prostate fibroblasts (WPMY-1) where transfection with miR-100-5p, miR-21-5p and miR-139-5p increased the expression of metalloproteinases (MMPs) -2, -9 and -13 and RANKL and fibroblast migration. The higher effect was achieved with miR21 transfection. As conclusion, miRNAs have a differential pattern between PCa bulk and CSCs exosomes that act collaboratively in PCa progression and metastasis. The most abundant miRNAs in PCa exosomes are interesting potential biomarkers and therapeutic targets. PMID:26675257

  6. [Jejunal perforation as initial metastatic manifestation of laryngeal carcinoma].

    PubMed

    Claros González, I; Santonja Garriga, J L; Rubio Barbón, S; Santamaría Girón, L; Triviño López, A; Velasco Alvarez, A

    1994-01-01

    A case of acute abdominal pain due to jejunal perforation in a patient with dissemination of laryngeal carcinoma is presented. Six jejunal intramural nodes of squamous cell carcinoma, one of them perforated, were observed at laparotomy. At the same time, a lesion suspicious of local recurrence in the tracheostomy orifice was observed. The patient died in the postoperative period. The rarity of intestinal perforation as an initial manifestation of metastatical dissemination of a laryngeal squamous cell carcinoma as well as its poor prognosis are discussed. The hematogenous spread is proposed in our case. Finally the inclusion of metastases in the differential diagnosis in a clinical episode of intestinal perforation in patients with a history of neoplasm is emphasized. PMID:8186002

  7. 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 ...

  8. Differential survival following trastuzumab treatment based on quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic breast cancer

    PubMed Central

    2010-01-01

    Background We have recently described the correlation between quantitative measures of HER2 expression or HER2 homodimers by the HERmark assay and objective response (RR), time-to progression (TTP), and overall survival (OS) in an expanded access cohort of trastuzumab-treated HER2-positive patients with metastatic breast cancer (MBC) who were stringently selected by fluorescence in situ hybridization (FISH). Multivariate analyses suggested a continuum of HER2 expression that correlated with outcome following trastuzumab. Here we investigate the relationship between HER2 expression or HER2 homodimers and OS in a clinic-based population of patients with MBC selected primarily by IHC. Methods HERmark, a proximity-based assay designed to detect and quantitate protein expression and dimerization in formalin-fixed paraffin-embedded (FFPE) tissues, was used to measure HER2 expression and HER2 homodimers in FFPE samples from patients with MBC. Assay results were correlated with OS using univariate Kaplan-Meier, hazard function plots, and multivariate Cox regression analyses. Results Initial analyses revealed a parabolic relationship between continuous measures of HER2 expression and risk of death, suggesting that the assumption of linearity for the HER2 expression measurements may be inappropriate in subsequent multivariate analyses. Cox regression analyses using the categorized variable of HER2 expression level demonstrated that higher HER2 levels predicted better survival outcomes following trastuzumab treatment in the high HER2-expressing group. Conclusions These data suggest that the quantitative amount of HER2 expression measured by Hermark may be a new useful marker to identify a more relevant target population for trastuzumab treatment in patients with MBC. PMID:20178580

  9. Klebsiella pneumoniae Liver Abscess and Metastatic Endophthalmitis

    PubMed Central

    Wells, Jason T.; Lewis, Catherine R.; Danner, Omar K.; Wilson, Kenneth L.; Matthews, L. Ray

    2015-01-01

    Introduction. Klebsiella pneumoniae is a well-known cause of liver abscess. Higher rates of liver abscess associated with Klebsiella pneumoniae are seen in Taiwan. Metastatic endophthalmitis is a common complication associated with a poor prognosis despite aggressive therapy. Case Report. We report a case of a 67-year-old Korean female with Klebsiella pneumoniae liver abscess. The patient developed metastatic endophthalmitis and ultimately succumbed to her disease despite aggressive medical and surgical treatment. Conclusion. Dissemination of Klebsiella pneumoniae is associated with significant morbidity and mortality. Liver abscesses preferably should be treated with percutaneous drainage, but surgical treatment is needed in some cases. Metastatic spread to the eye is a common complication that must be treated aggressively with intravenous antibiotics and surgical intervention if necessary. PMID:26788530

  10. 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.

  11. Curing Metastatic Breast Cancer.

    PubMed

    Sledge, George W

    2016-01-01

    Metastatic breast cancer is generally considered incurable, and this colors doctor-patient interactions for patients with metastatic disease. Although true for most patients, there appear to be important exceptions, instances where long-term disease-free survival occurs. Although these instances are few in number, they suggest the possibility of cure. How will we move toward cure for a much larger population of patients with metastatic disease? This article outlines a potential research agenda that might move us toward that distant goal. PMID:26759458

  12. Metastatic brain tumor

    MedlinePlus

    ... brain from an unknown location. This is called cancer of unknown primary (CUP) origin. Growing brain tumors can place pressure ... not know the original location. This is called cancer of unknown primary (CUP) origin. Metastatic brain tumors occur in about ...

  13. Metastatic Bone Disease

    MedlinePlus

    ... Bone Disease cont. Page ( 4 ) MBD vs. Primary Bone Cancer The diagnosis of metastatic bone disease should not ... from an unknown primary carcinoma or a primary bone cancer (sarcoma). For example, if an area of bone ...

  14. Metastatic melanoma treatment: Combining old and new therapies.

    PubMed

    Davey, Ryan J; van der Westhuizen, Andre; Bowden, Nikola A

    2016-02-01

    Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma. PMID:26616525

  15. Metastatic osteosarcoma: a challenging multidisciplinary treatment.

    PubMed

    Meazza, Cristina; Scanagatta, Paolo

    2016-05-01

    Osteosarcoma is the most common malignant bone tumor, currently treated with pre-and postoperative chemotherapy in association with the surgical removal of the tumor. About 15-20% of patients have evidence of metastases at diagnosis, mostly in the lungs. Patients with metastatic disease still have a very poor prognosis, with approximately 20-30% of long-term survivors, as compared with 65-70% of patients with localized disease. The optimum management of these patients has not been standardized yet due to several patterns of metastatic disease harboring different prognosis. Complete surgical resection of all sites of disease is mandatory and predictive of survival. Patients with multiple sites of disease not amenable to complete surgery removal should be considered for innovative therapeutic approaches because of poor prognosis. PMID:26999418

  16. Treatment for metastatic nasopharyngeal carcinoma.

    PubMed

    Bensouda, Y; Kaikani, W; Ahbeddou, N; Rahhali, R; Jabri, M; Mrabti, H; Boussen, H; Errihani, H

    2011-04-01

    Nasopharyngeal carcinoma (NPC) is a specific entity different from head and neck carcinoma. Incidence is higher in South-East Asia and North Africa. Prognosis, especially for locally advanced stages (IIB - IVB) and metastasis, remains poor: more than third of cases will present local and/or metastatic recurrence. Overall 5-year survival for all NPC stages ranges from 50% to 70%. The role of chemotherapy in metastasis is well established, and remains an important palliative treatment, although no randomized trial has been reported comparing the different chemotherapy regimens. As 1(st)-line treatment, platin-based regimens seems optimal; in 2(nd) line and after progression under platins, there is no consensus: monotherapy with drugs such as gemcitabine, capecitabine or taxanes has been the most widely tested, with acceptable results. Future trials should integrate targeted therapy, in the light of overexpression of EGFR1 and C-kit in NPC. The present study presents a review of the literature concerning the various studies of metastatic NPC. PMID:21177151

  17. Invented Spelling: An Indicator of Differential Problem-Solving Strategies of Good Spellers and Poor Spellers at Kindergarten and Grade One.

    ERIC Educational Resources Information Center

    Poole-Hayes, Una; Dionne, Jean-Paul

    A study examined the invented spelling of kindergarten and first grade students as an indicator of problem-solving strategies. The study explored the operations, by gender, of good spellers and poor spellers and how those operations change over time. A sample of 12 kindergarten girls and 12 kindergarten boys who were learning to read and write in…

  18. The Nlrp3 Inflammasome Suppresses Colorectal Cancer Metastatic Growth in the Liver by Promoting Natural Killer Cell Tumoricidal Activity.

    PubMed

    Dupaul-Chicoine, Jeremy; Arabzadeh, Azadeh; Dagenais, Maryse; Douglas, Todd; Champagne, Claudia; Morizot, Alexandre; Rodrigue-Gervais, Ian Gaël; Breton, Valérie; Colpitts, Sara L; Beauchemin, Nicole; Saleh, Maya

    2015-10-20

    The crosstalk between inflammation and tumorigenesis is now clearly established. However, how inflammation is elicited in the metastatic environment and the corresponding contribution of innate immunity pathways in suppressing tumor growth at secondary sites are poorly understood. Here, we show that mice deficient in Nlrp3 inflammasome components had exacerbated liver colorectal cancer metastatic growth, which was mediated by impaired interleukin-18 (IL-18) signaling. Control of tumor growth was independent of differential cancer cell colonization or proliferation, intestinal microbiota effects, or tumoricidal activity by the adaptive immune system. Instead, the inflammasome-IL-18 pathway impacted maturation of hepatic NK cells, surface expression of the death ligand FasL, and capacity to kill FasL-sensitive tumors. Our results define a regulatory signaling circuit within the innate immune system linking inflammasome activation to effective NK-cell-mediated tumor attack required to suppress colorectal cancer growth in the liver. PMID:26384545

  19. Transcription Factor NFIB Is a Driver of Small Cell Lung Cancer Progression in Mice and Marks Metastatic Disease in Patients.

    PubMed

    Semenova, Ekaterina A; Kwon, Min-Chul; Monkhorst, Kim; Song, Ji-Ying; Bhaskaran, Rajith; Krijgsman, Oscar; Kuilman, Thomas; Peters, Dennis; Buikhuisen, Wieneke A; Smit, Egbert F; Pritchard, Colin; Cozijnsen, Miranda; van der Vliet, Jan; Zevenhoven, John; Lambooij, Jan-Paul; Proost, Natalie; van Montfort, Erwin; Velds, Arno; Huijbers, Ivo J; Berns, Anton

    2016-07-19

    Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor, and no effective treatment is available to date. Mouse models of SCLC based on the inactivation of Rb1 and Trp53 show frequent amplifications of the Nfib and Mycl genes. Here, we report that, although overexpression of either transcription factor accelerates tumor growth, NFIB specifically promotes metastatic spread. High NFIB levels are associated with expansive growth of a poorly differentiated and almost exclusively E-cadherin (CDH1)-negative invasive tumor cell population. Consistent with the mouse data, we find that NFIB is overexpressed in almost all tested human metastatic high-grade neuroendocrine lung tumors, warranting further assessment of NFIB as a tumor progression marker in a clinical setting. PMID:27373156

  20. CT differentiation of enlarged mediastinal lymph node due to anthracosis from metastatic lymphadenopathy: a comparative study proven by endobronchial US-guided transbronchial needle aspiration

    PubMed Central

    Kirchner, Johannes; Broll, Michael; Müller, Phillip; Pomjanski, Natalia; Biesterfeld, Stepfan; Liermann, Dieter; Kickuth, Ralph

    2015-01-01

    PURPOSE Anthracosis often results in mediastinal nodal enlargement. The aim of this comparative study was to evaluate if it is possible to differentiate endobronchial ultrasound-guided trans-bronchial needle aspiration (EBUS-TBNA) proven anthracotic lymph nodes from malignant lymph node enlargement by means of multislice computed tomography (MSCT). METHODS We compared the MSCT findings of 89 enlarged lymph nodes due to anthracosis with 54 malignant lymph nodes (non-small cell lung cancer 75.9%, small cell lung cancer 18.5%, and non-Hodgkin lymphoma 5.6%). The lymph nodes were assessed for density (calcification, fat, and necrosis), shape (oval, round), contrast enhancement, and contour (sharp, ill-defined). RESULTS Malignant lymph nodes showed significantly greater axis diameters (P < 0.001). Both anthracotic and malignant nodes were most often oval (86.5% of all malignant nodes vs. 81.5% of all anthracotic nodes, P = 0.420) and showed confluence in a remarkable percentage (28.1% vs. 42.6%, P = 0.075). Anthracotic nodes showed calcifications more often (18% vs. 0%, P < 0.001). Malignant lymph nodes showed a significantly greater short and long axis diameter (P < 0.001), and they had a higher frequency of ill-defined contours (27.8% vs. 2.2%, P < 0.001) and contrast enhancement (27.8% vs. 5.6%, P < 0.001). Nodal necrosis, which appeared in one third of the malignant nodes, was not observed in anthracosis (35.2% vs. 0%, P < 0.001). Confluence of enlarged lymph nodes was seen in malignant lymph nodes (42.6%), as well as in lymph node enlargement due to anthracosis (28.1%, P = 0.075). CONCLUSION Our results show that there are significant differences in MSCT findings of malignant enlarged lymph nodes and benign lymph node enlargement due to anthracosis. PMID:25616268

  1. Chemotherapy in metastatic retinoblastoma.

    PubMed

    Kingston, J E; Hungerford, J L; Plowman, P N

    1987-03-01

    Eleven children with metastatic retinoblastoma diagnosed during the period 1970-1984 were treated with chemotherapy. Short-term complete responses were observed in three children treated with a four-drug combination which included cisplatinum, and in one child treated with vincristine and cyclophosphamide. The median duration of survival of the 11 children receiving chemotherapy was nine months, whilst the median survival of 13 children with metastatic retinoblastoma who were not given chemotherapy was only 2.3 months (p = 0.06). This suggests that retinoblastoma is a chemosensitive tumour and therefore adjuvant chemotherapy may have a role in children with retinoblastoma who at diagnosis are thought to be at high risk of developing metastatic disease. PMID:3587892

  2. Metastatic signet ring cell carcinoma of unknown primary origin: a case report and review of the literature

    PubMed Central

    Al-Taee, Ahmad; Almukhtar, Rawaa; Lai, Jinping

    2016-01-01

    In spite of the increasingly sophisticated diagnostic workup, detailed investigations fail to reveal a primary site of origin for about 3–5% of metastatic tumors. The most commonly reported subtype in cancer of unknown primary origin is adenocarcinoma. Signet ring cell carcinoma (SRCC) is a rare poorly differentiated aggressive subtype of adenocarcinoma that most commonly arise from the gastrointestinal tract. It usually presents late and is associated with poor prognosis. Treatment options remain limited to anecdotal reports. However, immunohistochemical studies can be useful in suggesting an origin and therefore may help guide investigations and treatment options. Here we present an unusual case of metastatic SRCC of unknown primary origin presenting as peritoneal carcinomatosis in a 73-year-old man. We also review the literature on metastatic SRCC of unknown primary origin and discuss the relevant findings. This work highlights the importance of collaboration between clinicians and pathologists as well as detailed histopathological, immunohistochemical, and molecular analyses which can help guide investigations and management options. PMID:27570777

  3. Intracardiac Metastatic Rhabdomyosarcoma

    PubMed Central

    Kim, Tae Ho; Sung, Kiick; Kim, Wook Sung; Lee, Young Tak; Park, Pyo Won; Jeong, Dong Seop

    2015-01-01

    A 70-year-old man who visited Samsung Medical Center reported experiencing palpitation for 2 weeks. He had undergone excision of a mass in the right buttock due to rhabdomyosarcoma 7 years prior to this visit. Transesophageal echocardiography showed a pedunculated mass in the left ventricle, which was thought to be a vegetation of infective endocarditis, metastasis of the primary tumor, or thrombus. He underwent removal of the cardiac tumor, and the pathologic report was metastatic rhabdomyosarcoma. Thus, here, we report a rare case of metastatic rhabdomyosarcoma in the left ventricle. PMID:26665113

  4. The role of indocyanine green angiography imaging in further differential diagnosis of patients with nAMD who are morphologically poor responders to ranibizumab in a real-life setting.

    PubMed

    Ozkaya, A; Alagoz, C; Garip, R; Alkin, Z; Perente, I; Yazici, A T; Taskapili, M

    2016-07-01

    PurposeTo evaluate the neovascular age-related macular degeneration (nAMD) in patients who were morphologically poor responders to intravitreal ranibizumab (IVR) treatment using indocyanine green angiography (ICGA) for further investigation.MethodsThis was a cross-sectional, retrospective study. The patients with an initial diagnosis of nAMD who made through the clinical examination, optical coherence tomography, and fluorescein angiography imaging, and were treated with at least three monthly IVR injections that resulted with a morphological poor response, were included. ICGA was obtained from the patients and evaluated in regard to differential diagnosis of other macular diseases, which might mimic nAMD.ResultsThe study included 132 eyes of 117 patients. The mean age was 67.4±9.4 years. After ICGA imaging, 13 eyes (9.8%) were diagnosed as true nAMD, 74 eyes (56.1%) as polypoidal choroidal vasculopathy (PCV), 35 eyes (26.5%) as chronic central serous chorioretinopathy (CSC), 3 eyes (2.3%) as retinal angiomatous proliferation (RAP), 3 eyes (2.3%) as choroidal neovascularization secondary to CSC, 2 eyes (1.5%) as adult-onset vitelliform macular dystrophy, and 2 eyes (1.5%) as drusenoid pigment epithelial detachment with vitelliform material, respectively. The duration between the initial diagnosis and the revised diagnosis was 15.6±10.5 months in the non-AMD group, and the mean injection number of these patients was 6.6±4.4.ConclusionsMost of the nAMD patients who were thought to be morphologically poor responders to IVR were diagnosed as having non-AMD diseases via ICGA. A detailed differential diagnostic work-up is needed before considering these patients as poor responders. PMID:27080484

  5. A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas.

    PubMed

    Tang, Laura H; Basturk, Olca; Sue, Jillian J; Klimstra, David S

    2016-09-01

    High-grade neuroendocrine neoplasms (World Health Organization [WHO] G3) of the pancreas include both well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC). According to the WHO classification scheme, the diagnosis of this group of tumors is based on both the histopathology of the tumor and the assessment of proliferation fraction. However, the former can be challenging due to the lack of well-defined histologic criteria, and the latter alone (ie, >20 mitoses/10 high-power fields or Ki67>20%) may not sufficiently distinguish WD-NETs from PD-NECs. Given the considerable differences in treatment strategies and clinical outcome, additional practical modalities are required to facilitate the accurate diagnosis of high-grade pancreatic neuroendocrine neoplasms. We examined 33 cases of WHO G3 neuroendocrine neoplasms of the pancreas and attempted to classify them into WD-NET, small cell PD-NEC (PD-NEC-SCC), and large cell PD-NEC (PD-NEC-LCC) or to designate them as "ambiguous" when an uncertain diagnosis was rendered by any of the observers or there was any disagreement in classification among the 3 observers. To simplify the interpretation, both PD-NEC-SCC and PD-NEC-LCC were considered together as PD-NECs in the final analysis. The initial approach was to assess microscopically a single morphologically challenging hematoxylin and eosin section from each case without the knowledge of Ki67 values, performed independently by 3 pathologists to assess the degree of diagnostic concordance, and then evaluate immunohistochemical staining for surrogate biomarkers of known genotypes of WD-NET and PD-NEC, respectively, and, lastly, complete a clinicopathologic review to establish a final definitive classification. Loss of DAXX or ATRX protein expression defined WD-NET, and abnormal p53, Rb, SMAD4 expression signified PD-NEC. When the chosen section displayed an element of WD histopathology, or other tumor sections contained

  6. Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer.

    PubMed

    Reddy, Opal L; Cates, Justin M; Gellert, Lan L; Crist, Henry S; Yang, Zhaohai; Yamashita, Hironobu; Taylor, John A; Smith, Joseph A; Chang, Sam S; Cookson, Michael S; You, Chaochen; Barocas, Daniel A; Grabowska, Magdalena M; Ye, Fei; Wu, Xue-Ru; Yi, Yajun; Matusik, Robert J; Kaestner, Klaus H; Clark, Peter E; DeGraff, David J

    2015-05-01

    We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14-positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression. PMID:25907831

  7. Loss of FOXA1 Drives Sexually Dimorphic Changes in Urothelial Differentiation and Is an Independent Predictor of Poor Prognosis in Bladder Cancer

    PubMed Central

    Reddy, Opal L.; Cates, Justin M.; Gellert, Lan L.; Crist, Henry S.; Yang, Zhaohai; Yamashita, Hironobu; Taylor, John A.; Smith, Joseph A.; Chang, Sam S.; Cookson, Michael S.; You, Chaochen; Barocas, Daniel A.; Grabowska, Magdalena M.; Ye, Fei; Wu, Xue-Ru; Yi, Yajun; Matusik, Robert J.; Kaestner, Klaus H.; Clark, Peter E.; DeGraff, David J.

    2016-01-01

    We previously found loss of forkhead box A1 (FOXA1) expression to be associated with aggressive urothelial carcinoma of the bladder, as well as increased tumor proliferation and invasion. These initial findings were substantiated by The Cancer Genome Atlas, which identified FOXA1 mutations in a subset of bladder cancers. However, the prognostic significance of FOXA1 inactivation and the effect of FOXA1 loss on urothelial differentiation remain unknown. Application of a univariate analysis (log-rank) and a multivariate Cox proportional hazards regression model revealed that loss of FOXA1 expression is an independent predictor of decreased overall survival. An ubiquitin Cre-driven system ablating Foxa1 expression in urothelium of adult mice resulted in sex-specific histologic alterations, with male mice developing urothelial hyperplasia and female mice developing keratinizing squamous metaplasia. Microarray analysis confirmed these findings and revealed a significant increase in cytokeratin 14 expression in the urothelium of the female Foxa1 knockout mouse and an increase in the expression of a number of genes normally associated with keratinocyte differentiation. IHC confirmed increased cytokeratin 14 expression in female bladders and additionally revealed enrichment of cytokeratin 14–positive basal cells in the hyperplastic urothelial mucosa in male Foxa1 knockout mice. Analysis of human tumor specimens confirmed a significant relationship between loss of FOXA1 and increased cytokeratin 14 expression. PMID:25907831

  8. Computational analysis of gene expression space associated with metastatic cancer

    PubMed Central

    2009-01-01

    Background Prostate carcinoma is among the most common types of cancer affecting hundreds of thousands people every year. Once the metastatic form of prostate carcinoma is documented, the majority of patients die from their tumors as opposed to other causes. The key to successful treatment is in the earliest possible diagnosis, as well as understanding the molecular mechanisms of metastatic progression. A number of recent studies have identified multiple biomarkers for metastatic progression. However, most of the studies consider only direct comparison between metastatic and non-metastatic classes of samples. Results We propose an alternative concept of analysis that considers the entire multidimensional space of gene expression and identifies the partition of this space in which metastatic development is possible. To apply this concept in cancer gene expression studies we utilize a modification of high-dimension natural taxonomy algorithm FOREL. Our analysis of microarray data containing primary and metastatic cancer samples has revealed not only differentially expressed genes, but also relations between different groups of primary and metastatic cancer. Metastatic samples tend to occupy a distinct partition of gene expression space. Further pathway analysis suggests that this partition is delineated by a specific pattern of gene expression in cytoskeleton remodeling, cell adhesion and apoptosis/cell survival pathways. We compare our findings with both report of original analysis and recent studies in molecular mechanism of metastasis. Conclusion Our analysis indicates a single molecular mechanism of metastasis. The new approach does not contradict previously reported findings, but reveals important details unattainable with traditional methodology. PMID:19811690

  9. Head injury mortality in a geriatric population: differentiating an "edge" age group with better potential for benefit than older poor-prognosis patients.

    PubMed

    Bouras, Triantafyllos; Stranjalis, George; Korfias, Stefanos; Andrianakis, Ilias; Pitaridis, Marianos; Sakas, Damianos E

    2007-08-01

    A comparison of outcomes between different modes of head-injury treatment in the elderly has important bearing on questions of cost-effectiveness and medical ethics. Here, we have examined rates of mortality in elderly head-trauma victims to determine whether it is valid to differentiate an "edge" age group of younger elderly patients, 65-74 years of age, from older elderly patients, considering possible benefit from intensive treatment and surgical intervention. We collected data from 1926 cases of head trauma and separated them into three age groups: 14-64 years, 65-74 years, and 75 years or older. We then compared these groups with respect to cause of injury, severity of injury, and whether or not treatment included either admission to an Intensive Care Unit (ICU) or surgical intervention. We found that road traffic accidents were the major cause of head injury in the younger age group, whereas in the elderly falls predominated. Mortality was higher in the elderly in all the head injury severity subgroups. Young subjects with a Glasgow Coma Scale (GCS) score of less than or equal to 8 tended to benefit from ICU treatment whereas patients 75 and over did not, regardless of their severity of injury. For these patients who were in the 65-74 age group, the data suggested that some benefit was likely. Patients 75 and older were significantly less likely to survive surgical intervention than younger patients. We conclude that it is valid to treat patients in the age group 65-74 years as a separate group from those patients 75 and older. Patients in this younger subset of the elderly may benefit from ICU treatment or surgical intervention. However, the patients in our older subset of elderly patients clearly did not, and they had a significantly higher risk of surgical mortality. PMID:17711397

  10. Metastatic Extrapulmonary Small Cell Carcinoma to the Cerebellopontine Angle: A Case Report and Review of the Literature

    PubMed Central

    Theodros, Debebe; Goodwin, C. Rory; Crane, Genevieve M.; Liauw, Jason; Kleinberg, Lawrence

    2015-01-01

    Extrapulmonary small cell carcinomas (EPSCC) are rare malignancies with poor patient prognoses. We present the case of a 63-year-old male who underwent surgical resection of a poorly differentiated small cell carcinoma, likely from a small intestinal primary tumor that metastasized to the cerebellopontine angle (CPA). A 63-year-old male presented with mild left facial paralysis, hearing loss, and balance instability. MRI revealed a 15 mm mass in the left CPA involving the internal auditory canal consistent with a vestibular schwannoma. Preoperative MRI eight weeks later demonstrated marked enlargement to 35 mm. The patient underwent a suboccipital craniectomy and the mass was grossly different visually and in consistency from a standard vestibular schwannoma. The final pathology revealed a poorly differentiated small cell carcinoma. Postoperative PET scan identified avid uptake in the small intestine suggestive of either a small intestinal primary tumor or additional metastatic disease. The patient underwent whole brain radiation therapy and chemotherapy and at last follow-up demonstrated improvement in his symptoms. Surgical resection and radiotherapy are potential treatment options to improve survival in patients diagnosed with NET brain metastases. We present the first documented case of skull base metastasis of a poorly differentiated small cell carcinoma involving the CPA. PMID:25810937

  11. Assigning site of origin in metastatic neuroendocrine neoplasms: a clinically significant application of diagnostic immunohistochemistry.

    PubMed

    Bellizzi, Andrew M

    2013-09-01

    The neuroendocrine epithelial neoplasms (NENs) include well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). Whereas PDNECs are highly lethal, with localized Merkel cell carcinoma somewhat of an exception, WDNETs exhibit a range of "indolent" biologic potentials-from benign to widely metastatic and eventually fatal. Within each of these 2 groups there is substantial morphologic overlap. In the metastatic setting, the site of origin of a WDNET has significant prognostic and therapeutic implications. In the skin, Merkel cell carcinoma must be distinguished from spread of a visceral PDNEC. This review intends to prove the thesis that determining the site of origin of a NEN is clinically vital and that diagnostic immunohistochemistry is well suited to the task. It will begin by reviewing current World Health Organization terminology for the NENs, as well as an embryologic and histologic pattern-based classification. It will present population-based data on the relative frequency and biology of WDNETs arising at various anatomic sites, including the frequency of metastases of unknown primary, and comment on limitations of contemporary imaging techniques, as a means of defining the scope of the problem. It will go on to discuss the therapeutic significance of site of origin. The heart of this review is a synthesis of data compiled from >100 manuscripts on the expression of individual markers in WDNETs and PDNECs, as regards site of origin. These include proteins that are considered "key markers" and others that are either useful "secondary markers," potentially very useful markers that need to be further vetted, or ones that are widely applied despite a lack of efficacy. It will conclude with my approach to the metastatic NEN of unknown origin. PMID:23939147

  12. Biventricular metastatic invasion from cervical squamous cell carcinoma.

    PubMed

    Kapoor, Karan; Evans, Matthew C; Shkullaku, Melsjan; Schillinger, Rachel; White, Charles S; Roque, Dana M

    2016-01-01

    Metastasis to the heart has been previously described with primary lung and breast carcinoma, lymphoma, leukaemia, mesothelioma and melanoma. However, left-ventricular cardiac metastasis from primary cervical squamous cell carcinoma is poorly described. This report describes the clinical presentation of a patient with cardiac metastatic invasion from cervical cancer. PMID:27371746

  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. Outcomes After Radiation Therapy to Metastatic Sites in Patients With Stage 4 Neuroblastoma

    PubMed Central

    Kandula, Shravan; Prabhu, Roshan S.; Nanda, Ronica; Switchenko, Jeffrey M.; Cash, Thomas; Qayed, Muna; Katzenstein, Howard; Esiashvili, Natia

    2016-01-01

    Summary In patients with high-risk metastatic neuroblastoma, the benefit of radiation therapy (RT) to metastatic sites as part of primary treatment has not been fully investigated. The purpose of this single-institution study was to evaluate local control of irradiated metastatic sites, and characterize metastatic disease burden and anatomic distribution in patients with high-risk metastatic neuroblastoma. The records of all patients diagnosed with stage 4 neuroblastoma between August 2000 and January 2010 were reviewed. Exclusion criteria included: bone-marrow only metastatic site, total body irradiation, or no imaging follow-up. A total of 37 patients met eligibility criteria. Median follow-up period for patients without relapse was 61 months. Five-year overall survival for all patients was 67%. Thirteen patients (35%) received RT to a metastatic site as part of their primary treatment. Among these patients, in-field recurrence occurred in three patients (23%), including two of three treated calvarial sites. In patients treated with or without RT to a metastatic site, respectively, there was no significant difference in 5-year overall survival (73% vs. 63%, P = 0.84) or relapse-free survival (46% and 55%, P = 0.48). Current metastatic site RT dose may be suboptimal, and certain locations may predict for a poor response. Further studies are necessary to elucidate the optimal role of RT to metastatic sites. PMID:25238225

  15. Origins of Metastatic Traits

    PubMed Central

    Vanharanta, Sakari; Massagué, Joan

    2014-01-01

    How cancer cells acquire the competence to colonize distant organs remains a central question in cancer biology. Tumors can release large numbers of cancer cells into the circulation, but only a small proportion of these cells survive on infiltrating distant organs and even fewer form clinically meaningful metastases. During the past decade, many predictive gene signatures and specific mediators of metastasis have been identified, yet how cancer cells acquire these traits has remained obscure. Recent experimental work and high-resolution sequencing of human tissues have started to reveal the molecular and tumor evolutionary principles that underlie the emergence of metastatic traits. PMID:24135279

  16. Black Pleural Effusion: A Unique Presentation of Metastatic Melanoma.

    PubMed

    Chhabra, Akansha; Mukherjee, Vikramjit; Chowdhary, Mudit; Danckers, Mauricio; Fridman, David

    2015-01-01

    Metastatic melanoma is a rare form of skin cancer, but one that comes with a high mortality rate. Pulmonary involvement is frequently seen in metastatic melanoma with only 2% of malignant melanoma patients with thorax metastasis presenting with pleural effusions. Herein, we report an extremely rare case of black pleural effusion from thoracic metastasis of cutaneous malignant melanoma. A 74-year-old man with known metastatic melanoma presented with a 1-month history of worsening lower back and hip pain and was found to have extensive osseous metastatic disease and multiple compression fractures. The patient underwent an uneventful kyphoplasty; however, the following day, he became acutely hypoxic and tachypneic with increased oxygen requirements. Radiographic evaluation revealed new bilateral pleural effusions. Bedside thoracentesis revealed a densely exudative, lymphocyte-predominant black effusion. Cytological examination showed numerous neoplastic cells with melanin deposition. A diagnosis of thoracic metastasis of malignant melanoma was established based on the gross and microscopic appearance of the pleural fluid. To the best of our knowledge, this is the first reported case of black pleural effusions secondary to metastatic melanoma in the United States. Despite the rarity of this presentation, it is important to determine the etiology of the black pleural effusion and to keep metastatic melanoma as a differential diagnosis. PMID:26078741

  17. Therapy for metastatic pancreatic neuroendocrine tumors

    PubMed Central

    Massironi, Sara; Conte, Dario; Peracchi, Maddalena

    2014-01-01

    Background Pancreatic neuroendocrine tumors (pNETs) are frequently malignant (50-80%, except for insulinoma) and may show an aggressive course with metastases to the liver as well as more distant sites. These heterogeneous neoplasms include functioning tumors, which secrete a variety of peptide hormones, and non-functioning tumors (up to 90% of pNETs), which often show metastases at the time of diagnosis. Methods A PubMed search was performed for English-language publications from 1995 through December 2012. Reference lists from studies selected were manually searched to identify further relevant reports. Manuscripts comparing different therapeutic options and advances for metastatic pNETs were selected. Results The therapeutic options for metastatic pNETs are expanding and include surgery, which remains the only curative approach, liver-directed therapies, and medical therapy. In selected cases also liver transplantation (OLT) may be considered. The option of OLT for metastatic disease is unique to neuroendocrine tumors. Recently, novel promising targeted therapies have been proposed for progressive well-differentiated pNETs. Conclusions The best therapeutic approach for pNETs is still matter of debating. However, since pNETs often show a more indolent behavior compared to other malignancies, the preservation of the quality of life of the patient and the personalization of the therapy according to tumor’s and patient’s features are mandatory. PMID:25332984

  18. Metastatic thymoma involving the bone marrow

    PubMed Central

    Wenceslao, Stella; Krause, John R.

    2016-01-01

    Although relatively rare, thymomas can be involved in a considerable variety of clinical presentations. Clinicians should be mindful of the breadth of associations with other diseases, including autoimmune disorders and many secondary nonthymic malignancies. For the pathologist, knowledge of the extremely varied histopathologic presentation of thymoma is vital to formulate a proper differential, workup, and diagnosis. The presented case illustrates the finding of very rare metastatic thymoma involvement of bone marrow, identified during evaluation for pancytopenia. The history of prior prostate cancer and an uncharacterized pancreatic lesion, as well as the familial presentation, also suggests a possible underlying hereditary syndrome. PMID:26722174

  19. 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

  20. Malignant metastatic carcinoid presenting as brain tumor.

    PubMed

    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

  1. Cancer of Unknown Primary Finally Revealed to Be a Metastatic Prostate Cancer: A Case Report

    PubMed Central

    Cho, Jung Yeon; Shim, Eun Jin; Kim, In Seon; Nam, Eun Mi; Choi, Moon Young; Lee, Kyung Eun; Mun, Yeung Chul; Seoung, Chu Myoung; Song, Dong Eun; Han, Woon Sup

    2009-01-01

    The vast majority of patients with metastatic prostate cancer present with bone metastases and high prostate specific antigen (PSA) level. Rarely, prostate cancer can develop in patients with normal PSA level. Here, we report a patient who presented with a periureteral tumor of unknown primary site that was confirmed as prostate adenocarcinoma after three years with using specific immunohistochemical examination. A 64-year old man was admitted to our hospital with left flank pain associated with masses on the left pelvic cavity with left hydronephrosis. All tumor markers including CEA, CA19-9, and PSA were within the normal range. After an exploratory mass excision and left nephrectomy, the pelvic mass was diagnosed as poorly differentiated carcinoma without specific positive immunohistochemical markers. At that time, we treated him as having a cancer of unknown primary site. After approximately three years later, he revisited the hospital with a complaint of right shoulder pain. A right scapular mass was newly detected with a high serum PSA level (101.7 ng/ml). Tissues from the scapular mass and prostate revealed prostate cancer with positive immunoreactivity for P504S, a new prostate cancer-specific gene. The histological findings were the same as the previous pelvic mass; however, positive staining for PSA was observed only in the prostate mass. This case demonstrates a patient with prostate cancer and negative serological test and tissue staining that turned out to be positive during progression. We suggest the usefulness of newly developed immunohistochemical markers such as P504S to determine the specific primary site of metastatic poorly differentiated adenocarcinoma in men. PMID:19688071

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

    PubMed Central

    Robles, Francisco E.; Deb, Sanghamitra; Wilson, Jesse W.; Gainey, Christina S.; Selim, M. Angelica; Mosca, Paul J.; Tyler, Douglas S.; Fischer, Martin C.; Warren, Warren S.

    2015-01-01

    Metastatic melanoma is associated with a poor prognosis, but no method reliably predicts which melanomas of a given stage will ultimately metastasize and which will not. While sentinel lymph node biopsy (SLNB) has emerged as the most powerful predictor of metastatic disease, the majority of people dying from metastatic melanoma still have a negative SLNB. Here we analyze pump-probe microscopy images of thin biopsy slides of primary melanomas to assess their metastatic potential. Pump-probe microscopy reveals detailed chemical information of melanin with subcellular spatial resolution. Quantification of the molecular signatures without reference standards is achieved using a geometrical representation of principal component analysis. Melanin structure is analyzed in unison with the chemical information by applying principles of mathematical morphology. Results show that melanin in metastatic primary lesions has lower chemical diversity than non-metastatic primary lesions, and contains two distinct phenotypes that are indicative of aggressive disease. Further, the mathematical morphology analysis reveals melanin in metastatic primary lesions has a distinct “dusty” quality. Finally, a statistical analysis shows that the combination of the chemical information with spatial structures predicts metastatic potential with much better sensitivity than SLNB and high specificity, suggesting pump-probe microscopy can be an important tool to help predict the metastatic potential of melanomas. PMID:26417529

  3. Systemic therapy for metastatic bladder cancer in 2016 and beyond.

    PubMed

    Collazo-Lorduy, Ana; Galsky, Matthew D

    2016-05-01

    Metastatic urothelial cancer is generally associated with poor outcomes. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly develops and the vast majority of patients ultimately experience disease progression. Despite several decades of clinical drug development focused on the treatment of platinum-resistant metastatic urothelial cancer, as of late 2015 there are no standard therapies approved by the US FDA in this setting. However, preliminary results from a series of recent trials exploring innovative approaches forecast a 'sea change' in the management of this difficult to treat malignancy. Herein, we review new approaches for the management of patients with metastatic urothelial cancer focused on three key therapeutic target areas: recurrent somatic alterations, the tumor neovasculature and tumor-associated immune escape. PMID:26922914

  4. Metastatic malignant melanoma of the conjunctiva: a case report

    PubMed Central

    2009-01-01

    Background Malignant melanoma of the conjunctiva is an extremely rare non-cutaneous neoplasm with infrequent skeletal metastatic spread. Case presentation We present the case of a 54 year old female Caucasian patient with osseous metastases originating from a malignant melanoma of her right conjunctiva. Metastatic deposits were identified in the left humeral diaphysis and left tibial metaphysis. Clinical, radiological and scintigraphic evaluation necessitated prompt stabilisation of both long bones. Following reamed intramedullary nailing and post-operative radiotherapy she remains asymptomatic six months post-operatively. Conclusion This unusual pattern of metastatic spread to the appendicular skeleton of an extremely rare melanomatous lesion requires diagnostic vigilance as well as a multidisciplinary approach for accurate diagnosis, staging and management. Due to the poor prognosis, treatment goals should be directed to palliation of symptoms and prolongation of the quality of life. PMID:19193228

  5. Stratification and therapeutic potential of PML in metastatic breast cancer

    PubMed Central

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D.; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R.; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M.; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H.; Scaltriti, Maurizio; Lawrie, Charles H.; Aransay, Ana M.; Iovanna, Juan L.; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; dM Vivanco, Maria; Matheu, Ander; Gomis, Roger R.; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  6. Stratification and therapeutic potential of PML in metastatic breast cancer.

    PubMed

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  7. Undifferentiated metastatic renal cell carcinoma presenting as a cutaneous nodular lesion.

    PubMed

    Paolino, Giovanni; Lido, Paolo; Bei, Roberto; Polisca, Patrizio

    2015-12-01

    Cutaneous metastases may be the first sign of clinically silent visceral cancer. Approximately 30% of patients with primary renal cell carcinoma present with metastatic disease, and only 8% of them have skin metastases. We present the case of a 59-year-old male patient with a subcutaneous nodular on the upper chest extending to the jugular region. The lesion appeared skin colored and was not painful and 5 cm × 3.5 cm in diameter. The histological examination of the cutaneous biopsy showed an infiltration of undifferentiated epithelial cells positive to cytokeratins AE1/AE3, whereas they were negative to CK-20, CK5/6, cluster of differentiation 10, vimentin, thyroid transcription factor-1, S-100, human melanoma black-45, hepatocyte-specific antigen, carcinoembryonic antigen, and chromogranin A. A total-body computed tomography (CT) showed the presence of a tumoral lesion in the left kidney with multiple metastases in the lung, brain, and bones. According to the cutaneous biopsy and total-body CT, a final diagnosis of an undifferentiated renal carcinoma presenting as a subcutaneous metastasis was made. A chemotherapeutic treatment with gemcitabine and cisplatin resulted in the stabilization of the renal and metastatic lesions with an improvement in the quality of life of the patient. Considering that the prognosis of patients with cutaneous metastases is very poor, it is necessary to obtain an appropriate diagnosis in order to identify patients with treatable disease with the purpose of starting a therapeutic protocol. PMID:26623153

  8. Poor Americans: How the Poor White Live.

    ERIC Educational Resources Information Center

    Pilisuk, Marc; Pilisuk, Phyllis

    Contents of this book include the following essays which originally appeared in "Transaction" magazine: (1) "Poor Americans: an introduction," Marc Pilisuk and Phyllis Pilisuk; (2) "How the white poor live," Marc Pilisuk and Phyllis Pilisuk; (3) "The culture of poverty," Oscar Lewis; (4) "Life in Appalachia--the case of Hugh McCaslin," Robert…

  9. Quantifying metastatic inefficiency: rare genotypes versus rare dynamics

    NASA Astrophysics Data System (ADS)

    Cisneros, Luis H.; Newman, Timothy J.

    2014-08-01

    We introduce and solve a ‘null model’ of stochastic metastatic colonization. The model is described by a single parameter θ: the ratio of the rate of cell division to the rate of cell death for a disseminated tumour cell in a given secondary tissue environment. We are primarily interested in the case in which colonizing cells are poorly adapted for proliferation in the local tissue environment, so that cell death is more likely than cell division, i.e. \\theta \\lt 1. We quantify the rare event statistics for the successful establishment of a metastatic colony of size N. For N\\gg 1, we find that the probability of establishment is exponentially rare, as expected, and yet the mean time for such rare events is of the form \\sim log (N)/(1-\\theta ) while the standard deviation of colonization times is \\sim 1/(1-\\theta ). Thus, counter to naive expectation, for \\theta \\lt 1, the average time for establishment of successful metastatic colonies decreases with decreasing cell fitness, and colonies seeded from lower fitness cells show less stochastic variation in their growth. These results indicate that metastatic growth from poorly adapted cells is rare, exponentially explosive and essentially deterministic. These statements are brought into sharper focus by the finding that the temporal statistics of the early stages of metastatic colonization from low-fitness cells (\\theta \\lt 1) are statistically indistinguishable from those initiated from high-fitness cells (\\theta \\gt 1), i.e. the statistics show a duality mapping (1-\\theta )\\to (\\theta -1). We conclude our analysis with a study of heterogeneity in the fitness of colonising cells, and describe a phase diagram delineating parameter regions in which metastatic colonization is dominated either by low or high fitness cells, showing that both are plausible given our current knowledge of physiological conditions in human cancer.

  10. Lineage factors and differentiation states in lung cancer progression.

    PubMed

    Cheung, W K C; Nguyen, D X

    2015-11-19

    Lung cancer encompasses a heterogeneous group of malignancies. Here we discuss how the remarkable diversity of major lung cancer subtypes is manifested in their transforming cell of origin, oncogenic dependencies, phenotypic plasticity, metastatic competence and response to therapy. More specifically, we review the increasing evidence that links this biological heterogeneity to the deregulation of cell lineage-specific pathways and the transcription factors that ultimately control them. As determinants of pulmonary epithelial differentiation, these poorly characterized transcriptional networks may underlie the etiology and biological progression of distinct lung cancers, while providing insight into innovative therapeutic strategies. PMID:25823023

  11. Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

    PubMed Central

    Shiozawa, Yusuke; Eber, Matthew R; Berry, Janice E; Taichman, Russell S

    2015-01-01

    Bone marrow is a heterogeneous organ containing diverse cell types, and it is a preferred metastatic site for several solid tumors such as breast and prostate cancer. Recently, it has been shown that bone metastatic cancer cells interact with the bone marrow microenvironment to survive and grow, and thus this microenvironment is referred to as the ‘metastatic niche'. Once cancer cells spread to distant organs such as bone, the prognosis for the patient is generally poor. There is an urgent need to establish a greater understanding of the mechanisms whereby the bone marrow niche influences bone metastasis. Here we discuss insights into the contribution of the bone marrow ‘metastatic niche' to progression of bone metastatic disease, with a particular focus on cells of hematopoietic and mesenchymal origin. PMID:26029360

  12. Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

    PubMed

    Cheng, Shaun Kian Hong; Chuah, Khoon Leong

    2016-06-01

    The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas. PMID:27232353

  13. Circulating Carnosine Dipeptidase 1 Associates with Weight Loss and Poor Prognosis in Gastrointestinal Cancer

    PubMed Central

    Arner, Peter; Henjes, Frauke; Schwenk, Jochen M.; Darmanis, Spyros; Dahlman, Ingrid; Iresjö, Britt-Marie; Naredi, Peter; Agustsson, Thorhallur; Lundholm, Kent; Nilsson, Peter; Rydén, Mikael

    2015-01-01

    Background Cancer cachexia (CC) is linked to poor prognosis. Although the mechanisms promoting this condition are not known, several circulating proteins have been proposed to contribute. We analyzed the plasma proteome in cancer subjects in order to identify factors associated with cachexia. Design/Subjects Plasma was obtained from a screening cohort of 59 patients, newly diagnosed with suspected gastrointestinal cancer, with (n = 32) or without (n = 27) cachexia. Samples were subjected to proteomic profiling using 760 antibodies (targeting 698 individual proteins) from the Human Protein Atlas project. The main findings were validated in a cohort of 93 patients with verified and advanced pancreas cancer. Results Only six proteins displayed differential plasma levels in the screening cohort. Among these, Carnosine Dipeptidase 1 (CNDP1) was confirmed by sandwich immunoassay to be lower in CC (p = 0.008). In both cohorts, low CNDP1 levels were associated with markers of poor prognosis including weight loss, malnutrition, lipid breakdown, low circulating albumin/IGF1 levels and poor quality of life. Eleven of the subjects in the discovery cohort were finally diagnosed with non-malignant disease but omitting these subjects from the analyses did not have any major influence on the results. Conclusions In gastrointestinal cancer, reduced plasma levels of CNDP1 associate with signs of catabolism and poor outcome. These results, together with recently published data demonstrating lower circulating CNDP1 in subjects with glioblastoma and metastatic prostate cancer, suggest that CNDP1 may constitute a marker of aggressive cancer and CC. PMID:25898255

  14. A Protein Deep Sequencing Evaluation of Metastatic Melanoma Tissues

    PubMed Central

    Welinder, Charlotte; Pawłowski, Krzysztof; Sugihara, Yutaka; Yakovleva, Maria; Jönsson, Göran; Ingvar, Christian; Lundgren, Lotta; Baldetorp, Bo; Olsson, Håkan; Rezeli, Melinda; Jansson, Bo; Laurell, Thomas; Fehniger, Thomas; Döme, Balazs; Malm, Johan; Wieslander, Elisabet; Nishimura, Toshihide; Marko-Varga, György

    2015-01-01

    Malignant melanoma has the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has very limited possibilities for cure. Recently, several protein kinase inhibitors and immune modifiers have shown promising clinical results but drug resistance in metastasized melanoma remains a major problem. The need for routine clinical biomarkers to follow disease progression and treatment efficacy is high. The aim of the present study was to build a protein sequence database in metastatic melanoma, searching for novel, relevant biomarkers. Ten lymph node metastases (South-Swedish Malignant Melanoma Biobank) were subjected to global protein expression analysis using two proteomics approaches (with/without orthogonal fractionation). Fractionation produced higher numbers of protein identifications (4284). Combining both methods, 5326 unique proteins were identified (2641 proteins overlapping). Deep mining proteomics may contribute to the discovery of novel biomarkers for metastatic melanoma, for example dividing the samples into two metastatic melanoma “genomic subtypes”, (“pigmentation” and “high immune”) revealed several proteins showing differential levels of expression. In conclusion, the present study provides an initial version of a metastatic melanoma protein sequence database producing a total of more than 5000 unique protein identifications. The raw data have been deposited to the ProteomeXchange with identifiers PXD001724 and PXD001725. PMID:25874936

  15. The brain metastatic niche.

    PubMed

    Winkler, Frank

    2015-11-01

    Metastasizing cancer cells that arrest in brain microvessels have to face an organ microenvironment that is alien, and exclusive. In order to survive and thrive in this foreign soil, the malignant cells need to successfully master a sequence of steps that includes close interactions with pre-existing brain microvessels, and other nonmalignant cell types. Unfortunately, a relevant number of circulating cancer cells is capable of doing so: brain metastasis is a frequent and devastating complication of solid tumors, becoming ever more important in times where the systemic tumor disease is better controlled and life of cancer patients is prolonged. Thus, it is very important to understand which environmental cues are necessary for effective brain colonization. This review gives an overview of the niches we know, including those who govern cancer cell dormancy, survival, and proliferation in the brain. Colonization of pre-existing niches related to stemness and resistance is a hallmark of successful brain metastasis. A deeper understanding of those host factors can help to identify the most vulnerable steps of the metastatic cascade, which might be most amenable to therapeutic interventions. PMID:26489608

  16. Sterilizing the Poor

    ERIC Educational Resources Information Center

    Rothman, Sheila M.

    1977-01-01

    Suggests that freedom for the middle classes may mean vulnerability for the poor. The enthusiasm for sterilization may be so intense as to deprive the poor of their right not to be sterilized. (Author/AM)

  17. Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma.

    PubMed

    Faria, Claudia C; Golbourn, Brian J; Dubuc, Adrian M; Remke, Marc; Diaz, Roberto J; Agnihotri, Sameer; Luck, Amanda; Sabha, Nesrin; Olsen, Samantha; Wu, Xiaochong; Garzia, Livia; Ramaswamy, Vijay; Mack, Stephen C; Wang, Xin; Leadley, Michael; Reynaud, Denis; Ermini, Leonardo; Post, Martin; Northcott, Paul A; Pfister, Stefan M; Croul, Sidney E; Kool, Marcel; Korshunov, Andrey; Smith, Christian A; Taylor, Michael D; Rutka, James T

    2015-01-01

    Medulloblastoma is the most common malignant pediatric brain tumor, with metastases present at diagnosis conferring a poor prognosis. Mechanisms of dissemination are poorly understood and metastatic lesions are genetically divergent from the matched primary tumor. Effective and less toxic therapies that target both compartments have yet to be identified. Here, we report that the analysis of several large nonoverlapping cohorts of patients with medulloblastoma reveals MET kinase as a marker of sonic hedgehog (SHH)-driven medulloblastoma. Immunohistochemical analysis of phosphorylated, active MET kinase in an independent patient cohort confirmed its correlation with increased tumor relapse and poor survival, suggesting that patients with SHH medulloblastoma may benefit from MET-targeted therapy. In support of this hypothesis, we found that the approved MET inhibitor foretinib could suppress MET activation, decrease tumor cell proliferation, and induce apoptosis in SHH medulloblastomas in vitro and in vivo. Foretinib penetrated the blood-brain barrier and was effective in both the primary and metastatic tumor compartments. In established mouse xenograft or transgenic models of metastatic SHH medulloblastoma, foretinib administration reduced the growth of the primary tumor, decreased the incidence of metastases, and increased host survival. Taken together, our results provide a strong rationale to clinically evaluate foretinib as an effective therapy for patients with SHH-driven medulloblastoma. PMID:25391241

  18. [Cancer cell plasticity and metastatic dissemination].

    PubMed

    Moyret-Lalle, Caroline; Pommier, Roxane; Bouard, Charlotte; Nouri, Ebticem; Richard, Geoffrey; Puisieux, Alain

    Metastatic dissemination consists of a sequence of events resulting in the invasion by cancer cells of tissues located away from the primary tumour. This process is highly inefficient, since each event represents an obstacle that only a limited number of cells can overcome. However, two biological phenomena intrinsically linked with tumour development facilitate the dissemination of cancer cells throughout the body and promote the formation of metastases, namely the genetic diversity of cancer cells within a given tumour, which arises from their genetic instability and from successive clonal expansions, and cellular plasticity conveyed to the cells by micro-environmental signals. Genetic diversity increases the probability of selecting cells that are intrinsically resistant to biological and physical constraints encountered during metastatic dissemination, whereas cellular plasticity provides cells with the capacity to adapt to stressful conditions and to changes in the microenvironment. The epithelial-mesenchymal transition, an embryonic trans-differentiation process frequently reactivated during tumour development, plays an important role in that context by endowing tumor cells with a unique capacity of motility, survival and adaptability to the novel environments and stresses encountered during the invasion-metastasis cascade. PMID:27615180

  19. Metastatic melanoma: Pathologic characterization, current treatment, and complications of therapy.

    PubMed

    Wick, Mark R; Gru, Alejandro A

    2016-07-01

    Metastatic melanoma (MM) has the potential to involve virtually any anatomical site, and it also has a wide spectrum of histological appearances. General clinicopathologic data pertaining to MM are presented in this review, together with a discussion of its differential diagnosis and therapy. "Biological" agents used in the treatment of melanoma are considered, along with the pathological features of the complications that they may cause. PMID:27234321

  20. Markers of metastatic carcinoma of breast origin.

    PubMed

    Gown, Allen M; Fulton, Regan S; Kandalaft, Patricia L

    2016-01-01

    This review summarizes the three major breast-associated markers that can be of assistance in evaluating metastatic carcinomas for which a breast primary diagnosis is entertained. These markers include gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, and GATA3. The first two are cytoplasmic markers that show comparable sensitivities for breast cancer, although relatively few of the published studies have employed the same antibodies against the target molecule, making direct comparisons challenging. GATA3 is a nuclear transcription factor that shows superior sensitivity to GCDFP-15 and mammaglobin. However, the specificity of GATA3 can pose challenges, inasmuch as carcinomas of the bladder and other sites can show significant levels of positivity. Determination of the optimal panel of antibodies employed in a given clinical setting will thus depend on the non-breast tumours included in the differential diagnosis. PMID:26768031

  1. ERBB4 confers metastatic capacity in Ewing sarcoma

    PubMed Central

    Mendoza-Naranjo, Ariadna; El-Naggar, Amal; Wai, Daniel H; Mistry, Priti; Lazic, Nikola; Ayala, Fernanda Rocha Rojas; da Cunha, Isabela Werneck; Rodriguez-Viciana, Pablo; Cheng, Hongwei; Tavares Guerreiro Fregnani, Jose H; Reynolds, Patrick; Arceci, Robert J; Nicholson, Andrew; Triche, Timothy J; Soares, Fernando A; Flanagan, Adrienne M; Wang, Yuzhuo Z; Strauss, Sandra J; Sorensen, Poul H

    2013-01-01

    Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK-Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES. PMID:23681745

  2. Surgical Management of Metastatic Disease.

    PubMed

    Keung, Emily Z; Fairweather, Mark; Raut, Chandrajit P

    2016-10-01

    Sarcomas are rare cancers of mesenchymal cell origin that include many histologic subtypes and molecularly distinct entities. For primary resectable sarcoma, surgery is the mainstay of treatment. Despite treatment, approximately 50% of patients with soft tissue sarcoma are diagnosed with or develop distant metastases, significantly affecting their survival. Although systemic therapy with conventional chemotherapy remains the primary treatment modality for those with metastatic sarcoma, increased survival has been achieved in select patients who receive multimodality therapy, including surgery, for their metastatic disease. This article provides an overview of the literature on surgical management of pulmonary and hepatic sarcoma metastases. PMID:27542649

  3. Metastatic large cell neuroendocrine carcinoma of the lung arising from the uterus: A pitfall in lung cancer diagnosis.

    PubMed

    Ono, Kyoko; Yokota, Naho Ruiz; Yoshioka, Emi; Noguchi, Akira; Washimi, Kota; Kawachi, Kae; Miyagi, Yohei; Kato, Hisamori; Yokose, Tomoyuki

    2016-07-01

    A 41-year-old female smoker presented with a vaginal mass. Gynecological examination showed a mass filling the uterine corpus, cervix, and vagina. A total abdominal hysterectomy was performed. Macroscopic findings included a large fragile mass involving the uterine cavity, cervix, and vagina. Histology revealed atypical ducts admixed with solid components consisting of large atypical cells. The initial pathological diagnosis was grade 3 endometrioid adenocarcinoma. The patient was designated as stage II according to the 2008 International Federation of Gynecology and Obstetrics (FIGO) staging. Two years later, two nodules were found in the upper lobe of the left lung, and the patient underwent an upper lobectomy. The masses, which exhibited solid and organoid growth patterns of large atypical cells, had histological characteristics of large cell neuroendocrine carcinoma (LCNEC) of the lung. However, the tumor was immunohistochemically positive for neuroendocrine markers, such as synaptophysin in addition to estrogen receptor and progesterone receptor, and the tumor was negative for thyroid transcription factor-1. These immunohistochemical results were almost identical to those of the solid portions of the uterine carcinoma. The final diagnosis was LCNEC combined with endometrioid adenocarcinoma of the uterine corpus and lung metastasis of the LCNEC component of the endometrial carcinoma. LCNEC often arises in the lung, but it rarely arises in other organs. Some patients with metastatic components exhibited only a LCNEC pattern although the primary tumor was a mixed carcinoma consisting of LCNEC and other histology, like the present case. LCNEC is often poorly differentiated, especially in extrapulmonary primary organ LCNEC. Therefore, pathologists should consider metastatic carcinoma when they encounter lung LCNEC in a patient with a preceding extrapulmonary carcinoma composed of a poorly differentiated component or LCNEC component, and they should clarify tumor

  4. A systems biology approach reveals common metastatic pathways in osteosarcoma

    PubMed Central

    2012-01-01

    Background Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. The survival rate of patients with metastatic disease remains very dismal. Nevertheless, metastasis is a complex process and a single-level analysis is not likely to identify its key biological determinants. In this study, we used a systems biology approach to identify common metastatic pathways that are jointly supported by both mRNA and protein expression data in two distinct human metastatic OS models. Results mRNA expression microarray and N-linked glycoproteomic analyses were performed on two commonly used isogenic pairs of human metastatic OS cell lines, namely HOS/143B and SaOS-2/LM7. Pathway analysis of the differentially regulated genes and glycoproteins separately revealed pathways associated to metastasis including cell cycle regulation, immune response, and epithelial-to-mesenchymal-transition. However, no common significant pathway was found at both genomic and proteomic levels between the two metastatic models, suggesting a very different biological nature of the cell lines. To address this issue, we used a topological significance analysis based on a “shortest-path” algorithm to identify topological nodes, which uncovered additional biological information with respect to the genomic and glycoproteomic profiles but remained hidden from the direct analyses. Pathway analysis of the significant topological nodes revealed a striking concordance between the models and identified significant common pathways, including “Cytoskeleton remodeling/TGF/WNT”, “Cytoskeleton remodeling/Cytoskeleton remodeling”, and “Cell adhesion/Chemokines and adhesion”. Of these, the “Cytoskeleton remodeling/TGF/WNT” was the top ranked common pathway from the topological analysis of the genomic and proteomic profiles in the two metastatic models. The up-regulation of proteins in the “Cytoskeleton remodeling/TGF/WNT” pathway in the SaOS-2/LM7 and HOS/143B models

  5. Rich Donors, Poor Countries

    ERIC Educational Resources Information Center

    Thomas, M. A.

    2012-01-01

    The shifting ideological winds of foreign aid donors have driven their policy towards governments in poor countries. Donors supported state-led development policies in poor countries from the 1940s to the 1970s; market and private-sector driven reforms during the 1980s and 1990s; and returned their attention to the state with an emphasis on…

  6. Inference in `poor` languages

    SciTech Connect

    Petrov, S.

    1996-10-01

    Languages with a solvable implication problem but without complete and consistent systems of inference rules (`poor` languages) are considered. The problem of existence of finite complete and consistent inference rule system for a ``poor`` language is stated independently of the language or rules syntax. Several properties of the problem arc proved. An application of results to the language of join dependencies is given.

  7. Quantitative mitochondrial redox imaging of breast cancer metastatic potential

    NASA Astrophysics Data System (ADS)

    Xu, He N.; Nioka, Shoko; Glickson, Jerry D.; Chance, Britton; Li, Lin Z.

    2010-05-01

    Predicting tumor metastatic potential remains a challenge in cancer research and clinical practice. Our goal was to identify novel biomarkers for differentiating human breast tumors with different metastatic potentials by imaging the in vivo mitochondrial redox states of tumor tissues. The more metastatic (aggressive) MDA-MB-231 and less metastatic (indolent) MCF-7 human breast cancer mouse xenografts were imaged with the low-temperature redox scanner to obtain multi-slice fluorescence images of reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp). The nominal concentrations of NADH and Fp in tissue were measured using reference standards and used to calculate the Fp redox ratio, Fp/(NADH+Fp). We observed significant core-rim differences, with the core being more oxidized than the rim in all aggressive tumors but not in the indolent tumors. These results are consistent with our previous observations on human melanoma mouse xenografts, indicating that mitochondrial redox imaging potentially provides sensitive markers for distinguishing aggressive from indolent breast tumor xenografts. Mitochondrial redox imaging can be clinically implemented utilizing cryogenic biopsy specimens and is useful for drug development and for clinical diagnosis of breast cancer.

  8. Aberrant metastatic behavior and particular features of early gastric cancer.

    PubMed

    Gurzu, Simona; Jung, Ioan; Kadar, Zoltan

    2015-12-01

    In this paper, we have focused on the metastatic behavior of EGC and its particularities. The main factors that are currently considered as predictors of the metastatic behavior and that are used in the therapeutic decision (endoscopic resection vs surgical removal) are the tumor size (upper or bellow 2 cm), depth of infiltration, angiolymphatic invasion, the presence or absence of ulceration, and histologic type (undifferentiated vs differentiated carcinomas). However, most of the metastatic cases were published as case reports or case series. This is the reason why a proper estimation of metastatic risk in EGC is not well known. To date, 79 cases presenting bone metastases, three reports of brain metastases, and one EGC that was associated with skin metastasis were published. However, occult metastasis, lymph node micrometastasis, and skip metastasis can also occur and should be identified. Making a synthesis of the literature data that is correlated with our experience, we finally proposed the inclusion of the six Japanese subgrouping system, tumor size, angiolymphatic invasion, and micrometastasis as components of the pTNM staging system, which should be particularly adapted for EGC. PMID:26547366

  9. Immunotherapy for metastatic prostate cancer

    PubMed Central

    Drake, Charles G.

    2016-01-01

    Chemotherapy with docetaxel is the standard treatment for men with metastatic prostate cancer, and results in statistically significant improvements in survival, as well as in quality of life. However, the response rate to single-agent docetaxel is approximately 40% to 45%, emphasizing a need for alternative approaches. More significantly, with the onset of early, PSA-based detection of prostate cancer and closer follow-up, many men present with metastatic disease that remains asymptomatic. For such patients, the side effects of chemotherapy would compromise their current performance status and, thus, a nontoxic, early treatment option that could improve overall survival would be highly desirable. Immunotherapy represents one such approach; a number of clinical trials have suggested a survival benefit for immunotherapy in metastatic prostate cancer and confirmed that these agents are generally well-tolerated. As is the case for chemotherapy, it is doubtful that maximal survival benefit will be achieved with single-agent immunotherapy; experimental treatments in which mechanistically distinct immunotherapy approaches are combined, as well as approaches in which immunotherapy is combined with chemotherapy or hormonal therapy are currently under investigation. This review will discuss the mechanisms of action of several immunotherapy approaches for metastatic prostate cancer, focusing on active immunotherapy as opposed to administration of anti-tumor antibodies. The relative advantages and disadvantages of current approaches will be noted, and ongoing clinical trials will be highlighted. PMID:18593624

  10. miR-221/222 Are Involved in Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma.

    PubMed

    Khella, Heba W Z; Butz, Henriett; Ding, Qiang; Rotondo, Fabio; Evans, Kenneth R; Kupchak, Peter; Dharsee, Moyez; Latif, Ashraf; Pasic, Maria D; Lianidou, Evi; Bjarnason, Georg A; Yousef, George M

    2015-11-01

    Sunitinib is a multitargeting tyrosine kinase inhibitor used for metastatic renal cancer. There are no biomarkers that can predict sunitinib response. Such markers are needed to avoid administration of costly medication with side effects to patients who would not benefit from it. We compared global miRNA expression between patients with a short (≤12 months) versus prolonged (>12 months) progression-free survival (PFS) under sunitinib as first-line therapy for metastatic renal cell carcinoma. We identified a number of differentially expressed miRNAs and developed miRNA statistical models that can accurately distinguish between the two groups. We validated our models in the discovery set and an independent set of 57 patients. Target prediction and pathway analysis showed that these miRNAs are involved in vascular endothelial growth factor (VEGF), TGFβ, and mammalian target of rapamycin (mTOR)-mediated signaling and cell-cell communication. We tested the effect of these miRNAs on cellular proliferation and angiogenesis. We validated the negative correlation between miR-221 and its target, VEGFR2.miR-221 overexpression was associated with a poor PFS while its target, VEGFR2 was associated with longer survival. Gain of function experiments showed that miR-221 and miR-222 decreased angiogenesis and cellular proliferation in human umbilical vein endothelial cells (HUVEC) while increasing cellular proliferation in ACHN cells. miRNAs represent potential predictive markers for sunitinib response. PMID:26201448

  11. Metastatic Malignant Ectomesenchymoma Initially Presenting as a Pelvic Mass: Report of a Case and Review of Literature

    PubMed Central

    Nael, A.; Siaghani, P.; Wu, W. W.; Nael, K.; Shane, Lisa; Romansky, S. G.

    2014-01-01

    Pediatric soft tissue sarcomas account for approximately 10% of all pediatric malignancies. Malignant ectomesenchymoma is rare biphasic sarcomas consisting of both mesenchymal and neuroectodermal elements. Approximately 64 cases have been reported in the literature and are believed to arise from pluripotent embryologic migratory neural crest cells. We report a 4-year-old boy who initially presented with a pelvic mass and inguinal lymphadenopathy at 6 months of age. Inguinal lymph node biopsy revealed a distinct biphasic tumor with microscopic and immunophenotypic characteristics diagnostic for both alveolar rhabdomyosarcoma and poorly differentiated neuroblastoma. The patient received national protocol chemotherapy against rhabdomyosarcoma with good response and presented with a cerebellar mass 21 months later. The metastatic tumor revealed sheets of primitive tumor cells and diagnostic areas of rhabdomyosarcoma and neuroblastoma were identified only by immunohistochemistry. Cytogenetic analysis of metastatic tumor demonstrated complex karyotype with multiple chromosomal deletions and duplications. The patient received national protocol chemotherapy against neuroblastoma and adjuvant radiotherapy after surgical resection of the cerebellar tumor with good response. He is currently off from any treatment for 18 months with no evidence of tumor recurrence or metastasis. PMID:25405050

  12. Continuation of trastuzumab beyond disease progression in HER2-positive metastatic gastric cancer: the MD Anderson experience

    PubMed Central

    Fahmawi, Yazan; Dahbour, Ibrahim; Tabash, Aziz; Rogers, Jane E.; Mares, Jeannette Elizabeth; Blum, Mariela A.; Estrella, Jeannelyn; Matamoros, Aurelio; Sagebiel, Tara; Devine, Catherine E.; Badgwell, Brian D.; Lin, Quan D.; Das, Prajnan; Ajani, Jaffer A.

    2016-01-01

    Background Despite the wide spread use of trastuzumab in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic gastric cancer patients, its optimal duration of administration beyond first-line disease progression is unknown. In HER2 overexpressing metastatic breast cancer, trastuzumab continuation beyond first-line disease progression has shown improvement in time to progression (TTP) without an increased risk of treatment related toxicity. Methods HER2-overexpressing metastatic gastric cancer patients were identified from our database between January 2010 and December 2014. We retrospectively reviewed the medical records of 43 patients who received trastuzumab in combination with chemotherapy as first-line and continued trastuzumab beyond disease progression. Results Forty-three cases were identified, 27 males (62.8%), median age of the patients was 58 years. Thirty-five (81.4%) presented with stage 4 as their initial presentation. Eighty one percent had 3+ HER2 overexpression by immunohistochemistry (IHC) and 18% had 2+ HER2 overexpression confirmed by fluorescence in situ hybridization (FISH). Thirteen (52%) were moderately differentiated, 16 (37.1%) were poorly differentiated. The most common sites of metastasis were liver 35 (81.4%) and lung 14 (32.5%). The most commonly used first-line regimen was oxaliplatin, 5-fluorouracil (5-FU), and trastuzumab in 22 (51.1%) patients. Twenty-five (58.1%) patients received irinotecan, 5-FU and trastuzumab in the second-line. Progression-free survival (PFS) was 5 months (95% CI: 4.01–5.99 months). Five patients are still alive and excluded from calculating the median overall survival (OS) which was 11 months (range, 5–53 months) for the remaining 20 subjects of this second-line group. Trastuzumab was not discontinued due to side effects in any of the study population. Conclusions In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in

  13. Are poor Chinese text comprehenders also poor in written composition?

    PubMed

    Guan, Connie Qun; Ye, Feifei; Meng, Wanjin; Leong, Che Kan

    2013-10-01

    We studied the performance in three genres of Chinese written composition (narration, exposition, and argumentation) of 158 grade 4, 5, and 6 poor Chinese text comprehenders compared with 156 good Chinese text comprehenders. We examined text comprehension and written composition relationship. Verbal working memory (verbal span working memory and operation span working memory) and different levels of linguistic tasks-morphological sensitivity (morphological compounding and morphological chain), sentence processing (syntax construction and syntax integrity), and text comprehension (narrative and expository texts)-were used to predict separately narrative, expository, and argumentation written compositions in these students. Grade for grade, the good text comprehenders outperformed the poor text comprehenders in all tasks, except for morphological chain. Hierarchical multiple regression analyses showed differential contribution of the tasks to different genres of writing. In particular, text comprehension made unique contribution to argumentation writing in the poor text comprehenders. Future studies should ask students to read and write parallel passages in the same genre for better comparison and incorporate both instructional and motivational variables. PMID:23666849

  14. A metastatic ovarian angiosarcoma mimicking hematologic neoplasia at diagnosis.

    PubMed

    Gaiolla, Rafael Dezen; Duarte, Ivison Xavier; Bacchi, Carlos Eduardo; Paiva, Carlos Eduardo

    2014-01-01

    Angiosarcomas are rare aggressive neoplasms of vascular endothelial origin with a high metastatic rate and poor prognosis. Involvement of the bone marrow by the angiosarcoma is exceedingly uncommon, and there have only been a few cases reported in the literature to date. Clinical manifestations and common laboratory findings of bone marrow involvement can mimic other more common bone marrow-replacing neoplasias such as lymphomas and acute leukemia. A definitive diagnosis is difficult to make from cytologic material, probably due to an associated bone marrow fibrosis, and requires bone marrow trephine biopsy with an immunohistochemical profile. Here we had the opportunity to study a case of metastatic angiosarcoma with positive cytologic findings and an unusual presentation that challenged its primary diagnosis. PMID:24847252

  15. A Metastatic Ovarian Angiosarcoma Mimicking Hematologic Neoplasia at Diagnosis

    PubMed Central

    Gaiolla, Rafael Dezen; Duarte, Ívison Xavier; Bacchi, Carlos Eduardo; Paiva, Carlos Eduardo

    2014-01-01

    Angiosarcomas are rare aggressive neoplasms of vascular endothelial origin with a high metastatic rate and poor prognosis. Involvement of the bone marrow by the angiosarcoma is exceedingly uncommon, and there have only been a few cases reported in the literature to date. Clinical manifestations and common laboratory findings of bone marrow involvement can mimic other more common bone marrow-replacing neoplasias such as lymphomas and acute leukemia. A definitive diagnosis is difficult to make from cytologic material, probably due to an associated bone marrow fibrosis, and requires bone marrow trephine biopsy with an immunohistochemical profile. Here we had the opportunity to study a case of metastatic angiosarcoma with positive cytologic findings and an unusual presentation that challenged its primary diagnosis. PMID:24847252

  16. Poorly controlled gout: who is doing poorly?

    PubMed Central

    Chia, Faith Li-Ann

    2016-01-01

    Gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals, is commonly seen in primary care and specialist clinics. In recent years, there has been a resurgence of interest in gout due to advances in therapies and the understanding of pathophysiology, with new guidelines being published by international bodies. However, there is still a gap between the goals of treatment and actual day-to-day practice. Barriers that result in poorly controlled gout include patient factors such as lack of understanding of the disease, stigma and nonadherence to treatment, as well as physician factors such as knowledge gaps, inadequate use of allopurinol and lack of ownership of the disease. The medical profession needs to do more to bridge the gap through physician and patient education, identification of treatment targets with appropriate use of drugs, and dissemination of guidelines. PMID:27549096

  17. Poorly controlled gout: who is doing poorly?

    PubMed

    Chia, Faith Li-Ann

    2016-08-01

    Gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals, is commonly seen in primary care and specialist clinics. In recent years, there has been a resurgence of interest in gout due to advances in therapies and the understanding of pathophysiology, with new guidelines being published by international bodies. However, there is still a gap between the goals of treatment and actual day-to-day practice. Barriers that result in poorly controlled gout include patient factors such as lack of understanding of the disease, stigma and nonadherence to treatment, as well as physician factors such as knowledge gaps, inadequate use of allopurinol and lack of ownership of the disease. The medical profession needs to do more to bridge the gap through physician and patient education, identification of treatment targets with appropriate use of drugs, and dissemination of guidelines. PMID:27549096

  18. Metastatic colon cancer from extrahepatic cholangiocarcinoma presenting as painless jaundice: case report and literature review

    PubMed Central

    Vabi, Benjamin W.; Carter, Jeffrey; Rong, Rong; Wang, Minhua; Corasanti, James G.

    2016-01-01

    Cholangiocarcinoma (CCA) is a rare cancer of the biliary epithelium comprising only about 3% of all gastrointestinal malignancies. It is a highly aggressive malignancy and confers a dismal prognosis with majority of patients presenting with metastatic disease. Metastatic CCA to the colon is extremely rare with only few cases reported in the literature. We present a 61-year-old patient with incidental synchronous metastatic colonic adenocarcinoma from extra-hepatic CCA. Laboratory data revealed significant indirect hyperbilirubinemia and transaminitis. Imaging study showed intrahepatic bile ducts prominence without mass lesions. Incidentally, there was diffuse colonic thickening without mass lesions or obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) showed a common bile duct stricture. Brushings were consistent with CCA. Screening colonoscopy identified nodularity and biopsy and immunostaining were consistent with CCA metastasis to colon. The patient elected for palliative and comfort care. Metastatic CCA to the colon is a rare pattern of distant spread that may pose a diagnostic challenge. Some salient characteristics may assist in the differentiation of primary colon cancer and metastatic colon cancer from CCA. Little remains known about the pathogenic behavior of metastatic secondary colorectal cancer. And more so, the management approach to such metastatic cancer still remains to be defined. Screening colonoscopy in patients presenting with resectable CCA may alter management. Furthermore, whether patients with history of resected CCA may benefit from a more frequent screening colonoscopy remains to be validated. PMID:27034804

  19. Metastatic colon cancer from extrahepatic cholangiocarcinoma presenting as painless jaundice: case report and literature review.

    PubMed

    Vabi, Benjamin W; Carter, Jeffrey; Rong, Rong; Wang, Minhua; Corasanti, James G; Gibbs, John F

    2016-04-01

    Cholangiocarcinoma (CCA) is a rare cancer of the biliary epithelium comprising only about 3% of all gastrointestinal malignancies. It is a highly aggressive malignancy and confers a dismal prognosis with majority of patients presenting with metastatic disease. Metastatic CCA to the colon is extremely rare with only few cases reported in the literature. We present a 61-year-old patient with incidental synchronous metastatic colonic adenocarcinoma from extra-hepatic CCA. Laboratory data revealed significant indirect hyperbilirubinemia and transaminitis. Imaging study showed intrahepatic bile ducts prominence without mass lesions. Incidentally, there was diffuse colonic thickening without mass lesions or obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) showed a common bile duct stricture. Brushings were consistent with CCA. Screening colonoscopy identified nodularity and biopsy and immunostaining were consistent with CCA metastasis to colon. The patient elected for palliative and comfort care. Metastatic CCA to the colon is a rare pattern of distant spread that may pose a diagnostic challenge. Some salient characteristics may assist in the differentiation of primary colon cancer and metastatic colon cancer from CCA. Little remains known about the pathogenic behavior of metastatic secondary colorectal cancer. And more so, the management approach to such metastatic cancer still remains to be defined. Screening colonoscopy in patients presenting with resectable CCA may alter management. Furthermore, whether patients with history of resected CCA may benefit from a more frequent screening colonoscopy remains to be validated. PMID:27034804

  20. Recombinant Arabidopsis HSP70 Sustains Cell Survival and Metastatic Potential of Breast Cancer Cells.

    PubMed

    Nigro, Alessandra; Mauro, Loredana; Giordano, Francesca; Panza, Salvatore; Iannacone, Rina; Liuzzi, Grazia Maria; Aquila, Saveria; De Amicis, Francesca; Cellini, Francesco; Indiveri, Cesare; Panno, Maria Luisa

    2016-05-01

    The chaperone HSP70 protein is widely present in many different tumors and its expression correlates with an increased cell survival, low differentiation, and poor therapeutic outcome in human breast cancer. The intracellular protein has prevalently a cytoprotective function, while the extracellular HSP70 mediates immunologic responses. Evolutionarily, HSPs are well conserved from prokaryotes to eukaryotes, and human HSP70 shows a strong similarity to that of plant origin. In the current article, we have tested the potential effect of recombinant HSP70, from Arabidopsis thaliana, on cell survival and metastatic properties of breast cancer cells. Our data show that HSP70 sustains cell viability in MCF-7 and MDA-MB-231 breast tumoral cells and increases Cyclin D1 and Survivin expression. The extracellular HSP70 triggers cell migration and the activation of MMPs particularly in MDA-MB-231 cells. Furthermore, under UV-induced stress condition, the low levels of phospho-AKT were increased by exogenous HSP70, together with the upregulation of Cyclin D1, particularly in the tumoral cell phenotype. On the other hand, UV increased TP53 expression, and the coincubation of HSP70 lowers the TP53 levels similar to the control. These findings correlate with the cytoprotective and antiapoptotic role of HSPs, as reported in different cellular contexts. This is the first study on mammary cells that highlights how the heterologous HSP70 from Arabidopsis thaliana sustains cell survival prevalently in breast cancer cell types, thus maintaining their metastatic potential. Therefore, targeting HSP70 would be of clinical importance since HSP70 blocking selectively targets tumor cells, in which it supports cell growth and survival. Mol Cancer Ther; 15(5); 1063-73. ©2016 AACR. PMID:26939699

  1. Metastatic cancer stem cells: new molecular targets for cancer therapy.

    PubMed

    Leirós, G J; Balañá, M E

    2011-11-01

    The cancer stem cell (CSC) hypothesis, predicts that a small subpopulation of cancer cells that possess "stem-like" characteristics, are responsible for initiating and maintaining cancer growth. According to the CSC model the many cell populations found in a tumour might represent diverse stages of differentiation. From the cellular point of view metastasis is considered a highly inefficient process and only a subset of tumour cells is capable of successfully traversing the entire metastatic cascade and eventually re-initiates tumour growth at distant sites. Some similar features of both normal and malignant stem cells suggest that CSCs are not only responsible for tumorigenesis, but also for metastases. The CSC theory proposes that the ability of a tumour to metastasize is an inherent property of a subset of CSCs. The similar biological characteristics shared by normal stem cells (NSCs) and CSCs mainly implicate self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements and specific homing to metastatic sites and may have important implications in terms of new approaches to cancer therapy in the metastatic setting. There are several agents targeting many of these CSC features that have shown to be effective both in vitro and in vivo. Although clinical trials results are still preliminary and continue under investigation, these new therapies are very promising. The identification of new therapeutic targets and drugs based on CSC model constitutes a great challenge. PMID:21470128

  2. Cutaneous metastatic pigmented breast carcinoma.

    PubMed

    Gaitan-Gaona, Francisco; Said, Mirra C; Valdes-Rodriguez, Rodrigo

    2016-01-01

    A 66-year-old woman presented with a 3 cm black, ulcerated nodule located on the skin of the upper abdomen, just below the breast. The lesion was painful to the touch, but the patient reported no other associated symptoms and was otherwise healthy. A 4-mm punch biopsy of the affected skin was obtained and the histological diagnosis was cutaneous metastatic pigmented breast carcinoma. PMID:27136637

  3. Metastatic Small-Cell Neuroendocrine Carcinoma Simulating Circumscribed Choroidal Hemangioma

    PubMed Central

    Leahy, Kate E.; Karaconji, Tanya; Thanni, Valli; Achan, Anita; Fung, Adrian T.

    2015-01-01

    Aim To report a case of metastatic small-cell neuroendocrine carcinoma presenting as an isolated choroidal mass and initially misdiagnosed as a circumscribed choroidal hemangioma. Methods The clinical history, fundus findings, imaging, cytology and immunohistochemical features are described. Results An otherwise healthy 66-year-old man was referred for a left nasal scotoma and a diagnosis of circumscribed choroidal hemangioma. Cytology showed cohesive clusters of small-to-intermediate malignant cells. The atypical cells stained positively for chromogranin, thyroid transcription factor-1 and synaptophysin consistent with small-cell neuroendocrine carcinoma. Conclusion Small-cell neuroendocrine carcinoma metastatic to the choroid is extremely rare; however, it is particularly aggressive and should be included in the differential diagnosis of isolated choroidal lesions, even in otherwise healthy patients. PMID:27171748

  4. Organ vascularity and metastatic frequency.

    PubMed Central

    Weiss, L.; Haydock, K.; Pickren, J. W.; Lane, W. W.

    1980-01-01

    The "hemodynamic" or "mechanical" theory proposes that the frequency of metastases in different organs is primarily determined by the numbers of cancer cells delivered to them in their arterial blood. This theory has not yet been adequately tested in man because reproducible, noninvasive measurements of organ blood flow have only recently become available. Correlation between these data and the metastatic frequency in 10 organs, in groups of patients with primary cancers in 15 anatomic sites, has therefore been sought. No correlation was obtained between metastatic frequency and organ weights, blood volumes, blood volumes per gram, "transit times," or blood flow. However, correlations significant at the 4-8% level were obtained between organ blood flow per gram and metastatic frequency in 4 of 5 groups of primary cancers with initial venous drainage into the portal system, compared with 1 of 10 draining into the caval system. At present, no definitive explanation can be offered for the apparent compliance of one set of primary cancers with the "hemodynamic" theory of metastasis, but not the others. PMID:7446696

  5. Characterization of the metastatic phenotype of a panel of established osteosarcoma cells.

    PubMed

    Ren, Ling; Mendoza, Arnulfo; Zhu, Jack; Briggs, Joseph W; Halsey, Charles; Hong, Ellen S; Burkett, Sandra S; Morrow, James; Lizardo, Michael M; Osborne, Tanasa; Li, Samuel Q; Luu, Hue H; Meltzer, Paul; Khanna, Chand

    2015-10-01

    Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metastatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models. PMID:26320182

  6. Poor school performance.

    PubMed

    Karande, Sunil; Kulkarni, Madhuri

    2005-11-01

    Education is one of the most important aspects of human resource development. Poor school performance not only results in the child having a low self-esteem, but also causes significant stress to the parents. There are many reasons for children to under perform at school, such as, medical problems, below average intelligence, specific learning disability, attention deficit hyperactivity disorder, emotional problems, poor socio-cultural home environment, psychiatric disorders and even environmental causes. The information provided by the parents, classroom teacher and school counselor about the child's academic difficulties guides the pediatrician to form an initial diagnosis. However, a multidisciplinary evaluation by an ophthalmologist, otolaryngologist, counselor, clinical psychologist, special educator, and child psychiatrist is usually necessary before making the final diagnosis. It is important to find the reason(s) for a child's poor school performance and come up with a treatment plan early so that the child can perform up to full potential. PMID:16391452

  7. Mesotheliomas show higher hyaluronan positivity around tumor cells than metastatic pulmonary adenocarcinomas.

    PubMed

    Törrönen, Kari; Soini, Ylermi; Pääkkö, Paavo; Parkkinen, Jyrki; Sironen, Reijo; Rilla, Kirsi

    2016-10-01

    Hyaluronan is a unique glycosaminoglycan of the extracellular matrix, abundant in normal connective tissues but highly increased in many pathological conditions like cancer. Mesothelioma, one of the most malignant cancer types, is associated with high content of hyaluronan, with elevated levels of hyaluronan in pleural effusions and serum of the patients. Metastatic lung adenocarcinomas are typically less aggressive and have a better prognosis as compared to mesotheliomas, a reason why it is highly important to find reliable tools to differentiate these cancer types. The main purpose of this study was to evaluate the amount of hyaluronan, hyaluronan producing synthases (HAS's) and hyaluronan receptor CD44, in mesothelioma and metastatic lung adenocarcinomas. Furthermore, we wanted to clarify the role of hyaluronan, CD44 and HAS's as putative markers for differentiating malignant mesothelioma from metastatic lung adenocarcinomas. The main finding of this study was that mesotheliomas are significantly more positive for hyaluronan staining than metastatic adenocarcinomas. Unexceptionally, a trend of CD44 positivity of stromal cells was higher in adenocarcinomas as compared to mesotheliomas. However, no statistically significant differences were found between the staining of any of the HAS isoenzymes either in tumor cells or stromal cells of different groups of cases. The results show that there are significant differences in hyaluronan content between metastatic lung adenocarcinomas and mesotheliomas. However, as previous studies have suggested, hyaluronan alone is not a sufficient independent marker for diagnostic differentiation of these cancer types, but could be utilized as a combination together with other specific markers. PMID:26912058

  8. Gene expression profiles of prostate cancer reveal involvement of multiple molecular pathways in the metastatic process

    PubMed Central

    Chandran, Uma R; Ma, Changqing; Dhir, Rajiv; Bisceglia, Michelle; Lyons-Weiler, Maureen; Liang, Wenjing; Michalopoulos, George; Becich, Michael; Monzon, Federico A

    2007-01-01

    Background Prostate cancer is characterized by heterogeneity in the clinical course that often does not correlate with morphologic features of the tumor. Metastasis reflects the most adverse outcome of prostate cancer, and to date there are no reliable morphologic features or serum biomarkers that can reliably predict which patients are at higher risk of developing metastatic disease. Understanding the differences in the biology of metastatic and organ confined primary tumors is essential for developing new prognostic markers and therapeutic targets. Methods Using Affymetrix oligonucleotide arrays, we analyzed gene expression profiles of 24 androgen-ablation resistant metastatic samples obtained from 4 patients and a previously published dataset of 64 primary prostate tumor samples. Differential gene expression was analyzed after removing potentially uninformative stromal genes, addressing the differences in cellular content between primary and metastatic tumors. Results The metastatic samples are highly heterogenous in expression; however, differential expression analysis shows that 415 genes are upregulated and 364 genes are downregulated at least 2 fold in every patient with metastasis. The expression profile of metastatic samples reveals changes in expression of a unique set of genes representing both the androgen ablation related pathways and other metastasis related gene networks such as cell adhesion, bone remodelling and cell cycle. The differentially expressed genes include metabolic enzymes, transcription factors such as Forkhead Box M1 (FoxM1) and cell adhesion molecules such as Osteopontin (SPP1). Conclusion We hypothesize that these genes have a role in the biology of metastatic disease and that they represent potential therapeutic targets for prostate cancer. PMID:17430594

  9. Morphosyntax in Poor Comprehenders

    ERIC Educational Resources Information Center

    Adlof, Suzanne M.; Catts, Hugh W.

    2015-01-01

    Children described as "poor comprehenders" (PCs) have reading comprehension difficulties in spite of adequate word reading abilities. PCs are known to display weakness with semantics and higher-level aspects of oral language, but less is known about their grammatical skills, especially with regard to morphosyntax. The purpose of this…

  10. Treatment of severe metastatic calcification and calciphylaxis in dialysis patients.

    PubMed

    Goel, Saurabh K; Bellovich, Keith; McCullough, Peter A

    2011-01-01

    Metastatic calcification is a frequent complication encountered in patients undergoing maintenance dialysis and has a complex pathogenesis. It is often difficult to treat and is associated with high morbidity and mortality. Early recognition and prompt initiation of treatment is vital. Local wound care and aggressive metabolic control remain the cornerstones of the therapy. Various novel treatment strategies including sodium thiosulfate and hyperbaric oxygen therapy have been utilized and reviewed in this paper. The response rate to treatment is poor and prevention is the best approach. PMID:21423552

  11. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    SciTech Connect

    Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B.; Sloggett, Clare; Cmero, Marek; Marass, Francesco; Tsui, Dana; Mangiola, Stefano; Lonie, Andrew; Naeem, Haroon; Sapre, Nikhil; Phal, Pramit M.; Kurganovs, Natalie; Chin, Xiaowen; Kerger, Michael; Warren, Anne Y.; Neal, David; Gnanapragasam, Vincent; Rosenfeld, Nitzan; Pedersen, John S.; Ryan, Andrew; Haviv, Izhak; Costello, Anthony J.; Corcoran, Niall M.; Hovens, Christopher M.

    2015-04-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. As a result, analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  12. SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors

    PubMed Central

    Malik, Shivani; Villanova, Lidia; Tanaka, Shinji; Aonuma, Misato; Roy, Nilotpal; Berber, Elisabeth; Pollack, Jonathan R.; Michishita-Kioi, Eriko; Chua, Katrin F.

    2015-01-01

    Metastasis is responsible for over 90% of cancer-associated mortality. In epithelial carcinomas, a key process in metastatic progression is the epigenetic reprogramming of an epithelial-to-mesenchymal transition-like (EMT) change towards invasive cellular phenotypes. In non-epithelial cancers, different mechanisms must underlie metastatic change, but relatively little is known about the factors involved. Here, we identify the chromatin regulatory Sirtuin factor SIRT7 as a key regulator of metastatic phenotypes in both epithelial and mesenchymal cancer cells. In epithelial prostate carcinomas, high SIRT7 levels are associated with aggressive cancer phenotypes, metastatic disease, and poor patient prognosis, and depletion of SIRT7 can reprogram these cells to a less aggressive phenotype. Interestingly, SIRT7 is also important for maintaining the invasiveness and metastatic potential of non-epithelial sarcoma cells. Moreover, SIRT7 inactivation dramatically suppresses cancer cell metastasis in vivo, independent of changes in primary tumor growth. Mechanistically, we also uncover a novel link between SIRT7 and its family member SIRT1, providing the first demonstration of direct interaction and functional interplay between two mammalian sirtuins. Together with previous work, our findings highlight the broad role of SIRT7 in maintaining the metastatic cellular phenotype in diverse cancers. PMID:25923013

  13. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    DOE PAGESBeta

    Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B.; Sloggett, Clare; Cmero, Marek; Marass, Francesco; et al

    2015-04-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones,more » even years after removal of the prostate. As a result, analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.« less

  14. 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

  15. Predictive Factors for Metastatic Infection in Patients With Bacteremia Caused by Methicillin-Sensitive Staphylococcus aureus

    PubMed Central

    Sato, Fumiya; Hosaka, Yumiko; Hoshina, Tokio; Tamura, Kumi; Nakaharai, Kazuhiko; Kato, Tetsuro; Nakazawa, Yasushi; Yoshida, Masaki; Hori, Seiji

    2015-01-01

    Abstract: Background: Metastatic infections such as infective endocarditis and psoas abscess are serious complications of Staphylococcus aureus bacteremia because failure to identify these infections may result in bacteremia relapse or poor prognosis. In the present study, we determined the predictive factors for metastatic infection due to methicillin-sensitive S. aureus bacteremia. Methods: A retrospective cohort study was conducted among patients with methicillin-sensitive S. aureus bacteremia at the Jikei University Hospital between January 2008 and December 2012. Factors analyzed included the underlying disease, initial antimicrobial treatment and primary site of infection. Results: During the 5-year study period, 73 patients met the inclusion criteria and were assessed. The most common primary site of bacteremia was catheter-related bloodstream infection (25/73 [34.2%]). Metastatic infection occurred in 14 of 73 patients (19.2%) (infective endocarditis [3], septic pulmonary abscess [3], spondylitis [4], psoas abscess [4], epidural abscess [3] and septic arthritis [1]). Six patients had multiple metastatic infections. Multivariate analysis revealed that the predictive factors associated with the development of metastatic infection were a delay in appropriate antimicrobial treatment of >48 hours, persistent fever for >72 hours after starting antibiotic treatment and lowest C-reactive protein levels of >3 mg/dL during 2 weeks after the onset of bacteremia. Conclusions: This study demonstrated that additional diagnostic tests should be conducted to identify metastatic infection, particularly in patients with delayed antimicrobial treatment, persistent fever and persistently high C-reactive protein levels. PMID:25250988

  16. Latest Advances in Chemotherapeutic, Targeted and Immune Approaches in the Treatment of Metastatic Melanoma

    PubMed Central

    Shah, Darshil J.; Dronca, Roxana S.

    2014-01-01

    Melanoma is the most dangerous form of skin cancer due to its metastatic potential and is an important public health concern. Melanoma incidence has been increasing worldwide. While potentially curable when diagnosed early, metastatic melanoma carries a poor prognosis. Until recently, systemic therapy for metastatic melanoma was ineffective, but the recent successes in the development of new therapies for metastatic melanoma, such as mitogen-activated protein kinase (MAPK) pathway inhibitors, anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/ Programmed cell death 1 ligand 1 (PD-L1) pathway blocking antibodies, as well as combinatorial strategies of cytotoxic chemotherapy and inhibitors of angiogenesis, have all yielded promising results, changing the continually evolving landscape of therapeutic options for patients with this disease. The aim of this review is to summarize the evolution of and recent advances in the treatment of metastatic melanoma. The present review is based on a comprehensive PubMed search between the dates of January 1, 1960, to November 15, 2013, using the search term melanoma or metastatic melanoma combined with terms, such as chemotherapy, immunotherapy, CTLA-4, PD-1, PDL-1, adoptive T cell, targeted therapy, MAPK, molecular biology and survival. PMID:24684873

  17. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

    PubMed Central

    Hong, Matthew K.H.; Macintyre, Geoff; Wedge, David C.; Van Loo, Peter; Patel, Keval; Lunke, Sebastian; Alexandrov, Ludmil B.; Sloggett, Clare; Cmero, Marek; Marass, Francesco; Tsui, Dana; Mangiola, Stefano; Lonie, Andrew; Naeem, Haroon; Sapre, Nikhil; Phal, Pramit M.; Kurganovs, Natalie; Chin, Xiaowen; Kerger, Michael; Warren, Anne Y.; Neal, David; Gnanapragasam, Vincent; Rosenfeld, Nitzan; Pedersen, John S.; Ryan, Andrew; Haviv, Izhak; Costello, Anthony J.; Corcoran, Niall M.; Hovens, Christopher M.

    2015-01-01

    Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood. PMID:25827447

  18. Caught in the act: revealing the metastatic process by live imaging

    PubMed Central

    Fein, Miriam R.; Egeblad, Mikala

    2013-01-01

    The prognosis of metastatic cancer in patients is poor. Interfering with metastatic spread is therefore important for achieving better survival from cancer. Metastatic disease is established through a series of steps, including breaching of the basement membrane, intravasation and survival in lymphatic or blood vessels, extravasation, and growth at distant sites. Yet, although we know the steps involved in metastasis, the cellular and molecular mechanisms of dissemination and colonization of distant organs are incompletely understood. Here, we review the important insights into the metastatic process that have been gained specifically through the use of imaging technologies in murine, chicken embryo and zebrafish model systems, including high-resolution two-photon microscopy and bioluminescence. We further discuss how imaging technologies are beginning to allow researchers to address the role of regional activation of specific molecular pathways in the metastatic process. These technologies are shedding light, literally, on almost every step of the metastatic process, particularly with regards to the dynamics and plasticity of the disseminating cancer cells and the active participation of the microenvironment in the processes. PMID:23616077

  19. Advances of Targeted Therapy in Treatment of Unresectable Metastatic Colorectal Cancer

    PubMed Central

    Lee, Suk-young; Oh, Sang Cheul

    2016-01-01

    Despite being one of the most frequently diagnosed cancers worldwide, prognosis of metastatic colorectal cancer (CRC) was poor. Development and introduction of biologic agents in treatment of patients with metastatic CRC have brought improved outcomes. Monoclonal antibodies directing epidermal growth factor receptors and vascular endothelial growth factor are main biologic agents currently used in treatment of metastatic CRC. Encouraged by results from many clinical trials demonstrating efficacy of those monoclonal antibodies, the combination therapy with those targeted agents and conventional chemotherapeutic agents has been established as the standard therapy for patients with metastatic CRC. However, emergency of resistance to those target agents has limited the efficacy of treatment, and strategies to overcome the resistance are now being investigated by newly developed biological techniques clarifying how to acquire resistance. Here, we introduce mechanisms of action of the biologic agents currently used for treatment of metastatic CRC and several landmark historical clinical studies which have changed the main stream of treatment. The mechanism of resistance to those agents, one of serious problems in treatment metastatic CRC, and ongoing clinical trials to overcome the limitations and improve treatment outcomes will also be presented in this review. PMID:27127793

  20. Advances in diagnosis and treatment of metastatic cervical cancer.

    PubMed

    Li, Haoran; Wu, Xiaohua; Cheng, Xi

    2016-07-01

    Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases. PMID:27171673

  1. Advances in diagnosis and treatment of metastatic cervical cancer

    PubMed Central

    2016-01-01

    Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases. PMID:27171673

  2. V-ATPase regulates communication between microvascular endothelial cells and metastatic cells.

    PubMed

    Sennoune, S R; Arutunyan, A; del Rosario, C; Castro-Marin, R; Hussain, F; Martinez-Zaguilan, R

    2014-01-01

    To metastasize distant organs, tumor cells and endothelial cells lining the blood vessels must crosstalk. The nature of this communication that allows metastatic cells to intravasate and travel through the circulation and to extravasate to colonize different organs is poorly understood. In this study, we evaluated one of the first steps in this process—the proximity and physical interaction of endothelial and metastatic cells. To do this, we developed a cell separator chamber that allows endothelial and metastatic cells to grow side by side. We have shown in our previous studies that V-ATPases at the cell surface (pmV-ATPase) are involved in angiogenesis and metastasis. Therefore, we hypothesized that the physical proximity/interaction between endothelial and metastatic cells expressing pmV-ATPase will increase its activity in both cell types, and such activity in turn will increase pmV-ATPase expression on the membranes of both cell types. To determine pmV-ATPase activity we measured the proton fluxes (JH+) across the cell membrane. Our data indicated that interaction between endothelial and metastatic cells elicited a significant increase of JH+ via pmV-ATPase in both cell types. Bafilomycin, a V-ATPase inhibitor, significantly decrease JH+. In contrast, JH+ of the non-metastatic cells were not affected by the endothelial cells and vice-versa. Altogether, our data reveal that one of the early consequences of endothelial and metastatic cell interaction is an increase in pmV-ATPase that helps to acidify the extracellular medium and favors protease activity. These data emphasize the significance of the acidic tumor microenvironment enhancing a metastatic and invasive phenotype. PMID:24606724

  3. Recognising metastatic spinal cord compression.

    PubMed

    Bowers, Ben

    2015-04-01

    Metastatic spinal cord compression (MSCC) is a potentially life changing oncological emergency. Neurological function and quality of life can be preserved if patients receive an early diagnosis and rapid access to acute interventions to prevent or reduce nerve damage. Symptoms include developing spinal pain, numbness or weakness in arms or legs, or unexplained changes in bladder and bowel function. Community nurses are well placed to pick up on the 'red flag' symptoms of MSCC and ensure patients access prompt, timely investigations to minimise damage. PMID:25839873

  4. Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer

    PubMed Central

    Cook, Leah M.; Araujo, Arturo; Pow-Sang, Julio M.; Budzevich, Mikalai M.; Basanta, David; Lynch, Conor C.

    2016-01-01

    The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an urgent need. Pre-clinical in vivo models are limited in their ability to define the temporal effects of therapies on simultaneous multicellular interactions in the cancer-bone microenvironment. Integrating biological and computational modeling approaches can overcome this limitation. Here, we generated a biologically driven discrete hybrid cellular automaton (HCA) model of bone metastatic prostate cancer to identify the optimal therapeutic window for putative targeted therapies. As proof of principle, we focused on TGFβ because of its known pleiotropic cellular effects. HCA simulations predict an optimal effect for TGFβ inhibition in a pre-metastatic setting with quantitative outputs indicating a significant impact on prostate cancer cell viability, osteoclast formation and osteoblast differentiation. In silico predictions were validated in vivo with models of bone metastatic prostate cancer (PAIII and C4-2B). Analysis of human bone metastatic prostate cancer specimens reveals heterogeneous cancer cell use of TGFβ. Patient specific information was seeded into the HCA model to predict the effect of TGFβ inhibitor treatment on disease evolution. Collectively, we demonstrate how an integrated computational/biological approach can rapidly optimize the efficacy of potential targeted therapies on bone metastatic prostate cancer. PMID:27411810

  5. Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer.

    PubMed

    Cook, Leah M; Araujo, Arturo; Pow-Sang, Julio M; Budzevich, Mikalai M; Basanta, David; Lynch, Conor C

    2016-01-01

    The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an urgent need. Pre-clinical in vivo models are limited in their ability to define the temporal effects of therapies on simultaneous multicellular interactions in the cancer-bone microenvironment. Integrating biological and computational modeling approaches can overcome this limitation. Here, we generated a biologically driven discrete hybrid cellular automaton (HCA) model of bone metastatic prostate cancer to identify the optimal therapeutic window for putative targeted therapies. As proof of principle, we focused on TGFβ because of its known pleiotropic cellular effects. HCA simulations predict an optimal effect for TGFβ inhibition in a pre-metastatic setting with quantitative outputs indicating a significant impact on prostate cancer cell viability, osteoclast formation and osteoblast differentiation. In silico predictions were validated in vivo with models of bone metastatic prostate cancer (PAIII and C4-2B). Analysis of human bone metastatic prostate cancer specimens reveals heterogeneous cancer cell use of TGFβ. Patient specific information was seeded into the HCA model to predict the effect of TGFβ inhibitor treatment on disease evolution. Collectively, we demonstrate how an integrated computational/biological approach can rapidly optimize the efficacy of potential targeted therapies on bone metastatic prostate cancer. PMID:27411810

  6. Metastatic Periampullary Tumor from Hepatocellular Carcinoma Presenting as Gastrointestinal Bleeding

    PubMed Central

    Nissen, Nicholas N.; Guindi, Maha; Jamil, Laith H.

    2015-01-01

    Periampullary tumors constitute a number of diverse neoplastic lesions located within 2 cm of the major duodenal papilla; among these, metastatic lesions account for only a small proportion of the periampullary tumors. To our knowledge, a metastatic periampullary tumor from hepatocellular carcinoma has never been reported. A 62-year-old male reported to our institute for fatigue and low hemoglobin. His medical history was remarkable for multifocal hepatocellular carcinoma (HCC) treated with selective transcatheter arterial chemoembolization (TACE). An esophagogastroduodenoscopy (EGD) was performed which revealed a periampullary mass. Histopathology was consistent with metastatic moderately differentiated HCC. Two endoloops were deployed around the base of the mass one month apart. The mass eventually sloughed off and patient's hemoglobin level stabilized. We postulated that periampullary metastasis in this patient was the result of tumor fragments migration through the biliary tracts and that TACE which increases tumor fragments burden might have played a contributory role. Metastasis of HCC to the gastrointestinal (GI) tract should be considered as a cause of GI bleeding. PMID:26064707

  7. Metastatic tumors to the jaws and oral cavity.

    PubMed

    Kumar, Gs; Manjunatha, Bs

    2013-01-01

    Cancer is a disease involving complex multiple sequential irreversible dysregulated processes showing metastasis that results in morbidity and mortality. Metastasis is a complex biological course that begins with detachment of tumor cells from the primary tumor, spreading into the distant tissues and/or organs, invading through the lymphovascular structures followed by their survival in the circulation. Metastatic tumors to the oro-facial region are uncommon and may occur in the oral soft tissues or jawbones. The clinical presentation of metastatic tumors can be variable, which may lead to erroneous diagnosis or may create diagnostic dilemma. Therefore, they should be considered in the differential diagnosis of inflammatory and reactive lesions that are common to the oral region. Most of the literature on oral metastases involves either single case reports or reviews of these reported cases from scattered geographical areas. Hence this present article is an attempt to provide a detailed review of pathogenesis, epidemiological details including clinical and radiographic presentations, microscopic features and treatment of metastatic tumors to the jaws and oral cavity. PMID:23798834

  8. Metastatic canine mammary carcinomas can be identified by a gene expression profile that partly overlaps with human breast cancer profiles

    PubMed Central

    2010-01-01

    Background Similar to human breast cancer mammary tumors of the female dog are commonly associated with a fatal outcome due to the development of distant metastases. However, the molecular defects leading to metastasis are largely unknown and the value of canine mammary carcinoma as a model for human breast cancer is unclear. In this study, we analyzed the gene expression signatures associated with mammary tumor metastasis and asked for parallels with the human equivalent. Methods Messenger RNA expression profiles of twenty-seven lymph node metastasis positive or negative canine mammary carcinomas were established by microarray analysis. Differentially expressed genes were functionally characterized and associated with molecular pathways. The findings were also correlated with published data on human breast cancer. Results Metastatic canine mammary carcinomas had 1,011 significantly differentially expressed genes when compared to non-metastatic carcinomas. Metastatic carcinomas had a significant up-regulation of genes associated with cell cycle regulation, matrix modulation, protein folding and proteasomal degradation whereas cell differentiation genes, growth factor pathway genes and regulators of actin organization were significantly down-regulated. Interestingly, 265 of the 1,011 differentially expressed canine genes are also related to human breast cancer and, vice versa, parts of a human prognostic gene signature were identified in the expression profiles of the metastatic canine tumors. Conclusions Metastatic canine mammary carcinomas can be discriminated from non-metastatic carcinomas by their gene expression profiles. More than one third of the differentially expressed genes are also described of relevance for human breast cancer. Many of the differentially expressed genes are linked to functions and pathways which appear to be relevant for the induction and maintenance of metastatic progression and may represent new therapeutic targets. Furthermore, dogs

  9. Characterization of the metastatic phenotype of a panel of established osteosarcoma cells

    PubMed Central

    Ren, Ling; Mendoza, Arnulfo; Zhu, Jack; Briggs, Joseph W.; Halsey, Charles; Hong, Ellen S.; Burkett, Sandra S.; Morrow, James J.; Lizardo, Michael M.; Osborne, Tanasa; Li, Samuel Q.; Luu, Hue H.; Meltzer, Paul; Khanna, Chand

    2015-01-01

    Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metatstatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models. PMID:26320182

  10. CT of Hepatic Sarcoidosis: Small Nodular Lesions Simulating Metastatic Disease

    PubMed Central

    Ufuk, Furkan; Herek, Duygu

    2015-01-01

    Summary Background Sarcoidosis is a multisystemic inflammatory disease of unknown origin. The lymphoid system and the lungs are the most commonly involved organs. The frequency of signs or symptoms of hepatic involvement is very low. Case Report We present a case of symptomatic granulomatous liver disease secondary to sarcoidosis, mimicking a metastatic disease on ultrasonography and CT. Conclusions Hepatic involvement in sarcoidosis might be a perplexing diagnostic problem. The decisive CT finding with respect to the differential diagnosis was the absence of a mass effect and intact vascular architecture around the lesions. PMID:25908950