Study of Efficacy and Safety of PDR001 in Patients With Advanced or Metastatic, Well-differentiated, Non-functional Neuroendocrine Tumors of Pancreatic, Gastrointestinal (GI), or Thoracic Origin or Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma (GEP-NEC)

ClinicalTrials.gov

2017-11-15

Well-differentiated Non-functional NET of Thoracic Origin; Well-differentiated Non-functional NET of Gastrointestinal Origin; Well-differentiated Non-functional NET of Pancreatic Origin; Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma

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

Poorly Differentiated Squamous Cell Carcinoma Arising in Tattooed Skin

PubMed Central

Sarma, Deba P.; Dentlinger, Renee B.; Forystek, Amanda M.; Stevens, Todd; Huerter, Christopher

2010-01-01

Introduction. Tattoos have increasingly become accepted by mainstream Western society. As a result, the incidence of tattoo-associated dermatoses is on the rise. The presence of a poorly differentiated squamous cell carcinoma in an old tattooed skin is of interest as it has not been previously documented. Case Presentation. A 79-year-old white homeless man of European descent presented to the dermatology clinic with a painless raised nodule on his left forearm arising in a tattooed area. A biopsy of the lesion revealed a poorly differentiated squamous cell carcinoma infiltrating into a tattoo. The lesion was completely excised and the patient remains disease-free one year later. Conclusion. All previous reports of squamous cell carcinomas arising in tattoos have been well-differentiated low-grade type or keratoacanthoma-type and are considered to be coincidental rather than related to any carcinogenic effect of the tattoo pigments. Tattoo-associated poorly differentiated invasive carcinoma appears to be extremely rare. PMID:21274289

[Poorly differentiated thyroid carcinomas: new therapeutic considerations].

PubMed

Graf, Hans

2005-10-01

For most differentiated thyroid carcinomas, as papillary and follicular carcinomas, following total thyroidectomy and 131I therapy for thyroid remnant ablation, treatment with thyroid hormones to suppress TSH levels will reduce the growth of any remaining thyroid cancer cells, and thyroid cell-specific radiation therapy will either cure or control the disease. Thyroid carcinomas are considered poorly differentiated when they start to lose such functions as iodine uptake and thyrotropin-dependence for growth and production of thyroid proteins like NIS, thyroglobulin and desiodases. One of the greatest challenges in the management of patients with follicular cell-derived thyroid cancer is the treatment of tumors that progressed despite surgery, (131)I and T4 suppression of TSH. With the better knowledge of the abnormal molecular signaling in thyroid cancer cells, actually known targeted cancer therapies, directed against molecules involved in neoplastic transformation, are being used. As the critical molecular requirements for tumor initiation, maintenance and progression are identified, combination therapies with targeted agents acting on each of them will improve the treatment of poorly differentiated thyroid carcinoma.

A rare case of metastatic squamous urachal carcinoma.

PubMed

Andrei, S; Andrei, A; Rusu Muntean, G; Ungureanu, M; Herlea, V; Becheanu, G; Popescu, I

2013-01-01

Squamous cell carcinoma is a very rare type of urachal malignancy, only a few cases being reported in the medical literature. We present the case of a 49-year-old male patient diagnosed with infected squamous cell urachal carcinoma with multiple pulmonary metastases, after complaints of lower abdominal pain, abdominal mass and fever, without respiratory symptoms. The abdominal ultrasonography and the CT scan revealed a tumoral mass in the lower abdomen in contact with the abdominal wall and the urinary bladder dome, displacing the small bowel. Pulmonary nodular lesions were described in the left lobe pyramid. The intraoperative diagnosis was necrotic urachal tumor with urinary bladder dome invasion and suspected pulmonary metastases, and tumor ablation with bladder dome resection and suture of the bladder were performed. The histopathological result was poorly differentiated squamous cell carcinoma (G3), with negative resection margins. The patient recovered well after surgery, but the prognosis is very poor due to the metastatic stage in which the tumor was diagnosed, no standard chemotherapy regimen for the treatment of metastatic urachal carcinoma being known as effective until now. Celsius.

[Thyroid carcinoma--differentiated, poorly differentiated and anaplastic carcinoma].

PubMed

Kakudo, Kennichi; Bai, Yanhua; Li, Yaqiong; Wakasa, Tomoko; Mori, Ichiro

2007-11-01

The poorly differentiated carcinoma was first added as a new member in the lists of classification of thyroid carcinomas in the WHO 2004 edition. However its histological criteria include necrosis and increased mitoses in addition to the original definition by Sakamoto's proposal, solid, trabecular and schirrhous growth. This modification creates a significant change in the incidence and prognosis of this carcinoma. This carcinoma, defined by the new WHO classification, is about 1-5% of all thyroid malignancy and has more aggressive outcome than the previous definition.

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

PubMed Central

Gonçalves da Silva, Patrícia Benites; Teixeira dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Leite Pereira, Márcia Cristina; Furukawa, Gabriela; Gimenes da Cruz, Daniel Sanzio; Goldfeder, Mauricio Barbugiani; Reily Rocha, Clarissa Ribeiro; Rosenberg, Carla; Okamoto, Oswaldo Keith

2017-01-01

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. PMID:28186969

High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

PubMed

da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

2017-03-21

Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

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

2016-01-04

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.

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

Metastatic Urothelial Carcinoma to the Uterine Cervix: A Case Report of a Rare Entity and Review of the Diagnostic Differential.

PubMed

Sams, Sharon B; Rosser, Julie A

2017-09-01

Urothelial carcinoma (UC) rarely metastasizes to the gynecologic tract, occurring in descending order of frequency, within the vagina, uterus, ovaries, and cervix. Significant morphologic overlap exists between primary gynecologic squamous lesions (both benign and malignant) and metastatic UC, thus potentially hindering a timely and accurate diagnosis. We present a case of UC metastatic to the uterine cervix in a 69-year-old female initially found to have noninvasive high-grade papillary UC of the bladder. Complaints of vaginal spotting lead to identification and biopsy of a mass in the uterine cervix. Histologic evaluation of the cervical mass showed a neoplastic proliferation of atypical epithelioid cells arranged in a papillary architecture. The differential in this case included primary uterine cervical tumors such as condyloma acuminatum, immature condyloma, verrucous carcinoma, warty/condylomatous carcinoma, and papillary squamotransitional cell carcinoma, as well as metastatic UC. A careful evaluation of histologic variances and a selective immunohistochemical panel allows differentiation of these tumors. We herein review the subtle, albeit significant, histologic and immunohistochemical differences of the aforementioned lesions.

Guanylyl Cyclase C Is a Specific Marker for Differentiating Primary and Metastatic Ovarian Mucinous Neoplasms

PubMed Central

Ciocca, Vincenzo; Bombonati, Alessandro; Palazzo, Juan P.; Schulz, Stephanie; Waldman, Scott A.

2011-01-01

Distinguishing primary ovarian mucinous neoplasms from metastatic mucinous adenocarcinomas with ovarian involvement can be difficult, especially when characteristic gross and microscopic features are not present. CK7/CK20 expression appears to be more useful for distinguishing metastatic gastrointestinal adenocarcinomas from the lower tract. The addition of CDX2 for distinguishing metastatic upper gastrointestinal tract adenocarcinomas from primary ovarian mucinous neoplasms offers little advantage over CK7/CK20 coordinate expression. Guanylyl cyclase C (GCC) is a brush border membrane receptor for the endogenous peptides guanylin and uroguanylin, and the homologous diarrheagenic bacterial heat-stable enterotoxins that is selectively expressed by epithelial cells from the duodenum to the rectum, but not by normal epithelia of the stomach or esophagus, or normal extramucosal cells in humans. We studied 50 ovarian tumors: 27 primary ovarian mucinous neoplasms (7 cystadenomas, 10 borderline tumors, and 10 cystadenocarcinomas) and 23 metastatic mucinous adenocarcinomas with ovarian involvement (13 colorectal adenocarcinomas, 4 gastric adenocarcinomas, 6 appendiceal mucinous tumors (4 adenocarcinomas, 1 with neuroendocrine features, and 2 appendiceal mucinous cystadenomas). For primary ovarian mucinous neoplasms, 25 of 27 were negative for GCC. Twelve of thirteen cases of colorectal adenocarcinoma (except for 1 neuroendocrine adenocarcinoma) were positive for GCC. Three of four appendiceal mucinous adenocarcinomas were positive for GCC in both the primary and metastatic tumors (except for 1 neuroendocrine adenocarcinoma). Two of two appendiceal mucinous cystadenomas were positive for GCC. Of four cases of gastric adenocarcinoma with ovarian involvement, only one (primary tumor) exhibited focal GCC staining. These findings suggest GCC may be a useful marker for differentiating primary and secondary ovarian mucinous neoplasms. PMID:19694825

Identification of genes differentially expressed in B16 murine melanoma sublines with different metastatic potentials.

PubMed

Ishiguro, T; Nakajima, M; Naito, M; Muto, T; Tsuruo, T

1996-02-15

B16-F10 and B16-BL6 are B16 mouse melanoma sublines that preferentially metastasize to the lung following i.v. and s.c. injections, respectively. To study molecular mechanisms underlying the different metastatic behaviors exhibited by the B16 melanoma sublines, we performed differential hybridization of the genes transcribed in these cells and compared their expression levels. We isolated four genes that were highly expressed in B16-F10 cells but not in B16-BL6 cells: TI-225 (polyubiquitin), TI-229 (pyruvate kinase), TI-241 (LRF-1 homologue), and TI-227 (novel gene). Triosephosphate isomerase, 10-formyltetrahydrofolate dehydrogenase, tyrosinase-related protein 2, cytochrome c oxidase, ATP synthetase alpha subunit, RNA helicase, and ribosomal protein (L37, J1, acidic phosphoprotein), however, showed higher expression in B16-BL6 cells than in B16-F10 cells. Among these clones, transfection of TI-241 into the low metastatic clone F1 converted the parental cells from low- into high-metastatic cells. TI-241 may regulate the expression of various genes as a transcription factor in the complex process of metastasis.

Iodine I-131 With or Without Selumetinib in Treating Patients With Recurrent or Metastatic Thyroid Cancer

ClinicalTrials.gov

2018-05-15

Metastatic Thyroid Gland Carcinoma; Poorly Differentiated Thyroid Gland Carcinoma; Recurrent Thyroid Gland Carcinoma; Stage IV Thyroid Gland Follicular Carcinoma; Stage IV Thyroid Gland Papillary Carcinoma; Stage IVA Thyroid Gland Follicular Carcinoma; Stage IVA Thyroid Gland Papillary Carcinoma; Stage IVB Thyroid Gland Follicular Carcinoma; Stage IVB Thyroid Gland Papillary Carcinoma; Stage IVC Thyroid Gland Follicular Carcinoma; Stage IVC Thyroid Gland Papillary Carcinoma

Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).

PubMed

Goldstein, J; Tran, B; Ensor, J; Gibbs, P; Wong, H L; Wong, S F; Vilar, E; Tie, J; Broaddus, R; Kopetz, S; Desai, J; Overman, M J

2014-05-01

The microsatellite instability-high (MSI-H) phenotype, present in 15% of early colorectal cancer (CRC), confers good prognosis. MSI-H metastatic CRC is rare and its impact on outcomes is unknown. We describe survival outcomes and the impact of chemotherapy, metastatectomy, and BRAF V600E mutation status in the largest reported cohort of MSI-H metastatic colorectal cancer (CRC). A retrospective review of 55 MSI-H metastatic CRC patients from two institutions, Royal Melbourne Hospital (Australia) and The University of Texas MD Anderson Cancer Center (United States), was conducted. Statistical analyses utilized Kaplan-Meier method, Log-rank test, and Cox proportional hazards models. Median age was 67 years (20-90), 58% had poor differentiation, and 45% had stage IV disease at presentation. Median overall survival (OS) from metastatic disease was 15.4 months. Thirteen patients underwent R0/R1 metastatectomies, with median OS from metastatectomy 33.8 months. Thirty-one patients received first-line systemic chemotherapy for metastatic disease with median OS from the start of chemotherapy 11.5 months. No statistically significant difference in progression-free survival or OS was seen between fluoropyrimidine, oxaliplatin, or irinotecan based chemotherapy. BRAF V600E mutation was present in 14 of 47 patients (30%). BRAF V600E patients demonstrated significantly worse median OS; 10.1 versus 17.3 months, P = 0.03. In multivariate analyses, BRAF V600E mutants had worse OS (HR 4.04; P = 0.005), while patients undergoing metastatectomy (HR 0.11; P = <0.001) and patients who initially presented as stage IV disease had improved OS (HR 0.27; P = 0.003). Patients with MSI-H metastatic CRC do not appear to have improved outcomes. BRAF V600E mutation is a poor prognostic factor in MSI-H metastatic CRC.

Metastatic Neuroendocrine Carcinoma of the Breast Identified by Tc-99m-HYNIC-TOC SPECT/CT: A Rare Case Report.

PubMed

Claimon, Apichaya; Chuthapisith, Suebwong; Samarnthai, Norasate; Pusuwan, Pawana

2015-08-01

The authors reported an uncommon presentation of metastatic neuroendocrine carcinoma to the breast detected by Tc-99m-HYNIC-TOC SPECT/CT in a 49 years old woman who, previously, had carcinoid tumor of left main bronchus and invasive ductal carcinoma of the right breast. Later, the patient developed left breast mass. Core needle biopsy of the mass revealed poorly differentiated invasive ductal carcinoma. The disease remained stable for 12 years without any treatment on that left breast (due to patient's rejection). On the later investigation using Tc-99m-HYNIC-TOC scintigraphy examination, rather than invasive ductal carcinoma, metastatic neuroendocrine cancer was suggested. The final diagnosis was confirmed by pathological examination after surgical excision. Multiple metastatic lesions of neuroendocrine carcinoma at lung, liver, ovaries, and bones were also depicted. Due to the good behavior of the disease, patient had been doing well for eight months, without specific treatment. This report confirmed the advantage and the accuracy of Tc-99m-HYNIC-TOC scintigraphy in detection of neuroendocrine carcinoma. Furthermore, metastatic neuroendocrine tumor should be in differential diagnosis for patient with breast mass together with history of neuroendocrine tumor

Differential changes in platelet VEGF, Tsp, CXCL12, and CXCL4 in patients with metastatic cancer.

PubMed

Wiesner, Tina; Bugl, Stefanie; Mayer, Frank; Hartmann, Jörg T; Kopp, Hans-Georg

2010-03-01

Data from animal studies indicate that platelets play a key role in tumor dissemination and metastasis. We therefore hypothesized that metastastic cancer patients may display a specific platelet phenotype. Percentage of activated, p-selectin positive platelets as well as platelet contents (i.e., plasma and platelet count-corrected serum levels of VEGF-A, CXCL12, CXCL4, and thrombospondin-1) were analyzed in 43 patients with newly diagnosed metastatic disease prior to treatment. Tumor patients had increased platelet counts and significantly elevated percentages of activated platelets. Moreover, the platelet content of VEGF-A in cancer patients was significantly increased compared to healthy controls, while thrombospondin-1, CXCL12 and CXCL4 were significantly decreased. Our data contain several unexpected results: firstly, CXCL12 was found in minute quantities in the serum as compared with murine studies. Secondly, CXCL4, which was found by mass spectrometry to be the single massively upregulated intraplatelet chemokine in mice after tumor xenotransplantation, was decreased in tumor patient platelets. While increased contents of VEGF-A have been attributed to platelet scavenger activity, the differential decrease of specific platelet contents may be due to differential secretion or altered megakaryopoiesis in metastatic cancer patients.

Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.

PubMed

Hunter, Karen E; Quick, Marsha L; Sadanandam, Anguraj; Hanahan, Douglas; Joyce, Johanna A

2013-01-01

Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.

NGF reprograms metastatic melanoma to a bipotent glial-melanocyte neural crest-like precursor

PubMed Central

Kasemeier-Kulesa, Jennifer C.; Romine, Morgan H.; Morrison, Jason A.; Bailey, Caleb M.; Welch, Danny R.

2018-01-01

ABSTRACT Melanoma pathogenesis from normal neural crest-derived melanocytes is often fatal due to aggressive cell invasion throughout the body. The identification of signals that reprogram de-differentiated, metastatic melanoma cells to a less aggressive and stable phenotype would provide a novel strategy to limit disease progression. In this study, we identify and test the function of developmental signals within the chick embryonic neural crest microenvironment to reprogram and sustain the transition of human metastatic melanoma to a neural crest cell-like phenotype. Results reveal that co-culture of the highly aggressive and metastatic human melanoma cell line C8161 upregulate a marker of melanosome formation (Mart-1) in the presence of embryonic day 3.5 chick trunk dorsal root ganglia. We identify nerve growth factor (NGF) as the signal within this tissue driving Mart-1 re-expression and show that NGF receptors trkA and p75 cooperate to induce Mart-1 re-expression. Furthermore, Mart-1 expressing C8161 cells acquire a gene signature of poorly aggressive C81-61 cells. These data suggest that targeting NGF signaling may yield a novel strategy to reprogram metastatic melanoma toward a benign cell type. PMID:29175861

Immunohistochemical staining of precursor forms of prostate-specific antigen (proPSA) in metastatic prostate cancer.

PubMed

Parwani, Anil V; Marlow, Cameron; Demarzo, Angelo M; Mikolajczyk, Stephen D; Rittenhouse, Harry G; Veltri, Robert W; Chan, Theresa Y

2006-10-01

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue. This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%). In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration. A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.

Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity

PubMed Central

Gooden, M J M; Wiersma, V R; Boerma, A; Leffers, N; Boezen, H M; ten Hoor, K A; Hollema, H; Walenkamp, A M E; Daemen, T; Nijman, H W; Bremer, E

2014-01-01

Background: In certain cancers, expression of CXCL16 and its receptor CXCR6 associate with lymphocyte infiltration, possibly aiding anti-tumour immune response. In other cancers, CXCL16 and CXCR6 associate with pro-metastatic activity. In the current study, we aimed to characterise the role of CXCL16, sCXCL16, and CXCR6 in ovarian cancer (OC). Methods: CXCL16/CXCR6 expression was analysed on tissue microarray containing 306 OC patient samples. Pre-treatment serum sCXCL16 was determined in 118 patients using ELISA. In vitro, (primary) OC cells were treated with an ADAM-10/ADAM-17 inhibitor (TAPI-2) and an ADAM-10-specific inhibitor (GI254023x), whereupon CXCL16 levels were evaluated on the cell membrane (immunofluorescent analysis, western blots) and in culture supernatants (ELISA). In addition, cell migration was assessed using scratch assays. Results: sCXCL16 independently predicted for poor survival (hazard ratio=2.28, 95% confidence interval=1.29–4.02, P=0.005), whereas neither CXCL16 nor CXCR6 expression correlated with survival. Further, CXCL16/CXCR6 expression and serum sCXCL16 levels did not associate with lymphocyte infiltration. In vitro inhibition of both ADAM-17 and ADAM-10, but especially the latter, decreased CXCL16 membrane shedding and strongly reduced cell migration of A2780 and cultured primary OC-derived malignant cells. Conclusions: High serum sCXCL16 is a prognostic marker for poor survival of OC patients, possibly reflecting ADAM-10 and ADAM-17 pro-metastatic activity. Therefore, serum sCXCL16 levels may be a pseudomarker that identifies patients with highly metastatic tumours. PMID:24518602

Sialomucins are characteristically O-acylated in poorly differentiated and colloid prostatic adenocarcinomas.

PubMed

Sáez, C; Japón, M A; Conde, A F; Poveda, M A; Luna-Moré, S; Segura, D I

1998-12-01

Mucinous glycoproteins are secreted by prostatic adenocarcinomas and might play important roles in tumor invasion and metastasis. Their histochemical properties on routine biopsy specimens have not been fully characterized. We present a histochemical study of mucin in 21 prostatic adenocarcinomas, with particular focus on the demonstration of different types of sialomucins. We applied the following histochemical techniques to routinely processed, formalin-fixed, paraffin-embedded tissue sections: Alcian blue (pH 2.5) and periodic acid-Schiff to reveal both acidic and neutral mucins; high iron diamine and Alcian blue (pH 2.5) to show sulfated and acidic nonsulfated mucosubstances simultaneously; periodic acid borohydride, potassium hydroxide, and periodic acid-Schiff to demonstrate O-acylated sialic acids; periodic acid thionine-Schiff, potassium hydroxide, and periodic acid-Schiff to differentiate pre-existing glycols from those revealed after saponification procedures; and periodic acid borohydride and periodic acid-Schiff to show C9-O-acylated sialic acid. These techniques are useful tools for demonstrating neutral and acidic (sialo- and sulfo-) mucins and di(C8,C9- or C7,C9-)-O-acylated, tri(C7,C8,C9-)-O-acylated and mono(C9)-O-acylated sialomucins. Most prostatic adenocarcinomas showed acidic mucins, with sialomucins predominating over sulfomucins. Well-differentiated and moderately differentiated noncolloid tumors had non-O-acylated sialomucins. Poorly differentiated tumors contained mono-O-acylated (C9) sialomucins, and colloid-type tumors secreted mono-, di-, and tri-O-acylated sialoglycoproteins. Acidic mucins, mainly sialomucins, constitute the major secretory component in prostatic adenocarcinomas, and our results show that the O-acylation of these sialoglycoproteins inversely correlates with tumor differentiation. Well-differentiated and moderately differentiated tumors are not O-acylated, whereas the poorly differentiated ones characteristically have O

CYTOLOGY ASSESSMENT CAN PREDICT SURVIVAL FOR PATIENTS WITH METASTATIC PANCREATIC NEUROENDOCRINE NEOPLASMS

PubMed Central

Sigel, Carlie S.; Guo, Huimin; Sigel, Keith M.; Zhang, Ming; Rekhtman, Natasha; Lin, Oscar; Klimstra, David S.; Jungbluth, Achim A.; Tang, Laura K.

2017-01-01

Background Histological features and Ki67 index have known utility for predicting prognosis and guiding therapy for metastatic pancreatic neuroendocrine neoplasms. Fine needle aspiration (FNA) may offer advantages for Ki67 assessment because the technique obtains highly cellular, well-preserved specimens with potential for broader tumor sampling. We evaluated concordance for grade and differentiation between concurrent core biopsy and cytology preparations. Secondly, cytological features and grade were correlated with survival. Methods Differentiation, grade by Ki67 index, and correlation of these features with survival were compared between concurrent core biopsy and cytology from 44 metastatic pancreatic neuroendocrine neoplasms. Results Differentiation by cytology smear was 38 (86%) well and 6 (14%) poor. Agreement for differentiation between smear and cell block, smear and biopsy, and cell block and biopsy was: 88%, 94%, and 83%, respectively and agreement for grade were: 68%, 54%, and 22%, respectively. Cytology differentiation and cytology grade were strong predictors of outcome with respective hazard ratio of 8.3 (95% CI: 3.1–22.1; p<0.001) and 1.9 (95% CI: 1.2–2.9) for each ascending grade. Cytology median disease specific survival projections (months) were G1= 121 (95% CI: 57–185 (estimated)); G2= 45 (95% CI 29–87); and G3=19 (95% CI 1–44) and WD=45; PD= 3; (P<.001)). Conclusions Pancreatic neuroendocrine neoplasm grading on cytology may not exactly correlate with concurrent core biopsy, but cytology differentiation and grade are predictive of survival based on stage-adjusted analysis. PMID:28094897

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer.

PubMed

Iñiguez-Ariza, Nicole M; Ryder, Mabel M; Hilger, Crystal R; Bible, Keith C

2017-07-01

Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required

Metastatic breast disease from cutaneous malignant melanoma.

PubMed

Moschetta, Marco; Telegrafo, Michele; Lucarelli, Nicola Maria; Martino, Gianluigi; Rella, Leonarda; Stabile Ianora, Amato Antonio; Angelelli, Giuseppe

2014-01-01

Malignant melanoma is one of the most rapidly increasing cancer in the world. Breast metastases from melanoma are uncommon but could reflect a widespread disease. We report a case of malignant widespread melanoma presenting with bilateral breast nodules in a 39 year-old pre-menopausal Caucasian woman with an history of cutaneous melanoma of the trunk. Breast clinical examination revealed the presence of a hard and mobile lump located on the left breast. Ultrasound detected two bilateral nodules corresponding to oval opacities with well-defined edges and without calcifications or architectural distortion on mammography. Fine needle aspiration cytology performed on both breast nodules confirmed that the breast lesions were metastases from primary cutaneous malignant melanoma. A total-body CT examination detected brain, lung and abdominal lymph nodes metastases. The breast represents an uncommon site of metastatic disease from extra-mammary tumors. Imaging features of breast metastases from melanoma usually do not allow a differential diagnosis with breast primary tumors. Breast metastases may be asymptomatic or palpable as dense and well-circumscribed nodules. Breast metastases indicate a widespread disease and should lead to avoid aggressive surgical procedures because of the poor prognosis of patients affected by metastatic melanoma. The detection of bilateral breast metastases from melanoma is highly suggestive of metastatic multi-organ disease and could be useful to address the therapeutic approach. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Elevated serum alpha-fetoprotein in poorly differentiated adenocarcinoma with neuroendocrine differentiation of the ascending colon: a case report.

PubMed

Lin, Hung-Hsin; Chang, Chia-Chu; Yang, Shung-Haur; Chang, Shih-Ching; Chen, Wei-Shone; Liang, Wen-Yih; Lin, Jen-Kou; Jiang, Jeng-Kai

2016-03-15

Colorectal cancer (CRC) is the most common form of cancer and the third leading cause of death in Taiwan. Serum alpha-fetoprotein (AFP) has been extensively used as a biomarker for hepatocellular carcinoma (HCC) and yolk sac tumors. This case report presents a 90-year-old woman with right abdominal pain and poor appetite for 1 week. The computed tomography (CT) showed wall thickening in the proximal ascending colon with ruptured appendicitis. Preoperative serum AFP was high. There was no definite liver metastasis or other abnormal findings in the hepatobiliary systems. After initial empirical antibiotic treatment, we performed laparoscopic right hemicolectomy. The pathological assessment was poorly differentiated adenocarcinoma with neuroendocrine differentiation in the ascending colon. The tumor cells did not produce AFP. Amazingly, the follow-up serum AFP level 1 month after the surgery declined to normal range. The patient had an uneventful course after the surgery and was free of recurrence or metastasis within 5 months of follow-up. AFP may be a useful tumor marker in poorly differentiated colorectal cancer with neuroendocrine component patients and a prediction of early treatment response.

Gene expression profiles help identify the tissue of origin for metastatic brain cancers.

PubMed

Wu, Alan H B; Drees, Julia C; Wang, Hangpin; VandenBerg, Scott R; Lal, Anita; Henner, William D; Pillai, Raji

2010-04-26

Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA) is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3%) cases. This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers.

Gene expression profiles help identify the Tissue of Origin for metastatic brain cancers

PubMed Central

2010-01-01

Background Metastatic brain cancers are the most common intracranial tumor and occur in about 15% of all cancer patients. In up to 10% of these patients, the primary tumor tissue remains unknown, even after a time consuming and costly workup. The Pathwork® Tissue of Origin Test (Pathwork Diagnostics, Redwood City, CA, USA) is a gene expression test to aid in the diagnosis of metastatic, poorly differentiated and undifferentiated tumors. It measures the expression pattern of 1,550 genes in these tumors and compares it to the expression pattern of a panel of 15 known tumor types. The purpose of this study was to evaluate the performance of the Tissue of Origin Test in the diagnosis of primary sites for metastatic brain cancer patients. Methods Fifteen fresh-frozen metastatic brain tumor specimens of known origins met specimen requirements. These specimens were entered into the study and processed using the Tissue of Origin Test. Results were compared to the known primary site and the agreement between the two results was assessed. Results Fourteen of the fifteen specimens produced microarray data files that passed all quality metrics. One originated from a tissue type that was off-panel. Among the remaining 13 cases, the Tissue of Origin Test accurately predicted the available diagnosis in 12/13 (92.3%) cases. Discussion This study demonstrates the accuracy of the Tissue of Origin Test when applied to predict the tissue of origin of metastatic brain tumors. This test could be a very useful tool for pathologists as they classify metastatic brain cancers. PMID:20420692

Metastatic human hepatocellular carcinoma models in nude mice and cell line with metastatic potential

PubMed Central

Tang, Zhao-You; Sun, Fan-Xian; Tian, Jian; Ye, Sheng-Long; Liu, Yin-Kun; Liu, Kang-Da; Xue, Qiong; Chen, Jie; Xia, Jing-Lin; Qin, Lun-Xiu; Sun, Hui-Chuan; Wang, Lu; Zhou, Jian; Li, Yan; Ma, Zeng-Chen; Zhou, Xin-Da; Wu, Zhi-Quan; Lin, Zhi-Ying; Yang, Bing-Hui

2001-01-01

Metastatic human HCC model is needed for the studies on mechanism and interven tion of metastatic recurrence. By using orthotopic implantation of histologically intact tissues of 30 surgical specimens, a patient-like metastatic model of hu man HCC in nude mice (LCI-D20) and a low metastatic model of human HCC in nude mice (LCI-D35) have been established. All mice with transplanted LCI-D20 tumors exhibited extremely high metastatic ability including spontaneous metasta sis to liver, lungs, lymph nodes and peritoneal seeding. Remarkable difference was also found in expression of some of the invasiveness related genes and growth factors between the LCI-D20 and LCI-D35 tumors. PAI-1 increased gradually following tumor progression in LCI-D20 model, and correlated with tumor size and AFP level. Phasic expression of tissue intercellular adhesio nmolecule-1 in this model was also observed. Using corneal micropocket model, it was demonstrated that the vascular response induced by LCI-D20 tumor was stronger than that induced by LCI-D35 tumor. Similar report on metastatic human HCC model in nude mice and human HCC cell line with metastatic potential was rarely found in the literature. This LCI-D20 model has been widely used for the studies on intervention of metastasis, including anti-angiogenesis, antisense approach, metallopro teinase inhibitor, differentiation inducer, etc. It is concluded that the establ ishment of metastatic human HCC model in nude mice and human HCC cell line with metastatic potential will provide important models for the in vivo and in vitro study of HCC invasiveness, angiogenesis as well as intervention of HCC recurrence. PMID:11819839

Metastatic malignant blue nevus: a case report.

PubMed

Ozgür, F; Akyürek, M; Kayikçioğlu, A; Barişta, I; Gököz, A

1997-10-01

This report presents a 63-year-old Caucasian woman with a malignant blue nevus, which is an extremely rare form of melanoma originating from or associated with a preexisting blue nevus. The background blue nevus on the left upper arm, which had been present for 5 to 6 years, increased in size and darkened in color for 3 months prior to histological diagnosis of malignant blue nevus. Although the tumor looked much like a nodular melanoma clinically, the diagnosis of malignant blue nevus was established histologically. The patient had a poor outcome due to metastatic spread of the tumor to the visceral organs 1 year following the initial excision of the tumor. To distinguish this rare tumor from other melanocytic lesions, strict histological criteria are needed to make the diagnosis of malignant blue nevus. Differential diagnosis includes cellular blue nevus, atypical cellular blue nevus, primary malignant melanoma, and metastatic melanoma to the dermis. Malignant blue nevus is most commonly seen on the scalp. The tumor has an aggressive behavior and metastasizes in the majority of patients. This paper describes the second reported case of malignant blue nevus involving the upper arm. Clinical and histological features of this uncommon tumor are presented, along with a review of the literature.

Paranuclear blue inclusions in metastatic undifferentiated small cell carcinoma in the bone marrow.

PubMed

Wittchow, R; Laszewski, M; Walker, W; Dick, F

1992-09-01

Paranuclear blue inclusions (PBIs) are frequently identified within metastatic undifferentiated small cell carcinoma (SCC) cells on air-dried bone marrow aspirates stained with Wright's stain. To determine the sensitivity and specificity of this finding, 116 bone marrow aspirates containing metastatic neoplasms were evaluated for the presence and frequency of PBIs. Bone marrow specimens included 47 cases of metastatic SCC of the lung, 13 cases of large cell lymphoma, 19 cases of neuroblastoma, five cases of small, noncleaved cell lymphoma, seven cases of rhabdomyosarcoma, three cases of Ewing's sarcoma, three cases of other sarcomas, and 19 cases of non-small cell carcinoma (adenocarcinoma). PBIs were identified in 40 of 47 (85%) cases of SCC and their frequency varied from 0 to 24% of tumor cells among different cases. In approximately half the cases of SCC, PBIs were identified in 1 to 4% tumor cells; and in eight cases, PBIs were present in 5% or more of tumor cells. PBIs were also identified in two of seven (29%) cases of rhabdomyosarcoma and one case of malignant peripheral nerve sheath tumor, but they were not seen in Ewing's sarcoma, small non-cleaved cell lymphoma, large cell lymphoma, neuroblastoma, or non-small cell carcinoma. In addition, PBIs were not seen in alcohol-fixed, Papanicolaou-stained cytology specimens containing SCC. Ultrastructurally, PBIs may represent phagocytized nuclear/cellular material. PBIs are a feature of small cell carcinoma on air-dried, cytologic material stained with Romanowsky type stains. Their presence may provide diagnostic information with regard to the differential diagnosis of metastatic SCC in the bone marrow. Future studies evaluating non-bone marrow Wright's stained fine-needle aspiration specimens are needed to determine if PBIs are useful in distinguishing SCC from other poorly differentiated tumors in the cytology laboratory.

A human thyroid cancer cell line, DH-14-3, newly established from poorly differentiated thyroid carcinoma.

PubMed

Teshima, Jin; Doi, Hideyuki; Fujimori, Keisei; Watanabe, Michio; Nakajima, Noriaki; Nakano, Tomoyuki; Takahashi, Yoshio; Ohuchi, Noriaki; Satomi, Susumu

2013-06-01

Poorly differentiated thyroid carcinoma (PDTC) is a newly recognized histological type of malignant thyroid tumor, accounting for about 2 - 13% of all thyroid carcinomas. PDTC is considered as a morphologically and biologically intermediate stage between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma. PDTC preferentially manifests bone metastases. We here established a cell line from a resected tumor specimen from a 70-year-old male patient with PDTC who presented with multiple bone metastases. This new thyroid tumor cell line was designated as DH-14-3 and was subsequently grown in culture for several years. DH-14-3 cells express thyroglobulin in the cytoplasm and thyroid transcription factor-1 in the nuclei, both proteins of which are specific markers for the thyroid gland. Importantly, triiodothyronine (T3) was detected in the cultured medium of DH-14-3 cells, in which, however, thyroxine (T4) was undetectable. Moreover, DH-14-3 cells secreted interleukin-8, transforming growth factor-β1, vascular endothelial growth factor, matrix metalloproteinase-1 and parathyroid hormone-related protein, all of which may be responsible for the aggressiveness or bone metastasis of PDTC. Thus, the production of these proteins may reflect the metastatic potential of this cell line. DH-14-3 cells also express CXC chemokine receptor-4 and epidermal growth factor receptor, and carry a missense mutation in the p53 tumor suppressor gene. In fact, transplantation of DH-14-3 cells into the back of nude mice resulted in the formation of tumors, thereby confirming the capability of tumorigenesis. DH-14-3 cells may be useful for investigating the biological features of PDTC and will contribute to the therapeutic study of thyroid cancer.

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

Patients with metastatic breast cancer leading to CD4+ T cell lymphopaenia have poor outcome.

PubMed

Trédan, Olivier; Manuel, Manuarii; Clapisson, Gilles; Bachelot, Thomas; Chabaud, Sylvie; Bardin-dit-Courageot, Christine; Rigal, Chantal; Biota, Cathy; Bajard, Agathe; Pasqual, Nicolas; Blay, Jean-Yves; Caux, Christophe; Ménétrier-Caux, Christine

2013-05-01

Low lymphocyte count is a prognostic factor in cancer patients including metastatic breast cancer patients (MBC) but the relative role of each lymphocyte subtype is unclear in MBC. The impact of lymphocyte subsets was analysed in two prospective MBC patients' cohorts. Cohort A patients (n=103) were included before the first line of chemotherapy and cohort B patients (n=101) were included after at least one line of chemotherapy. Extensive phenotypic analyses were performed on fresh whole blood. Plasma cytokines levels were measured using commercially available Luminex-based multiplex kits. Prognostic value of lymphocyte subsets and circulating cytokines was analysed. In both cohorts, severe lymphopaenia (<0.7 Giga/L) correlated with poor overall survival (OS) (median OS: 6.6 months versus 21.7 months in cohort A and 4.5 versus 9 months in cohort B). CD8(+), CD19(+) and CD56(+) T cell counts had no significant prognostic value for OS. After stratification (≤0.2, [0.20-0.45], >0.45 Giga/L), CD4 lymphopaenia appeared to be correlated with poor OS in both cohorts. Furthermore, severe CD4(+) lymphopaenia (≤0.2 Giga/L) was strongly correlated with poor OS in both cohorts (1.2 months versus 24.9 months in cohort A and 5.7 versus 13.1 months in cohort B). In multivariate analysis, after stratification CD4(+) lymphopaenia appeared to be an independent prognostic factor for OS in both cohorts. CD4(+) lymphopaenia correlated with low plasmatic levels of CCL22 that might directly contribute to CD4(+) lymphopaenia. CD4(+) lymphopaenia was associated with reduced OS in MBC patients regardless of the chemotherapy line. Decreased levels of plasmatic CCL22 may contribute to CD4(+) lymphopaenia. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cetuximab plus FOLFOX for Patients with Metastatic Colorectal Cancer with Poor Performance Status and/or Severe Tumor-Related Complications

PubMed Central

Shitara, Kohei; Yokota, Tomoya; Takahari, Daisuke; Shibata, Takashi; Sato, Yozo; Tajika, Masahiro; Ura, Takashi; Muro, Kei

2010-01-01

Introduction Cetuximab-based chemotherapy showed a statistically significantly higher response rate compared with chemotherapy such as FOLFOX. Therefore, FOLFOX plus cetuximab is suspected to be the best regimen to alleviate tumor-related symptoms with a high response rate. Case Report Here we present the results of 8 consecutive patients with metastatic colorectal cancer with poor performance status and/or severe complications who were treated with first-line FOLFOX with cetuximab. Six of 8 patients achieved an apparent clinical benefit, including radiological response and symptoms improvement. Two patients with BRAF mutation could achieve neither clinical benefit nor radiological response. Conclusion Although an optimal line of therapy with cetuximab is unclear yet with bevacizumab in mind, we propose that patients who need a tumor response to alleviate their symptoms due to advanced disease might be candidates for first-line cetuximab-based therapy as shown in our cases. Additionally, patients with BRAF mutant tumors might be important candidates for novel targeted therapy in the future to improve their poor prognosis. PMID:21347194

Validation of pathological grading systems for predicting metastatic potential in pheochromocytoma and paraganglioma

PubMed Central

Koh, Jung-Min; Ahn, Seong Hee; Kim, Hyeonmok; Kim, Beom-Jun; Sung, Tae-Yon; Kim, Young Hoon; Hong, Suck Joon; Song, Dong Eun

2017-01-01

Purpose The Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP) was proposed for predicting the metastatic potential of pheochromocytoma and paraganglioma to overcome the limitations of the Pheochromocytoma of the Adrenal Scaled Score (PASS). However, to date, no study validating the GAPP has been conducted, and previous studies did not include mutations in the succinate dehydrogenase type B (SDHB) gene in the score calculation. In this retrospective cohort study, we validated the prediction ability of GAPP and assessed whether it would be improved by inclusion of the loss of SDHB immunohistochemical staining. Methods We divided the tumors into non-metastatic and metastatic groups based on the presence of synchronous or metachronous metastases. The GAPP score and PASS at the initial operation were measured. Moreover, we combined some GAPP parameters with the immunohistochemical staining of SDHB to obtain a modified GAPP (M-GAPP) score. Results Metastasis occurred in 15/72 (20.8%) patients, with a mean follow-up of 43.5 months. Loss of SDHB staining was more frequent (P = 0.044) in the metastatic group. The GAPP score (P = 0.006), PASS (P = 0.003), and M-GAPP score (P<0.001) were all higher in the metastatic group. Twelve of 40 (30.0%) moderately or poorly differentiated tumors, as defined by the GAPP score, and 12/34 (35.3%) tumors with a PASS ≥4 were metastatic. Conversely, 10/19 (52.6%) tumors with an M-GAPP score ≥3 were metastatic. The area under the curve of the M-GAPP score (0.822) was significantly higher than that of the GAPP (0.728) (P = 0.012), but similar to that of the PASS (0.753) (P = 0.411). The GAPP (P = 0.032) and M-GAPP scores (P = 0.040), but not PASS (P = 0.200), negatively correlated with metastasis-free survival. Conclusion The GAPP was validated, and M-GAPP, a combination of some GAPP parameters and loss of SDHB staining, might be useful for the prediction of the metastatic potential of pheochromocytoma and paraganglioma

The CEA-/lo colorectal cancer cell population harbors cancer stem cells and metastatic cells.

PubMed

Yan, Chang; Hu, Yibing; Zhang, Bo; Mu, Lei; Huang, Kaiyu; Zhao, Hui; Ma, Chensen; Li, Xiaolan; Tao, Deding; Gong, Jianping; Qin, Jichao

2016-12-06

Serum carcinoembryonic antigen (CEA) is the most commonly used tumor marker in a variety of cancers including colorectal cancer (CRC) for tumor diagnosis and monitoring. Recent studies have shown that colonic crypt cells expressing little or no CEA may enrich for stem cells. Numerous studies have clearly shown that there exist CRC patients with normal serum CEA levels during tumor progression or even tumor relapse, although CEA itself is considered to promote metastasis and block cell differentiation. These seemingly contradictory observations prompted us to investigate, herein, the biological properties as well as tumorigenic and metastatic capacity of CRC cells that express high (CEA+) versus low CEA (CEA-/lo) levels of CEA. Our findings show that the abundance of CEA-/lo cells correlate with poor differentiation and poor prognosis, and moreover, CEA-/lo cells form more spheres in vitro, generate more tumors and exhibit a higher potential in developing liver and lung metastases than corresponding CEA+ cells. Applying RNAi-mediated approach, we found that IGF1R mediated tumorigenic and capacity of CEA-/lo cells but did not mediate those of CEA+ cells. Notably, our data demonstrated that CEA molecule was capable of protecting CEA-/lo cells from anoikis, implying that CEA+ cells, although themselves possessing less tumorigenic and metastatic capacity, may promote metastasis of CEA-/lo cells via secreting CEA molecule. Our observations suggest that, besides targeting CEA molecule, CEA-/lo cells may represent a critical source of tumor progression and metastasis, and should therefore be the target of future therapies.

Genetic rearrangements, hotspot mutations, and microRNA expression in the progression of metastatic adenoid cystic carcinoma of the salivary gland

PubMed Central

Andreasen, Simon; Agander, Tina Klitmøller; Bjørndal, Kristine; Erentaite, Daiva; Heegaard, Steffen; Larsen, Stine R.; Melchior, Linea Cecilie; Tan, Qihua; Ulhøi, Benedicte Parm; Wessel, Irene; Homøe, Preben

2018-01-01

Adenoid cystic carcinoma (ACC) is among the most common salivary gland malignancies, and is notorious for its unpredictable clinical course with frequent local recurrences and metastatic spread. However, the molecular mechanisms for metastatic spread are poorly understood. This malignancy is known to frequently harbor gene fusions involving MYB, MYBL1, and NFIB, and to have a low mutational burden. Most studies have focused on primary tumors to understand the biology of ACC, but this has not revealed a genetic cause for metastatic dissemination in the majority of cases. Hence, other molecular mechanisms are likely to be involved. Here, we characterize the genetic and microRNA expressional landscape of primary ACC and corresponding metastatic lesions from 11 patients. FISH demonstrated preservation of MYB aberrations between primary tumors and metastases, and targeted next-generation sequencing identified mutations exclusive for the metastatic lesions in 3/11 cases (27.3%). Global microRNA profiling identified several differentially expressed miRNAs between primary ACC and metastases as compared to normal salivary gland tissue. Interestingly, individual tumor pairs differed in miRNA profile, but there was no general difference between primary ACCs and metastases. Collectively, we show that MYB and NFIB aberrations are consistently preserved in ACC metastatic lesions, and that additional mutations included in the 50-gene hotspot panel used are infrequently acquired by the metastatic lesions. In contrast, tumor pairs differ in microRNA expression and our data suggest that they are heterogeneous according to their microRNA profile. This adds an additional layer to the complex process of ACC metastatic spread. PMID:29731974

Differential membranous E-cadherin expression, cell proliferation and O-GlcNAcylation between primary and metastatic nodal lesion in colorectal cancer.

PubMed

Jang, Tae Jung

2016-02-01

O-GlcNAcylation is an O-linked β-N-acetylglucosamine (O-GlcNAc) moiety linked to the side chain hydroxyl of a serine or threonine residue. The E-cadherin/β-catenin system, an integral component of epithelial to mesenchymal transition (EMT)/mesenchymal to epithelial transition (MET), is affected through O-GlcNAcylation. The current study examined the status of EMT/MET in both the tumor center and invasive front of the primary colorectal carcinoma (CRC) and metastatic nodal lesions, which were compared to O-GlcNAcylation expression levels in those areas. In addition, the cliniopathological significance of O-GlcNAcylation was studied Immunohistochemical staining for E-cadherin, β-catenin, Snail, O-GlcNAc and Ki67 was performed in 40 primary CRC tissues, 40 nonneoplastic colons, and 17 nodal metastatic lesions. Western blot was also conducted in primary CRC tissue Membranous E-cadherin expression was lowest in the invasive front, but showed greater increases in metastatic nodal lesions. Moreover, its expression level was negatively correlated with that of nuclear β-catenin and Snail. The Ki67 labeling index (LI) was lowest in the invasive front, and increased in metastatic nodal lesions. Primary CRC showed higher expression of O-GlcNAcylation and O-GlcNAc-transferase (OGT) than nonneoplastic colons. O-GlcNAcylation expression decreased in metastatic nodal lesions compared to the invasive front and tumor center, and was inversely correlated with Ki67 LI. However, O-GlcNAcylation expression was only slightly changed between tumor center and invasive front. In addition, there was no correlation between its expression and the level of nuclear β-catenin, membranous E-cadherin and Snail. No significant relationship was observed between O-GlcNAcylation level and cliniopathological parameters. Differential membranous E-cadherin expression, cell proliferation and O-GlcNAcylation in metastatic nodal lesion compared to primary CRC may play role in establishing its lesions

Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

PubMed

Treese, Christoph; Sanchez, Pedro; Grabowski, Patricia; Berg, Erika; Bläker, Hendrik; Kruschewski, Martin; Haase, Oliver; Hummel, Michael; Daum, Severin

2016-01-01

5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

Metastatic Urothelial Carcinoma with Glandular Differentiation That Confirmed the Response by Autopsy Specimen to Second-Line mFOLFOX6 (Fluorouracil, Oxaliplatin, and Leucovorin) plus Bevacizumab Chemotherapy

PubMed Central

Naiki, Taku; Etani, Toshiki; Naiki-Ito, Aya; Fujii, Kana; Ando, Ryosuke; Iida, Keitaro; Nagai, Takashi; Sugiyama, Yosuke; Nakagawa, Motoo; Kawai, Noriyasu; Yasui, Takahiro

2017-01-01

The prognostic significance of glandular differentiation in urothelial carcinoma (UC) is controversial, and thus far there is no established treatment strategy against metastasis of glandular component. We describe here a case of metastatic UC with glandular differentiation that had histological disappearance of adenocarcinoma components at autopsy after sequential chemotherapy with S-1 and cisplatin (CDDP) and with mFOLFOX6 (fluorouracil, oxaliplatin, and leucovorin) plus bevacizumab (mFOLFOX6+Bev). A 62-year-old Asian male was diagnosed with invasive UC with glandular differentiation (T2N0M0) by radical cystectomy and ileal conduit, and careful follow-up observation was made. Eight years after radical operation, peritoneal metastases occurred, and a biopsy specimen using colon fiber revealed high-grade adenocarcinomas with an immunohistochemical profile that included positivity for cytokeratin 7 (CK7) and negativity for cytokeratin 20 (CK20) and uroplakin, which was identical to the radical cystectomy specimen. Thus, he received combination chemotherapy consisting of S-1 and CDDP; however, the peritoneal metastasis worsened after 2 cycles. Therefore, second-line mFOLFOX6+Bev chemotherapy was performed for a total of 5 courses. In spite of this, the patient died, and the final diagnosis by autopsy was multiple metastases of infiltrating pure UC to the lung, bone, and peritoneum. Interestingly, there were no pathological findings of adenocarcinoma, and the immunohistochemical profile of the metastatic lesions was identical to that of the previous specimens from the bladder and colon. This suggests that sequential chemotherapy of S-1 and CDDP and second-line mFOLFOX6+Bev might be a feasible option in metastatic UC with glandular differentiation. PMID:29515396

Metastatic patterns and metastatic sites in mucosal melanoma: a retrospective study.

PubMed

Grözinger, Gerd; Mann, Steven; Mehra, Tarun; Klumpp, Bernhard; Grosse, Ulrich; Nikolaou, Konstantin; Garbe, Claus; Clasen, Stephan

2016-06-01

Melanomas arising from mucosa are rare and associated with a poor prognosis. This study aims to provide an analysis of metastatic pathways, time intervals, factors influencing metastatic spread and organs for distant metastases. A total of 116 patients with mucosal melanomas of different sites were included. The mean follow-up interval was 47 ± 52 months. Patients were assigned to two different metastatic pathways, either presenting loco-regional lymph node metastases as first spread or direct distant metastases. The distribution of distant metastases was assessed. Twenty-six patients presented with a pre-existing metastatic spread and were not assigned to pathways. Of the included patients, 44 developed metastases after treatment of the primary tumour; 25 patients directly developed distant metastases; 16 patients developed regional lymph node metastases prior to distant metastases. Location of the primary tumour in the upper airway or GI tract and advanced T stage were significant risk factors of direct distant metastases. Distant metastases are mainly located in the lung, the liver and non-regional lymph nodes. Mucosal melanomas show a high rate of direct distant metastases rather than regional lymph node metastases. Thus the follow-up should always include a whole-body cross-sectional imaging in high-risk tumours. • Mucosal melanomas show a high rate of direct distant metastases. • T stage and primary location are predictors for direct distant metastases. • Distant metastases were mainly found in lung, liver and lymph nodes. • Follow-up of a high-risk mucosal melanoma should include whole-body imaging.

Metastatic pathways in patients with cutaneous melanoma.

PubMed

Adler, Nikki R; Haydon, Andrew; McLean, Catriona A; Kelly, John W; Mar, Victoria J

2017-01-01

Metastasis represents the end product of an elaborate biological process, which is determined by a complex interplay between metastatic tumour cells, host factors and homoeostatic mechanisms. Cutaneous melanoma can metastasize haematogenously or lymphogenously. The three predominant models that endeavour to explain the patterns of melanoma progression are the stepwise spread model, the simultaneous spread model and the model of differential spread. The time course to the development of metastases differs between the different metastatic routes. There are several clinical and histopathological risk factors for the different metastatic pathways. In particular, patient sex and the anatomical location of the primary tumour influence patterns of disease progression. There is limited existing evidence regarding the relationship between tumour mutation status, other diagnostic and prognostic biomarkers and the metastatic pathways of primary cutaneous melanoma. This knowledge gap needs to be addressed to better identify patients at high risk of disease recurrence and personalize surveillance strategies. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Synchronous diagnosis of metastatic cancer to the thyroid is associated with poor prognosis.

PubMed

Chen, Jeng-Yeou; Chen, I-Wen; Hsueh, Chuen; Chao, Tzu-Chieh; Gao, Bing-Ru; Lin, Jen-Der

2015-03-01

The incidence and histopathological characteristics of metastatic cancers to the thyroid (MCT) are different in various geographic areas. The aim of this study was to elucidate the clinical features of MCT, including histocytological diagnosis and therapeutic outcomes. A retrospective analysis of patients with thyroid cancer treated and followed up at the Chang Gung Medical Center in Linkou was performed. Among 3957 patients with thyroid cancer, a total of 56 patients with MCT were evaluated. Of them, 47 patients (83.9 %) were diagnosed with malignancy or suspected malignancy via fine needle aspiration cytology of the thyroid. Synchronous primary cancers were diagnosed in 44 of the patients with MCT. Of the MCT, metastasis of lung cancer to the thyroid was the leading category. Other primary sites of MCT were the head and neck, gastrointestinal tract, kidneys, breast, cervix, and unknown primary site. The mean 5-, 10-, 20-, and 60-month survival rates were 46.4, 32.1, 21.4, and 7.9 % for the patients. Patients with metachronous thyroid carcinoma had significantly better survival than patients with synchronous cancer. In conclusions, the incidence of MCT in patients with thyroid cancer is low; however, the prognosis of patients with MCT is poor, especially in patients diagnosed with synchronous primary tumors. In this study, MCT commonly originated in organs located near the thyroid, such as the lungs, head, and neck. Close monitoring of these malignancies may improve the prognosis of patients with MCT in the future.

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation

PubMed Central

Miller, Daniel H.; Peterson, Jennifer L.; Buskirk, Steven J.; Vallow, Laura A.; Ta, Randy; Joseph, Richard; Krishna, Murli; Ko, Stephen J.; Tzou, Katherine S.

2015-01-01

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease. PMID:26500736

Management of Metastatic Apocrine Hidradenocarcinoma with Chemotherapy and Radiation.

PubMed

Miller, Daniel H; Peterson, Jennifer L; Buskirk, Steven J; Vallow, Laura A; Ta, Randy; Joseph, Richard; Krishna, Murli; Ko, Stephen J; Tzou, Katherine S

2015-09-07

Hidradenocarcinoma is a rare aggressive form of cutaneous adnexal skin carcinoma originating from the sweat gland. Due to its low incidence, prognostic and treatment strategies are still being explored both for primary and advanced disease. This tumor most often presents as either solid or cystic appearing subcutaneous nodules, which may be associated with pruritus or ulceration. To date the mainstay of treatment for local disease has been surgical excision; however, the paucity of historical data available has shown that these tumors often behave aggressively with high rates of local recurrence, metastasis, and poor overall outcomes. There are few case reports describing the utility of radiation therapy in the treatment of hidradenocarcinoma. Herein, we present a case of metastatic apocrine hidradenocarcinoma in a 32-year-old Caucasian male. The patient initially underwent excisional biopsy which confirmed the diagnosis of poorly differentiated, highly infiltrative, apocrine hidradenocarcinoma. He received systemic chemotherapy for metastatic disease, followed by radiation therapy to areas of grossly palpable adenopathy. Prior to radiation therapy the patient had an enlarged hypermetabolic conglomerate of lymph nodes in the right axilla, and borderline enlarged low activity nodes within the left axilla. He received 3 cycles of chemotherapy followed by tamoxifen and radiation therapy (50.4 Gy in 28 fractions) to areas of progressive disease in the bilateral axilla, lower neck, and axillary skin. Following treatment, the patient had complete resolution of skin nodules and improvement of his pruritus. While the role of radiation therapy in the treatment of hidradenocarcinoma has not been well established, this case report demonstrated the potential benefit of external beam radiotherapy in the management of this rare disease.

The extended leukocyte differential count using the Cytodiff flow cytometric system reveals that higher CD16+ cytotoxic NK+T lymphocyte levels predict superior survival outcomes in patients with metastatic carcinoma.

PubMed

Park, Borae G; Park, Chan-Jeoung; Yoon, Chan-Hee; Jang, Seongsoo; Chi, Hyun-Sook; Ryu, Min-Hee; Kim, Sang-We

2013-05-01

The recently developed Cytodiff flow cytometric system (Beckman Coulter, Miami, FL) enables leukocyte analysis using a single immunophenotyping panel tube composed of six markers and five colors and that can detect 16 leukocyte subpopulations. We performed a preliminary investigation of whether changes in any of 16 leukocyte differentials were associated with survival and treatment outcomes in patients with metastatic carcinoma or not. We measured 16 leukocyte differential counts using the Cytodiff flow cytometric system in peripheral blood samples from 40 patients with metastatic malignancy (27 stomach cancer and 13 lung cancer) before chemotherapy and at 15 day intervals after chemotherapy for 2 months. A higher percentage of CD16+ cytotoxic NK+T lymphocytes was found to be the only significant prognostic factor among by Cox regression analysis and a higher percentage of CD16+ cytotoxic NK+T lymphocytes (>5.0%) showed significantly longer survival outcomes by Kaplan-Meier analysis (P = 0.003). The Cytodiff system enables 16 leukocyte subpopulations in a one tube assay and also can operate with only small amounts of sample, although it cannot differentiate NK cells from T lymphocytes. Hence, the monitoring of all leukocyte subpopulations using Cytodiff flow cytometry may be a helpful prognostic tool for patients with metastatic carcinoma. Copyright © 2012 International Clinical Cytometry Society.

Olaparib With or Without Cediranib in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

ClinicalTrials.gov

2018-06-04

Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma With Focal Neuroendocrine Differentiation; Prostate Carcinoma Metastatic in the Bone; Prostate Small Cell Carcinoma; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

Constitutive Proteasomal Degradation of TWIST-1 in Epithelial Ovarian Cancer Stem Cells Impacts Differentiation and Metastatic Potential

PubMed Central

Yin, Gang; Alvero, Ayesha B.; Craveiro, Vinicius; Holmberg, Jennie C.; Fu, Han-Hsuan; Montagna, Michele K.; Yang, Yang; Chefetz-Menaker, Ilana; Nuti, Sudhakar; Rossi, Michael; Silasi, Dan-Arin; Rutherford, Thomas; Mor, Gil

2013-01-01

Epithelial-mesenchymal transition (EMT) is a critical process for embryogenesis but is abnormally activated during cancer metastasis and recurrence. This process enables epithelial cancer cells to acquire mobility and traits associated with stemness. It is unknown whether epithelial stem cells or epithelial cancer stem cells are able to undergo EMT, and what molecular mechanism regulates this process in these specific cell types. We found that Epithelial Ovarian Cancer Stem cells (EOC stem cells) are the source of metastatic progenitor cells through a differentiation process involving EMT and Mesenchymal-Epithelial Transition (MET). We demonstrate both in vivo and in vitro the differentiation of EOC stem cells into mesenchymal spheroid-forming cells (MSFCs) and their capacity to initiate an active carcinomatosis. Furthermore, we demonstrate that human EOC stem cells injected i.p in mice are able to form ovarian tumors, suggesting that the EOC stem cells have the ability to “home” to the ovaries and establish tumors. Most interestingly, we found that TWIST1 is constitutively degraded in EOC stem cells, and that the acquisition of TWIST1 requires additional signals that will trigger the differentiation process. These findings are relevant for understanding the differentiation and metastasis process in EOC stem cells. PMID:22349827

Re-irradiation of metastatic disease in the neck from xeroderma pigmentosum.

PubMed

Wei, C C; Sanfilippo, N J; Myssiorek, D

2010-06-01

Xeroderma pigmentosum, an autosomal recessive disease that occurs with a frequency of 1:250,000, is caused by a genetic defect in nucleotide excision repair enzymes. Mutation of these enzymes leads to the development of multiple basal cell and squamous cell carcinomas. We present a case of xeroderma pigmentosum in a patient with cervical and intraparotid metastatic disease from recurrent cutaneous squamous cell carcinomas of the face and scalp, treated with neck dissection and re-irradiation. With the illustrative case report, we include a literature review of diagnosis, prognostic factors, and treatment, with emphasis on surgical and radiation treatment of cervical metastatic disease from recurrent skin carcinomas. A xeroderma pigmentosum patient presented to our clinic with a 2-cm right submental and 1-cm right infra-auricular mass after resection of multiple squamous cell carcinomas of the scalp and face, and external-beam radiation therapy to the right face and neck. Fine-needle aspiration biopsy of the submental mass revealed poorly differentiated squamous cell carcinoma. The patient was brought to the operating room for a right modified radical neck dissection and excision of the right submental and intraparotid mass. Surgical pathology revealed 3 level ia and supraclavicular lymph nodes that were positive for metastatic squamous cell carcinoma. Re-irradiation to the entire right hemi-neck and left submandibular nodal region was performed using opposed oblique portals for the upper neck and a low anterior en face hemi-neck portal. The left parotid region was also included in the re-irradiation volume. Treatment was completed without delayed complications or recurrences to date. To our knowledge, this is the first case report in the literature of a patient with xeroderma pigmentosum who subsequently developed metastatic disease from recurrent cutaneous squamous cell carcinoma. Because of the rarity of xeroderma pigmentosum, this case report is also the first

Metastatic Regulation of Differential Splicing of CD44

DTIC Science & Technology

2001-08-01

Ft. Detrick, MD 21702-5012. AUTHORITY USAMRMC ltr, 8 Jan 2003 THIS PAGE IS UNCLASSIFIED AD Award Number: DAMD17-96- 1 -6084 TITLE: Metastatic Regulation...MANUFACTURE, USE, OR SELL ANY PATENTED INVENTION THAT MAY RELATE TO THEM. LIMITED RIGHTS LEGEND Award Number: DAMD17-96- 1 -6084 Organization: Baylor...HAS BEEN REVIEWED AND IS APPROVED FOR PUBLICATION. Nt At~Y-. ""-0- 1 " tV~Lt~- __________________ Form Approved REPORT DOCUMENTATION PAGE OIMB No. 074

A Differential Abundance Analysis of Very Metal-poor Stars

NASA Astrophysics Data System (ADS)

O'Malley, Erin M.; McWilliam, Andrew; Chaboyer, Brian; Thompson, Ian

2017-04-01

We have performed a differential line-by-line chemical abundance analysis, ultimately relative to the Sun, of nine very metal-poor main-sequence (MS) halo stars, near [Fe/H] = -2 dex. Our abundances range from -2.66≤slant [{Fe}/{{H}}]≤slant -1.40 dex with conservative uncertainties of 0.07 dex. We find an average [α/Fe] = 0.34 ± 0.09 dex, typical of the Milky Way. While our spectroscopic atmosphere parameters provide good agreement with Hubble Space Telescope parallaxes, there is significant disagreement with temperature and gravity parameters indicated by observed colors and theoretical isochrones. Although a systematic underestimate of the stellar temperature by a few hundred degrees could explain this difference, it is not supported by current effective temperature studies and would create large uncertainties in the abundance determinations. Both 1D and < 3{{D}}> hydrodynamical models combined with separate 1D non-LTE effects do not yet account for the atmospheres of real metal-poor MS stars, but a fully 3D non-LTE treatment may be able to explain the ionization imbalance found in this work.

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.

HSP-enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells.

PubMed

Ono, Kisho; Eguchi, Takanori; Sogawa, Chiharu; Calderwood, Stuart K; Futagawa, Junya; Kasai, Tomonari; Seno, Masaharu; Okamoto, Kuniaki; Sasaki, Akira; Kozaki, Ken-Ichi

2018-05-16

Cancer cells often secrete extracellular vesicles (EVs) that carry heat shock proteins (HSPs) with roles in tumor progression. Oral squamous cell carcinoma (OSCC) belongs to head and neck cancers (HNC) whose lymph-node-metastases often lead to poor prognosis. We have examined the EV proteome of OSCC cells and found abundant secretion of HSP90-enriched EVs in lymph-node-metastatic OSCC cells. Double knockdown of HSP90α and HSP90β, using small interfering RNA significantly reduced the survival of the metastatic OSCC cells, although single knockdown of each HSP90 was ineffective. Elevated expression of these HSP90 family members was found to correlate with poor prognosis of HNC cases. Thus, elevated HSP90 levels in secreted vesicles are potential prognostic biomarkers and therapeutic targets in metastatic OSCC. © 2018 Wiley Periodicals, Inc.

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

DOE PAGES

Hong, Matthew K. H.; Macintyre, Geoff; Wedge, David C.; ...

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

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

PubMed

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. 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.

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

Metastatic Breast Cancer in Uterine Cervix: A Rare Presentation.

PubMed

Proença, Sara; Reis, Maria Inês; Cominho, Joana; Conde, Pedro Casado; Santos E Pereira, Helena; Ribeiro, Filipa Castro

2016-01-01

Uterine cervix involvement by a distant primary tumor is a rare event. We report the following 2 cases of breast tumor metastasis to the uterine cervix with different presentations: case 1 is an isolated cervix metastasis and case 2 is a disseminated metastatic disease with cervix involvement. In both, clinical examination raised the suspicion of cervical tumor, which was confirmed to be a metastatic adenocarcinoma.The poor outcome and lack of symptoms suggest that although its rareness, all patients with breast cancer should undergo a careful routine gynecologic examination.

Predictive factors for lymph node metastasis in poorly differentiated early gastric cancer and their impact on the surgical strategy

PubMed Central

Li, Hua; Lu, Ping; Lu, Yang; Liu, Cai-Gang; Xu, Hui-Mian; Wang, Shu-Bao; Chen, Jun-Qing

2008-01-01

AIM: To identify the predictive clinicopathological factors for lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC) and to further expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of poorly differentiated EGC. METHODS: Data were collected from 85 poorly-differentiated EGC patients who were surgically treated. Association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. RESULTS: Univariate analysis showed that tumor size (OR = 5.814, 95% CI = 1.050 - 32.172, P = 0.044), depth of invasion (OR = 10.763, 95% CI = 1.259 - 92.026, P = 0.030) and lymphatic vessel involvement (OR = 61.697, 95% CI = 2.144 - 175.485, P = 0.007) were the significant and independent risk factors for LNM. The LNM rate was 5.4%, 42.9% and 50%, respectively, in poorly differentiated EGC patients with one, two and three of the risk factors, respectively. No LNM was found in 25 patients without the three risk factors. Forty-four lymph nodes were found to have metastasis, 29 (65.9%) and 15 (34.1%) of the lymph nodes involved were within N1 and beyond N1, respectively, in 12 patients with LNM. CONCLUSION: Endoscopic mucosal resection alone may be sufficient to treat poorly differentiated intramucosal EGC (≤ 2.0 cm in diameter) with no histologically-confirmed lymphatic vessel involvement. When lymphatic vessels are involved, lymph node dissection beyond limited (D1) dissection or D1+ lymph node dissection should be performed depending on the tumor location. PMID:18636670

Metastatic polyp of the gallbladder from renal cell carcinoma.

PubMed

Shyr, Bor-Uei; Chen, Shih-Chin; Shyr, Yi-Ming; Lee, Rheun-Chuan; Wang, Shin-E

2017-04-04

Gallbladder metastasis from renal cell carcinoma (RCC) is extremely rare. The purpose of this study is to clarify the characteristics of metastatic RCC to gallbladder. The pooled data for analysis were collected from the case of metastatic RCC to gallbladder encountered by our institution along with sporadic cases reported in literature from 1991 to 2015. A total of 50 cases of metastatic RCC to gallbladder were recruited for study. Fifty-seven percentage of the primary RCC was from the right kidney and 43% from the left. The median interval between diagnoses of primary and metastatic RCC to gallbladder was 36 months, with the longest duration up to 324 months. Most (70%) were asymptomatic. The size of metastatic RCC to gallbladder ranged from 0.8 cm to 9 cm, with median of 2.6 cm. Majority (91%) of the metastatic RCCs presented as a polypoid mass with narrow stalk, and 82% were hypervascular lesion. The overall 1 year, 3 year and 5 year survival rate was 91.5%, 76.2% and 59.3% respectively, with a median of 26.5 months. Number of the metastatic site, timing of gallbladder metastasis, symptom, tumor size and operation type of cholecystectomy seemed to have no impact on survival. Metastatic RCC to the gallbladder should be taken into account for a gallbladder polypoid mass with narrow hypervascular stalk during the diagnosis and/or follow-up of primary RCC. Gallbladder metastasis from RCC is not necessarily to be an advanced stage with poor outcome, and cholecystectomy is recommended whenever possible.

Secretomes reveal several novel proteins as well as TGF-β1 as the top upstream regulator of metastatic process in breast cancer.

PubMed

Erin, Nuray; Ogan, Nur; Yerlikaya, Azmi

2018-03-20

Metastatic breast cancer is resistant to many conventional treatments and novel therapeutic targets are needed. We previously isolated subsets of 4T1 murine breast cancer cells which metastasized to liver (4TLM), brain (4TBM), and heart (4THM). Among these cells, 4TLM is the most aggressive one, demonstrating mesenchymal phenotype. Here we compared secreted proteins from 4TLM, 4TBM, and 4THM cells and compared with that of hardly metastatic 67NR cells to detect differentially secreted factors involved in organ-specific metastasis. Label-free LC-MS/MS proteomic technique was used to detect the differentially secreted proteins. Eighty-five of over 500 secreted proteins were significantly altered in metastatic breast cancer cells. Differential expression of several proteins such as fibulin-4, Bone Morphogenetic Protein 1, TGF-β1 MMP-3, MMP-9, and Thymic Stromal Lymphopoietin were further verified using ELISA or Western blotting. Many of these identified proteins were also present in human metastatic breast carcinomas. Annexin A1 and A5, laminin beta 1, Neutral alpha-glucosidase AB were commonly found at least in three out of six studies examined here. Ingenuity Pathway Analysis showed that proteins differentially secreted from metastatic cells are involved primarily in carcinogenesis and TGF-β1 is the top upstream regulator in all metastatic cells. Cells metastasized to different organs displayed significant differences in several of secreted proteins. Proteins differentially altered were fibronectin, insulin-like growth factor-binding protein 7, and Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1. On the other hand, many exosomal proteins were also common to all metastatic cells, demonstrating involvement of key universal factors in distant metastatic process.

Arterial spin labeling perfusion-weighted MR imaging: correlation of tumor blood flow with pathological degree of tumor differentiation, clinical stage and nodal metastasis of head and neck squamous cell carcinoma.

PubMed

Abdel Razek, Ahmed Abdel Khalek; Nada, Nadia

2018-05-01

The prognostic parameters of head and neck squamous cell carcinoma (HNSCC) include the pathological degree of tumor differentiation, clinical staging, and presence of metastatic cervical lymph nodes. To correlate tumor blood flow (TBF) acquired from arterial spin labeling (ASL) perfusion-weighted MR imaging with pathological degree of tumor differentiation, clinical stage, and nodal metastasis of HNSCC. Retrospective analysis of 43 patients (31 male, 12 female with a mean age of 65 years) with HNSCC that underwent ASL of head and neck and TBF of HNSCC was calculated. Tumor staging and metastatic lymph nodes were determined. The stages of HNSCC were stage 1 (n = 7), stage II (n = 12), stage III (n = 11) and stage IV (n = 13). Metastatic cervical lymph nodes were seen in 24 patients. The degree of tumor differentiation was determined through pathological examination. The mean TBF of poorly and undifferentiated HNSCC (157.4 ± 6.7 mL/100 g/min) was significantly different (P = 0.001) than that of well-to-moderately differentiated (142.5 ± 5.7 mL/100 g/min) HNSCC. The cut-off TBF used to differentiate well-moderately differentiated from poorly and undifferentiated HNSCC was 152 mL/100 g/min with an area under the curve of 0.658 and accuracy of 88.4%. The mean TBF of stages I, II (146.10 ± 9.1 mL/100 g/min) was significantly different (P = 0.014) than that of stages III, IV (153.33 ± 9.3 mL/100 g/min) HNSCC. The cut-off TBF used to differentiate stages I, II from stages III and IV was 148 mL/100 g/min with an area under the curve of 0.701 and accuracy of 69.8%. The TBF was higher in patients with metastatic cervical lymph nodes. The cut-off TBF suspect metastatic node was 147 mL/100 g/min with an area under the curve of 0.671 and accuracy of 67.4%. TBF is a non-invasive imaging parameter that well correlated with pathological degree of tumor differentiation, clinical stage of tumor and nodal metastasis of HNSCC.

Metastatic gastric carcinoma from breast cancer mimicking primary linitis plastica: A case report.

PubMed

Yagi, Yasumichi; Sasaki, Shozo; Yoshikawa, Akemi; Tsukioka, Yuji; Fukushima, Wataru; Fujimura, Takashi; Hirosawa, Hisashi; Izumi, Ryohei; Saito, Katsuhiko

2015-12-01

Metastases to the gastrointestinal tract rarely occur in breast cancer except in invasive lobular carcinoma. The present study reports a rare case of metastatic gastric cancer from invasive ductal carcinoma (IDC) of the breast mimicking primary gastric linitis plastica. A 51-year-old premenopausal female, who had a history of partial mastectomy for right breast cancer at the age of 40, was referred to Toyama City Hospital (Toyoma, Japan) for an endoscopic diagnosis of gastric linitis plastica. Abdominal computed tomography (CT) revealed left hydronephrosis, while peritoneal metastasis and malignant ascites were not detected. Chest CT detected a left lung tumor, which had invaded the left upper bronchus. Biopsy specimens were obtained and the histopathological findings on both the gastric tumor and lung tumor demonstrated poorly differentiated adenocarcinoma, whereas the histology of the original breast cancer was IDC with a solid-tubular type. Immunohistochemistry revealed that the biopsied specimens of the gastric and lung tumors were positive for estrogen receptor (ER), progesterone receptor (PgR) and negative for human epithelial growth factor receptor-2 (HER2). These molecular characteristics indicated the case was metastatic gastric carcinoma from the breast cancer with lung metastasis, since the statuses of ER, PgR and HER2 were concordant with those of the original breast cancer. However, the possibility of primary gastric cancer could not be completely ruled out. Therefore, a total gastrectomy was performed for the purpose of both diagnosis and treatment. Pathological examination of the resected specimen provided a definite diagnosis of multiple metastatic gastric carcinomas from the breast. To the best of our knowledge, metastatic gastric cancer derived from the breast presenting as linitis plastica 11 years following the surgical removal of IDC has not been described previously.

Prostate carcinoma metastatic to the skin as an extrammamary Paget’s disease

PubMed Central

2012-01-01

Aim The current paper describes a case of prostatic adenocarcinoma metastatic to the skin presenting as an extrammamary Paget's disease, a very rare and poorly characterised morphological entity. We report a case of prostatic carcinoma metastatic to skin showing a pattern of extramammary Paget's disease which has not been clearly illustrated in the literature Case presentation: A 63 year-old man with prostatic adenocarcinoma developed cutaneous metastases after 16 years. The inguinal metastases were sessile and 'keratotic.' The tumour displayed solid, glandular areas as well as a polypoid region suggestive of extramammary Paget's disease were identified. Discussion and conclusions We review the diagnostic criteria that have led to the correct histopathological diagnosis in this case. A differential diagnosis of the pagetoid spread in the skin and various forms of cutaneous metastases determined by a prostatic adenocarcinoma as well as the role of immunohistochemistry in establishing the prostatic origin are presented in the context of this case. Although, morphologically the cells presented in the skin deposits were not characteristic for adenocarcinoma of prostate, immunohistochemistry for PSA and PSAP suggested a prostatic origin. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1395450057455276 PMID:22901743

Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes

PubMed Central

Winnard, Paul T.; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

2017-01-01

Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities – a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy. PMID:28145887

Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes.

PubMed

Winnard, Paul T; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

2017-03-21

Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities - a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy.

Avelumab: A Review in Metastatic Merkel Cell Carcinoma.

PubMed

Shirley, Matt

2018-05-24

Avelumab (Bavencio ® ) is a fully human IgG1 monoclonal antibody that is directed against programmed cell death ligand 1 (PD-L1). Avelumab functions as an immune checkpoint inhibitor and has recently been approved in the USA, the EU and Japan for the treatment of metastatic Merkel cell carcinoma (MCC). It is thus the first therapeutic agent specifically approved for use in this indication, and is approved for use independent of line of treatment. Approval for avelumab in metastatic MCC was based on the two-part, single-arm, phase II trial, JAVELIN Merkel 200. In Part A of the study, confirmed objective responses were observed in approximately one-third of patients with chemotherapy-refractory metastatic MCC treated with avelumab. The responses were observed early and appeared to be durable, with an estimated 74% of responses having a duration ≥ 12 months. Furthermore, interim results from a separate cohort of patients (Part B) indicate an objective response rate for avelumab of > 60% in patients who were chemotherapy-naïve in the metastatic disease setting. Avelumab is associated with a risk of immune-related adverse events but, overall, has an acceptable and manageable safety and tolerability profile. In conclusion, currently available data suggest that avelumab presents a clinically beneficial new treatment option for metastatic MCC, a rare but aggressive cancer associated with a poor prognosis.

Telotristat ethyl: proof of principle and the first oral agent in the management of well-differentiated metastatic neuroendocrine tumor and carcinoid syndrome diarrhea.

PubMed

Masab, Muhammad; Saif, Muhammad Wasif

2017-12-01

Metastatic neuroendocrine tumors (NETs) are associated with carcinoid syndrome that is typically characterized by diarrhea, cutaneous flushing and bronchospasm. Treatment with somatostatin analogues (SSA) improves the symptom burden but a significant proportion of patients stop responding to SSA therapy eventually. Novel agents with the potential to effectively control the symptoms are urgently needed. This article reviews an in-depth analysis of the phase I-III clinical trials determining the clinical rationale for the use of tryptophan hydroxylase inhibitor, telotristat ethyl in patients with well-differentiated metastatic NETs and uncontrolled carcinoid syndrome. Telotristat ethyl has already been approved for the treatment of inadequately controlled carcinoid syndrome symptoms in metastatic NET patients on SSA therapy. Results from multiple phase I-III clinical studies of telotristat ethyl therapy have reported a significant decrease in the daily bowel movement frequency, increase in quality of life and the subsequent decrease in annual health costs related to carcinoid syndrome symptoms in NET patients. The associated decrease in urinary 5-hydroxyindoleacetic acid (u5-HIAA) provides evidence that telotristat ethyl effectively decreases serotonin production, and therefore, offers a rationale to investigate this agent to mitigate serotonin-mediated complications in this patient population, especially cardiac valvular disease or mesenteric fibrosis.

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

Bronchogenic adenocarcinoma metastatic tumor mimicking a dentoalveolar abscess in the maxilla.

PubMed

Salarić, Ivan; Miloš, Mate; Brajdić, Davor; Manojlović, Spomenka; Trutin Ostović, Karmen; Macan, Darko

2016-01-01

Intraosseous metastatic tumors (IOM) in maxilla are less frequent than the soft tissue metastatic tumors. Lung and bronchogenic metastatic tumors are uncommon in the maxilla. We present a maxillary bronchogenic metastasis with a rare clinical appearance. IOM was misdiagnosed as a dentoalveolar abscess and treated with antibiotics for 3 weeks. After not responding to antibiotics, the patient's general dental practitioner forwarded the patient to the Department of Oral and Maxillofacial Surgery. The associated tooth was extracted and the patient was recalled 1 week later. No signs of improvement were observed, and cytology, biopsy, and radiology diagnostics were performed. Cytologic results and biopsy could not differentiate a metastatic tumor from a salivary duct carcinoma. Ultimately, negative androgen receptors immunohistochemistry supported the diagnosis of bronchogenic metastatic adenocarcinoma. This case report stresses the importance of taking a thorough medical history. To our knowledge, this is the third bronchogenic IOM to the maxilla reported, mimicking a dentoalveolar abscess. General dental practitioners are among the first in contact with oral metastatic tumors and it is therefore important to report unusual clinical cases, as they present a diagnostic challenge for both the clinician and the pathologist.

Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status

PubMed Central

Mudali, Shiyama V.; Fu, Baojin; Lakkur, Sindhu S.; Luo, Mingde; Embuscado, Erlinda E.

2009-01-01

EphA2 is a transmembrane receptor tyrosine kinase that functions in the regulation of cell growth, survival, angiogenesis, and migration and EphA2 targeting has been proposed as a novel therapeutic strategy for neoplasms that overexpress this protein. EphA2 overexpression has been correlated with increased invasive and metastatic ability in pancreatic cancer cell lines. However, the patterns of EphA2 expression in human pancreatic cancers and associated metastases is unknown, as are the genetics of EphA2 in this tumor type. We collected clinicopathologic data and paraffin-embedded materials from 98 patients with primary and/or metastatic pancreatic cancer and performed immunohistochemical labeling for EphA2 protein. EphA2 protein immunolabeling was found in 207 of 219 samples (95%). The expression was predominantly cytoplasmic, although predominant membranous staining was observed in a minority of cases. When evaluated specifically for labeling intensity, primary and metastatic carcinomas were more strongly positive compared to benign ducts and PanIN lesions (P < 0.00001 and P < 0.01, respectively) and poorly differentiated carcinomas were more strongly positive for EphA2 than well and moderately differentiated tumors (P < 0.005). When primary carcinomas without metastatic disease were specifically compared to carcinomas with associated metastatic disease, the advanced carcinomas showed relatively less strong positive labeling for EphA2 (P < 0.008). Moreover, decreased EphA2 labeling was more commonly found in liver (P < 0.002), lung (P < 0.004) or peritoneal metastases (P < 0.01) as compared to distant lymph node metastases (P < 0.01). Genetic sequencing of the tyrosine kinase domain of EPHA2 in 22 samples of xenograft enriched pancreatic cancer did not reveal any inactivating mutations. However, EPHA2 amplification was found in 1 of 33 pancreatic cancers corresponding to a lymph node metastasis, indicating EPHA2 genomic amplification may underlie EphA2

Heparan sulfate proteoglycans undergo differential expression alterations in right sided colorectal cancer, depending on their metastatic character.

PubMed

Fernández-Vega, Iván; García-Suárez, Olivia; García, Beatriz; Crespo, Ainara; Astudillo, Aurora; Quirós, Luis M

2015-10-20

Heparan sulfate proteoglycans (HSPGs) are complex molecules involved in the growth, invasion and metastatic properties of cancerous cells. This study analyses the alterations in the expression patterns of these molecules in right sided colorectal cancer (CRC), both metastatic and non-metastatic. Twenty right sided CRCs were studied. A transcriptomic approach was used, employing qPCR to analyze both the expression of the enzymes involved in heparan sulfate (HS) chains biosynthesis, as well as the proteoglycan core proteins. Since some of these proteoglycans can also carry chondroitin sulfate (CS) chains, we include the study of the genes involved in the biosynthesis of these glycosaminoglycans. Immunohistochemical techniques were also used to analyze tissue expression of particular genes showing significant expression differences, of potential interest. Changes in proteoglycan core proteins differ depending on their location; those located intracellularly or in the extracellular matrix show very similar alteration patterns, while those located on the cell surface vary greatly depending on the nature of the tumor: glypicans 1, 3, 6 and betaglycan are affected in the non-metastatic tumors, whereas in the metastatic, only glypican-1 and syndecan-1 are modified, the latter showing opposing alterations in levels of RNA and of protein, suggesting post-transcriptional regulation in these tumors. Furthermore, in non-metastatic tumors, polymerization of glycosaminoglycan chains is modified, particularly affecting the synthesis of the tetrasaccharide linker and the initiation and elongation of CS chains, HS chains being less affected. Regarding the enzymes responsible for the modificaton of the HS chains, alterations were only found in non-metastatic tumors, affecting N-sulfation and the isoforms HS6ST1, HS3ST3B and HS3ST5. In contrast, synthesis of the CS chains suggests changes in epimerization and sulfation of the C4 and C2 in both types of tumor. Right sided CRCs show

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

Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer

PubMed Central

Xue, Mengzhu; Liu, Haiyue; Zhang, Liwen; Chang, Hongyuan; Liu, Yuwei; Du, Shaowei; Yang, Yingqun; Wang, Peng

2017-01-01

Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance. Hence, a systematic identification of additional drivers may provide useful insights into the development of effective therapies. Numerous microRNAs that are critical for metastasis are dysregulated in metastatic prostate cancer, but the underlying molecular mechanism is poorly understood. We perform an integrative analysis of transcription factor (TF) and microRNA expression profiles and computationally identify three master TFs, AR, HOXC6 and NKX2-2, which induce the aberrant metastatic microRNA expression in a mutually exclusive fashion. Experimental validations confirm that the three TFs co-dysregulate a large number of metastasis-associated microRNAs. Moreover, their overexpression substantially enhances cell motility and is consistently associated with a poor clinical outcome. Finally, the mutually exclusive overexpression between AR, HOXC6 and NKX2-2 is preserved across various tissues and cancers, suggesting that mutual exclusivity may represent an intrinsic characteristic of driver TFs during tumorigenesis. PMID:28397780

Gene expression profiles in primary pancreatic tumors and metastatic lesions of Ela-c-myc transgenic mice.

PubMed

Thakur, Archana; Bollig, Aliccia; Wu, Jiusheng; Liao, Dezhong J

2008-01-24

Pancreatic carcinoma usually is a fatal disease with no cure, mainly due to its invasion and metastasis prior to diagnosis. We analyzed the gene expression profiles of paired primary pancreatic tumors and metastatic lesions from Ela-c-myc transgenic mice in order to identify genes that may be involved in the pancreatic cancer progression. Differentially expressed selected genes were verified by semi-quantitative and quantitative RT-PCR. To further evaluate the relevance of some of the selected differentially expressed genes, we investigated their expression pattern in human pancreatic cancer cell lines with high and low metastatic potentials. Data indicate that genes involved in posttranscriptional regulation were a major functional category of upregulated genes in both primary pancreatic tumors (PT) and liver metastatic lesions (LM) compared to normal pancreas (NP). In particular, differential expression for splicing factors, RNA binding/pre-mRNA processing factors and spliceosome related genes were observed, indicating that RNA processing and editing related events may play critical roles in pancreatic tumor development and progression. High expression of insulin growth factor binding protein-1 (Igfbp1) and Serine proteinase inhibitor A1 (Serpina1), and low levels or absence of Wt1 gene expression were exclusive to liver metastatic lesion samples. We identified Igfbp1, Serpina1 and Wt1 genes that are likely to be clinically useful biomarkers for prognostic or therapeutic purposes in metastatic pancreatic cancer, particularly in pancreatic cancer where c-Myc is overexpressed.

Expression of Lipid Metabolism-Related Proteins in Metastatic Breast Cancer.

PubMed

Jung, Yoon Yang; Kim, Hye Min; Koo, Ja Seung

2015-01-01

The tumor biology of metastatic breast cancers differ according to the metastatic sites, and the features of cancer metabolism may also be different. The aim of this study is to investigate the expression of lipid metabolism-related proteins in metastatic breast cancer according to metastatic site and discuss the clinical significance thereof. Immunohistochemical staining for lipid metabolism-related proteins [fatty acid synthase (FASN), hormone-sensitive lipase (HSL), carnitine palmitoyltransferase IA (CPT-1A), acyl-CoA oxidase 1 (ACOX1), fatty acid binding protein 4 (FABP4,) and perilipin 1 (PLIN1)] was performed using a tissue microarray of 149 cases of metastatic breast cancer (bone metastasis = 39, brain metastasis = 37, liver metastasis = 21, and lung metastasis = 52). The expression levels of ACOX1 (p = 0.009) and FASN (p = 0.007) varied significantly according to metastatic site, with the highest expression in brain metastasis and the lowest expression in liver metastasis. ACOX1 positivity (p = 0.005) and FASN positivity (p = 0.003) correlated with HER-2 positivity. The expression of FASN was significantly higher in HER-2 type breast cancer, and lower in luminal A and TNBC type breast cancer (p<0.001). Among lipid metabolism-related proteins, PLIN1 positivity was found to be an independent poor prognostic factor on multivariate analysis (Hazard ratio: 4.979, 95% CI: 1.054-22.59, p = 0.043). Different expression levels of lipid metabolism-related proteins were observed according to metastatic site. The expression of ACOX1 and FASN was highest in brain metastasis. These results suggest that the metastatic site should be considered when using lipid metabolism inhibitors for targeted therapy.

Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

PubMed Central

Halabi, Susan; Sanford, Ben L.; Hahn, Olwen; Michaelson, M. Dror; Walsh, Meghara K.; Feldman, Darren R.; Olencki, Thomas; Picus, Joel; Small, Eric J.; Dakhil, Shaker; George, Daniel J.; Morris, Michael J.

2017-01-01

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23% to 44%) for cabozantinib versus 12% (95% CI, 5.4% to 21%) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC. PMID:28199818

Small size of metastatic lymph nodes with extracapsular spread greatly impacts treatment outcomes in oral squamous cell carcinoma patients.

PubMed

Michikawa, C; Izumo, T; Sumino, J; Morita, T; Ohyama, Y; Michi, Y; Uzawa, N

2018-07-01

Extracapsular spread (ECS) of metastatic lymph nodes from oral carcinoma is the most significant prognostic predictor of a poor treatment outcome. However, only a few reports on prognostic factors in ECS-positive cases have been investigated. To address this problem, a detailed examination of ECS pathology was conducted to determine the prognostic factors of oral squamous cell carcinoma (OSCC) with ECS of metastatic lymph nodes. This study involved 63 OSCC patients with at least one pathologically metastatic node with ECS. Among the 229 metastatic lymph nodes, 149 exhibited ECS. Univariate analysis revealed that a poor outcome and recurrence were significantly associated with the number of ECS-positive nodes, density of ECS, and the minor axis of the smallest ECS-positive node. However, multivariate analysis identified only small size of ECS-positive nodes as a significant and independent factor predicting recurrence and a poor outcome. Thus, small size of ECS-positive nodes is the most important prognostic indicator for OSCC with ECS in metastatic lymph nodes. The classification of ECS status using the minor axis of ECS-positive nodes may be useful for further prediction of a poorer prognosis in OSCC cases. Standardization of ECS diagnosis and multicenter prospective studies will be required to confirm and refine these findings. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

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.

KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis

PubMed Central

Murgai, Meera; Ju, Wei; Eason, Matthew; Kline, Jessica; Beury, Daniel; Kaczanowska, Sabina; Miettinen, Markku M; Kruhlak, Michael; Lei, Haiyan; Shern, Jack F; Cherepanova, Olga A.; Owens, Gary K; Kaplan, Rosandra N

2017-01-01

A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche composed of hematopoietic cells, stromal cells, and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesize that perivascular cells similarly regulate tumor cell fate at metastatic sites. Using perivascular cell-specific and pericyte-specific lineage-tracing models, we trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC/pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration, and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically-switched perivascular cells promotes a less differentiated state characterized by enhanced ECM production that establishes a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreases pre-metastatic niche formation and metastasis. Our data reveal a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncover novel strategies for limiting metastasis. PMID:28920957

Predicting survival of de novo metastatic breast cancer in Asian women: systematic review and validation study.

PubMed

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G M; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M

2014-01-01

In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48-0.53) to 0.63 (95% CI, 0.60-0.66). The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making.

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

LYMPHOCYTIC THYROIDITIS IS ASSOCIATED WITH INCREASED NUMBER OF BENIGN CERVICAL NODES AND FEWER CENTRAL NECK COMPARTMENT METASTATIC LYMPH NODES IN PATIENTS WITH DIFFERENTIATED THYROID CANCER.

PubMed

Donangelo, Ines; Walts, Ann E; Bresee, Catherine; Braunstein, Glenn D

2016-10-01

Whether or not autoimmune thyroid disease influences the progression of differentiated thyroid cancer (DTC) remains controversial. Findings of previous studies are influenced by lead time bias and/or procedure bias selection. These biases can be reduced by studying a single-institution patient population that underwent a similar extent of surgical resection. From a cohort of 660 patients with DTC who underwent thyroidectomy, we retrospectively studied 357 patients who underwent total thyroidectomy and central compartment node dissection (CCND) for DTC between 2003 and 2013. Forty-one percent (140/345) of study patients had lymphocytic thyroiditis (LT), and 30% (91/301) had serum positive for thyroglobulin antibody (TgAb). LT was reported in 78% of the TgAb-positive cases. Sixty percent (213/357) of cases had metastatic thyroid carcinoma in 1 or more neck lymph nodes (55% [198/357] central compartment, and 22% [77/356] lateral compartment). Patients with LT had fewer metastatic cervical lymph nodes than those with no LT (2.7 ± 4.7 vs 3.5 ± 4.8, respectively, P = .0285). Patients with positive TgAb and thyroiditis had a larger number of benign cervical lymph nodes removed than those with negative TgAb or no LT. No significant difference was observed in age, tumor size, multifocality, extrathyroidal extension, vascular invasion, or frequency of cervical lymph node metastasis between TgAb-negative and -positive cases or between cases with and without LT. Lymphocytic thyroiditis is associated with fewer central neck compartment metastatic lymph nodes and a larger number of excised reactive benign cervical lymph nodes. Whether this association indicates a protective role of thyroid autoimmunity in lymph node spreading remains unclear. CCND = central compartment node dissection DTC = differentiated thyroid cancer HT = Hashimoto thyroiditis LT = lymphocytic thyroiditis TgAb = thyroglobulin antibody TPO = thyroid peroxidase.

Role of endoscopic ultrasonography in evaluation of metastatic lesions to the pancreas: a tertiary cancer center experience.

PubMed

Atiq, Muslim; Bhutani, Manoop S; Ross, William A; Raju, Gottumukkala S; Gong, Yun; Tamm, Eric P; Javle, Milind; Wang, Xuemei; Lee, Jeffrey H

2013-04-01

Metastatic lesions to the pancreas pose diagnostic challenges with regards to their differentiation from primary pancreatic cancer. Data on the yield of endoscopic ultrasonography (EUS)-guided fine-needle aspiration in detection of these lesions are limited. This is a retrospective review of 23 patients referred to a tertiary referral center for further evaluation of suspected pancreatic metastases. Main outcome measures were diagnostic yield of endoscopic ultrasonography-guided fine-needle aspiration in evaluation of metastatic lesions to the pancreas. Of 644 patients, 23 (3.6%) undergoing EUS of the pancreas were diagnosed to have metastatic disease to the pancreas based on clinical, radiological, and cytological results. Mean (SD) age was 64.3 (11.7) years. Of the 23 patients, 18 (78.3%) were asymptomatic. Mean (SD) size of lesion on EUS was 39.1 (19.9) mm. A diagnosis of malignant lesion was made in 21 of 23 cases, with a diagnostic accuracy of 91.3%. Metastatic lesions to the pancreas present as incidental, solitary mass lesions on staging or surveillance imaging. Endoscopic ultrasonography-guided fine-needle aspiration is an important tool in the characterization and further differentiation of metastatic lesions to the pancreas from primary pancreatic cancer.

A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.

PubMed

Dela Cruz, Filemon S; Diolaiti, Daniel; Turk, Andrew T; Rainey, Allison R; Ambesi-Impiombato, Alberto; Andrews, Stuart J; Mansukhani, Mahesh M; Nagy, Peter L; Alvarez, Mariano J; Califano, Andrea; Forouhar, Farhad; Modzelewski, Beata; Mitchell, Chelsey M; Yamashiro, Darrell J; Marks, Lianna J; Glade Bender, Julia L; Kung, Andrew L

2016-10-31

Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities. We utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient's tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options. WES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK. This clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.

Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated.

PubMed

Raj, Nitya; Valentino, Emily; Capanu, Marinela; Tang, Laura H; Basturk, Olca; Untch, Brian R; Allen, Peter J; Klimstra, David S; Reidy-Lagunes, Diane

2017-03-01

Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3-86.9 months) compared with 10.1 months (95% confidence interval, 6.9-12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.

Phase II study of 4'-(9-acridinylamino) methanesulfon-m- anisidide (AMSA) in metastatic melanoma.

PubMed

Legha, S S; Hall, S W; Powell, K C; Burgess, M A; Benjamin, R S; Gutterman, J U; Bodey, G P

1980-01-01

A phase II study of AMSA in previously treated patients with metastatic malignant melanoma was conducted. The dose schedule of AMSA was 40 mg/m2/day for 3 days repeated at 3-week intervals. Among the 30 evaluable patients, one achieved a complete response, one a partial response, and four had minor responses. Side effects included mild nausea and vomiting and moderate degree of myelosuppression. AMSA has poor activity against previously treated metastatic melanoma.

Anaplastic transformation of follicular thyroid carcinoma in a metastatic skeletal lesion presenting with paraneoplastic leukocytosis.

PubMed

Nakayama, Robert; Horiuchi, Keisuke; Susa, Michiro; Hosaka, Seiichi; Hayashi, Yuichiro; Kameyama, Kaori; Suzuki, Yoshihisa; Yabe, Hiroo; Toyama, Yoshiaki; Morioka, Hideo

2012-02-01

Anaplastic transformation of differentiated thyroid carcinoma (DTC) is a rare event with a poor clinical outcome. It usually occurs in the primary site or in regional lymph nodes, but rarely in distant metastatic lesions. A 55-year-old woman with persistent pain in the left hip joint visited our hospital. She had a history of DTC that had been surgically removed 12 years earlier. Clinical images showed a tumorous mass in the left pelvis, indicative of bone metastasis. The patient underwent surgery to remove the tumor and remained stable until local recurrence was found 5 weeks after the surgery. The patient subsequently underwent radiation therapy; however, she died of respiratory failure due to lung metastases 2 months after the surgery for the recurrent lesion. The surgical specimens were diagnosed as anaplastic thyroid carcinoma, indicating that anaplastic transformation of thyroid follicular carcinoma occurred in the metastatic skeletal lesion. In addition, the patient had an unusually high white blood cell count throughout the course. Based on elevated serum granulocyte colony-stimulating factor (G-CSF) levels and positive immunostaining for G-CSF in the surgical specimens, the patient was diagnosed with paraneoplastic leukocytosis. To our knowledge, this is the first case of anaplastic transformation of DTC arising in a metastatic bone lesion described in the literature. In addition, the present case also exhibited severe leukocytosis accompanied by elevated serum G-CSF levels. Clinicians should be aware of the possibility of this occurring in their patients with DTC, as this development calls for a rapid change from observational follow-up to aggressive treatment.

Genistein versus ICI 182, 780: an ally or enemy in metastatic progression of prostate cancer.

PubMed

Nakamura, Hisae; Wang, Yuwei; Xue, Hui; Romanish, Mark T; Mager, Dixie L; Helgason, Cheryl D; Wang, Yuzhuo

2013-12-01

Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen in synergy with androgen is essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen and the estrogen receptor play in prostate carcinogenesis remains unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor beta (ERβ) agonist (genistein) in a patient-derived PCa xenograft model mimicking localized and metastatic disease. To test the hypothesis that the tumor-promoting activity of genistein was due to its estrogenic properties, we treated the xenograft-bearing mice with genistein and an anti-estrogen compound (ICI 182, 780) and compared the differential gene expression using microarrays. Using a second xenograft model which was derived from another patient, we showed that genistein promoted disease progression in vivo and ICI 182, 780 inhibited metastatic spread. The microarray analysis revealed that the metallothionein (MT) gene family was differentially expressed in tumors treated by these compounds. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumor lines, both of which were originally derived from the same PCa patient. Together our data provide evidence that genistein stimulates and ICI 182, 780 inhibits metastatic progression, suggesting that these effects may be mediated by ERβ signalling. © 2013 Wiley Periodicals, Inc.

Predicting Survival of De Novo Metastatic Breast Cancer in Asian Women: Systematic Review and Validation Study

PubMed Central

Miao, Hui; Hartman, Mikael; Bhoo-Pathy, Nirmala; Lee, Soo-Chin; Taib, Nur Aishah; Tan, Ern-Yu; Chan, Patrick; Moons, Karel G. M.; Wong, Hoong-Seam; Goh, Jeremy; Rahim, Siti Mastura; Yip, Cheng-Har; Verkooijen, Helena M.

2014-01-01

Background In Asia, up to 25% of breast cancer patients present with distant metastases at diagnosis. Given the heterogeneous survival probabilities of de novo metastatic breast cancer, individual outcome prediction is challenging. The aim of the study is to identify existing prognostic models for patients with de novo metastatic breast cancer and validate them in Asia. Materials and Methods We performed a systematic review to identify prediction models for metastatic breast cancer. Models were validated in 642 women with de novo metastatic breast cancer registered between 2000 and 2010 in the Singapore Malaysia Hospital Based Breast Cancer Registry. Survival curves for low, intermediate and high-risk groups according to each prognostic score were compared by log-rank test and discrimination of the models was assessed by concordance statistic (C-statistic). Results We identified 16 prediction models, seven of which were for patients with brain metastases only. Performance status, estrogen receptor status, metastatic site(s) and disease-free interval were the most common predictors. We were able to validate nine prediction models. The capacity of the models to discriminate between poor and good survivors varied from poor to fair with C-statistics ranging from 0.50 (95% CI, 0.48–0.53) to 0.63 (95% CI, 0.60–0.66). Conclusion The discriminatory performance of existing prediction models for de novo metastatic breast cancer in Asia is modest. Development of an Asian-specific prediction model is needed to improve prognostication and guide decision making. PMID:24695692

PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse.

PubMed

Yang, Jing; Wu, Ning-Ni; Huang, De-Jia; Luo, Yao-Chang; Huang, Jun-Zhen; He, Hai-Yuan; Lu, Hai-Lin; Song, Wen-Ling

2017-07-01

Although the oncogenic role of PPFIA1 (liprin-α1) in breast cancer has been reported, whether its dysregulation is associated with metastasis risk or survival outcomes in breast cancer patients is not clear. Our primary data showed that PPFIA1 expression was significantly higher in liver metastatic breast tumors than in the primary tumors. Then, we tried to pool previous annotated genomic data to assess the prognostic value of PPFIA1 in distant metastasis-free survival, the risk of metastatic relapse, and metastatic relapse-free survival in breast cancer patients by data mining in two large databases, Kaplan-Meier plotter and bc-GenExMiner 4.0. Results from Kaplan-Meier plotter showed that although high PPFIA1 expression was generally associated with decreased distant metastasis-free survival in estrogen receptor+ patients, subgroup analysis only confirmed significant association in estrogen receptor+/N- (nodal negative) group (median survival, high PPFIA1 group vs low PPFIA1 cohort: 191.21 vs 236.22 months; hazard ratio: 2.23, 95% confidence interval: 1.42-3.5, p < 0.001), but not in estrogen receptor+/N+ (nodal positive) group (hazard ratio: 1.63, 95% confidence interval: 0.88-3.03, p = 0.12). In estrogen receptor- patients, there was no association between PPFIA1 expression and distant metastasis-free survival, no matter in Nm (nodal status mixed), N-, or N+ subgroups. In bc-GenExMiner 4.0, Nottingham Prognostic Index- and Adjuvant! Online-adjusted analysis validated the independent prognostic value of PPFIA1 in metastatic risks in estrogen receptor+/N- patients. Based on these findings, we infer that high PPFIA1 expression might be an independent prognostic indicator of increased metastatic relapse risk in patients with estrogen receptor+/N- breast cancer, but not in estrogen receptor+/N+ or estrogen receptor- patients.

Role of connexins in metastatic breast cancer and melanoma brain colonization

PubMed Central

Stoletov, Konstantin; Strnadel, Jan; Zardouzian, Erin; Momiyama, Masashi; Park, Frederick D.; Kelber, Jonathan A.; Pizzo, Donald P.; Hoffman, Robert; VandenBerg, Scott R.; Klemke, Richard L.

2013-01-01

Summary Breast cancer and melanoma cells commonly metastasize to the brain using homing mechanisms that are poorly understood. Cancer patients with brain metastases display poor prognosis and survival due to the lack of effective therapeutics and treatment strategies. Recent work using intravital microscopy and preclinical animal models indicates that metastatic cells colonize the brain, specifically in close contact with the existing brain vasculature. However, it is not known how contact with the vascular niche promotes microtumor formation. Here, we investigate the role of connexins in mediating early events in brain colonization using transparent zebrafish and chicken embryo models of brain metastasis. We provide evidence that breast cancer and melanoma cells utilize connexin gap junction proteins (Cx43, Cx26) to initiate brain metastatic lesion formation in association with the vasculature. RNAi depletion of connexins or pharmacological blocking of connexin-mediated cell–cell communication with carbenoxolone inhibited brain colonization by blocking tumor cell extravasation and blood vessel co-option. Activation of the metastatic gene twist in breast cancer cells increased Cx43 protein expression and gap junction communication, leading to increased extravasation, blood vessel co-option and brain colonization. Conversely, inhibiting twist activity reduced Cx43-mediated gap junction coupling and brain colonization. Database analyses of patient histories revealed increased expression of Cx26 and Cx43 in primary melanoma and breast cancer tumors, respectively, which correlated with increased cancer recurrence and metastasis. Together, our data indicate that Cx43 and Cx26 mediate cancer cell metastasis to the brain and suggest that connexins might be exploited therapeutically to benefit cancer patients with metastatic disease. PMID:23321642

Metastatic tonsillar squamous cell carcinoma masquerading as a pancreatic cystic tumor and diagnosed by EUS-guided FNA.

PubMed

Glass, Ryan; Andrawes, Sherif A; Hamele-Bena, Diane; Tong, Guo-Xia

2017-11-01

Metastatic carcinoma to the pancreas is uncommon and head and neck squamous carcinoma metastatic to the pancreas is extremely rare. Metastatic squamous cell carcinoma to the pancreas presents a unique diagnostic challenge: in addition to mimicking the rare primary squamous cell carcinoma of the pancreas based on cytologic, histologic, and immunohistochemical features, it may be mistaken for a cystic neoplasm of the pancreas because of its high predilection for cystic degeneration in metastatic sites. Herein, we report a case of tonsillar squamous cell carcinoma with a cystic pancreatic metastasis diagnosed by ultrasound-guided fine needle aspiration biopsy (EUS-FNA). This represents a third reported case of metastatic squamous cell carcinoma to the pancreas from the head and neck region. Metastatic squamous cell carcinoma should be considered in the differential diagnosis of EUS-FNA during evaluation of pancreatic cystic lesion. © 2017 Wiley Periodicals, Inc.

Metastatic prostate adenocarcinoma to the penis: a series of 29 cases with predilection for ductal adenocarcinoma.

PubMed

Ellis, Carla L; Epstein, Jonathan I

2015-01-01

Twenty-nine men with metastatic prostate adenocarcinoma to the penis were identified at our institution between 1993 and 2013. Of the 29 patients, 19 had a prior history of adenocarcinoma of the prostate, and 8 of those had ductal features in the primary lesion. Sixteen of 29 revealed ductal features in the metastasis. Seven of the 8 cases with ductal features in the primary had ductal features in the penile metastasis. Seven penile metastases were proven to be of prostatic origin solely by immunohistochemistry. Three cases were originally misdiagnosed as urothelial carcinoma upon review of the penile lesion. Other variant morphologies in the metastases included sarcomatoid carcinoma, small cell carcinoma, and adenosquamous carcinoma. In summary, prostate carcinoma involving the penis displays ductal features considerably more often than prostate cancer in general. Features that can cause difficulty in recognizing metastatic prostate adenocarcinoma to the penis include the unusual anatomic site for prostate cancer, poor differentiation, an increased prevalence of variant morphology, a long interval from the primary lesion, and, in some cases, no documented history of a primary prostatic lesion. Immunohistochemical analysis should be performed to rule out prostate carcinoma in penile/penile urethral tumors with morphology that differs from typical squamous or urothelial carcinoma. Even in the setting of metastatic disease, there is a critical need for an accurate diagnosis so that the appropriate therapy can be initiated, symptomatic relief can be provided, and long-term survival achieved in some cases, while at the same time avoiding penectomy for a misdiagnosis of a primary penile cancer.

Immunotherapy of patients with metastatic melanoma.

PubMed

Yu, Zhe; Si, Lu

2017-04-01

Malignant melanoma (MM) is the primary cause of skin cancer related death and the incidence is increasing in the past years. Advanced MM still has a poor prognosis, but in recent years, the development of immunotherapy has changed its poor prognosis. Immune checkpoints show the revolutionary treatment of metastatic melanoma. Ipilimumab and pembrolizumab, monoclonal antibodies against the CTLA-4 and PD-1 respectively, have been shown to prolong overall survival (OS) in patients with advanced melanoma. The combination immunotherapy seems to be superior to monotherapy. In this review, recently immunotherapy clinical trial results are presented. The combination of immunotherapy provides new options for the treatment of MM patients. However, further studies are necessary to answer such question as optimal treatment, combination of immunotherapies, crowd selection and risk balance in patients with melanoma.

Intravital imaging of tumor bioenergetics in metastatic and non-metastatic breast cancer

NASA Astrophysics Data System (ADS)

Rasul, Raisa; Harper, Mason; Rajaram, Narasimhan

2018-02-01

Early detection of metastatic cancer can reduce patient mortality and decrease cost of cancer treatment. However, current methods of prognosis or genetic screening are expensive and might not be applicable to all tumors. Although previous studies indicated that cancer cells are glycolytic, the link between metabolism and metastatic progression is not fully understood. To better understand the tumor bioenergetics, we investigated in vivo the vascular oxygenation, glucose intake, and optical redox ratio between a metastatic breast cancer cell line (4T1), a non-metastatic isogenic cell line (168FARN), and a non-metastatic derivative of 4T1 (TWIST gene knockout). The vascular oxygenation was measured by injecting 10,000 cells into mouse dorsal window chambers and acquiring and processing trans-illumination images of the tumor from 520 nm-620 nm light wavelength in 10 nm intervals. Glucose intake was measured by continuous fluorescent imaging of the glucose analog, 2-NBDG, for 90 minutes. Optical redox ratio was measured by intrinsic fluorescence imaging of electron carrying intermediates, NADH and FAD, where an increase in the ratio (FAD/FAD+NADH) meant increased oxidative phosphorylation. Our data show that the optical redox ratio and vascular oxygenation are higher and glucose intake is lower in metastatic tumors compared to non-metastatic tumors, suggesting that metastatic tumors display decreased glycolysis and increased oxidative phosphorylation. We observed a similar trend in vitro, where the redox ratio increased as the cell metastatic potential increased, indicating that metastatic cells can efficiently produce energy. These findings indicate that optical redox ratio can be a potential prognosis tool for detecting malignant tumors.

Adenocarcinoma metastatic to the uterine cervix: a case series.

PubMed

Pérez-Montiel, Delia; Serrano-Olvera, Alberto; Salazar, Luz Calderón; Cetina-Pérez, Lucely; Candelaria, Myrna; Coronel, Jaime; Montalvo, Luis Alonso Herrera; de León, David Cantú

2012-03-01

The objectives of this report are, first, to describe the clinical behavior of cases of carcinoma metastatic to the uterine cervix treated at our institution in order to carry out a systematic review to establish the behavioral patterns of the most frequent metastases to the cervix and, second, to generate guidelines for their diagnosis and treatment. At the National Institute of Cancer of Mexico (INCan), we performed a review of the clinical files with a diagnosis of malignant neoplasm metastatic to the uterine cervix between 1990 and 2009. For a systematic review, we conducted a PubMed search between the years 1970 and 2009 of case reports and series of cases of patients with metastatic gastric, breast, ovarian and colorectal cancer. We analyzed each report individually and extracted the patients' clinical data from our cases and reports, including the primary tumor, cervical metastases and survival rates. There were 10 cases of tumors metastatic to the uterine cervix. Metastasis was documented in one-half of the patients during follow up, with two of these cases having the cervix as the only site. We included the following reports in the systematic review: 13 reports of gastric-associated cancer, 30 related to breast cancer, nine with ovarian-associated cancer and 10 related to colorectal cancer. Metastatic cervical activity is an infrequent event. The prognosis of survival is poor in the presence of gastric or ovarian cancer and cervical metastases. © 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.

A case of metastatic follicular thyroid carcinoma complicated with Graves' disease after total thyroidectomy.

PubMed

Aoyama, Mariko; Takizawa, Hiromitsu; Tsuboi, Mitsuhiro; Nakagawa, Yasushi; Tangoku, Akira

2017-12-28

Thyroid cancer and Graves' disease may present simultaneously in one patient. The incidence of the development of hyperthyroidism from metastatic differentiated thyroid carcinoma is rare. We herein report a case of metastatic follicular carcinoma complicated with Graves' disease after total thyroidectomy. A 57-year-old woman underwent right hemithyroidectomy for follicular carcinoma. Metastatic lesions appeared in the lungs and skull two years after the first surgery, and remnant thyroidectomy was performed for radioactive iodine-131 (RAI) therapy, during which the TSH receptor antibody (TRAb) was found to be negative. The patient was treated with RAI therapy four times for four years and was receiving levothyroxine suppressive therapy. Although radioiodine uptake was observed in the lesions after the fourth course of RAI therapy, metastatic lesions had progressed. Four years after the second surgery, she had heart palpitations and tremors. Laboratory data revealed hyperthyroidism and positive TRAb. She was diagnosed with Graves' disease and received a fifth course of RAI therapy. 131I scintigraphy after RAI therapy showed strong radioiodine uptake in the metastatic lesions. As a result, the sizes and numbers of metastatic lesions decreased, and thyroid function improved. Metastatic lesions produced thyroid hormone and caused hyperthyroidism. RAI therapy was effective for Graves' disease and thyroid carcinoma.

Emerging insights into recurrent and metastatic human papillomavirus‐related oropharyngeal squamous cell carcinoma

PubMed Central

Faraji, Farhoud; Eisele, David W.

2017-01-01

ABSTRACT Objective To review recent literature on human papillomavirus‐related (HPV‐positive) oropharyngeal squamous cell carcinoma (OPC) and focus on implications of recurrent and metastatic disease. Methods Primary articles from 1990 to 2016 indexed in MEDLINE (1) pertaining to the epidemiology of HPV‐positive OPC and (2) providing clinical insight into recurrent and metastatic OPC. Results The incidence of HPV‐positive OPC is increasing globally. HPV‐positive OPC is a subtype with distinct molecular and clinical features including enhanced treatment response and improved overall survival. While disease recurrence is less common in patients with HPV‐positive OPC, up to 36% of patients experience treatment failure within eight years. Recurrent and metastatic OPC has historically signified poor prognosis, however recent data are challenging this dogma. Here, we discuss recurrent and metastatic OPC in the context of HPV tumor status. Conclusion HPV‐positive OPC exhibits distinct genetic, cellular, epidemiological, and clinical features from HPV‐negative OPC. HPV tumor status is emerging as a marker indicative of improved prognosis after disease progression in both locoregionally recurrent and distant metastatic OPC. Level of Evidence N/A. PMID:28894817

Metastatic craniopharyngioma: case report and literature review.

PubMed

Frangou, Evan Mark; Tynan, Jennifer Ruth; Robinson, Christopher Adam; Ogieglo, Lissa Marie; Vitali, Aleksander Michal

2009-09-01

Distant spread of craniopharyngioma is a rare but important complication. Most cases are a result of spread along the surgical path. We describe a rare case of metastatic leptomeningeal craniopharyngioma as a result of dissemination along CSF pathways in a child. A review of previously described cases is provided. A 14-year-old male was diagnosed with metastatic craniopharyngioma on routine follow-up imaging after multiple surgeries and radiation for locally recurrent craniopharyngioma. The lesion was erosive through the right parietal bone, but had remained clinically silent. The lesion was distant from previous surgical paths. The patient underwent right parietal craniotomy and resection of the lesion. Duraplasty and cranioplasty were necessary for closure. Histopathology confirmed adamantinomatous craniopharyngioma. One-year follow-up demonstrated no recurrence. A review of reported cases suggests that leptomeningeal implantation may be an important step in metastases of craniopharyngioma, although the mechanism is poorly understood. Attention to tumor spillage at the time of surgery may be important in preventing distant recurrences.

Subjective ultrasound assessment, the ADNEX model and ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer.

PubMed

Epstein, E; Van Calster, B; Timmerman, D; Nikman, S

2016-01-01

To compare subjective ultrasound assessment and the ADNEX model with ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer. This was a prospective study including 143 consecutive women with disseminated malignancy of unknown primary origin, with a pelvic tumor/carcinosis. Women underwent either transvaginal or transrectal ultrasound as well as transabdominal ultrasound examination followed by tru-cut biopsy. The ultrasound examiner assessed tumor morphology, spread in the pelvis and abdomen, and predicted tumor origin as primary ovarian or metastatic using both subjective assessment and the ADNEX model. Histology from tru-cut biopsy served as the gold standard for assessment of diagnostic accuracy. Biopsy adequacy and the complication rate were assessed. Tru-cut biopsy was performed transvaginally in 131/143 (92%) women. Two women needed inpatient care (one had abdominal wall hematoma, and one infection). Biopsy resulted in a conclusive diagnosis in 126/143 (88%) women, amongst whom cytoreductive surgery was performed in 30/126 confirming the diagnosis in all cases. Non-ovarian metastatic cancer was found in 37/126 (29%) women and primary ovarian cancer in 89/126 (71%) women. Subjective ultrasound evaluation had a sensitivity of 82% (73/89) and a specificity of 70% (26/37) in predicting primary ovarian cancer. The ADNEX model had an area under the receiver-operating characteristics curve of 0.891 (95% CI, 0.794-0.946) (in women with an ovarian lesion, n = 104). Tumor origin was associated with age, CA 125, previous neoplasia, presence of omental cake and tumor mobility. Subjective ultrasound assessment and the ADNEX model can both be used to predict whether a pelvic tumor is metastatic and of non-ovarian origin, indicating the need for tru-cut biopsy, which is associated with very few complications and will provide a conclusive diagnosis in nine out of 10 women. Copyright © 2015 ISUOG

Diagnosis of metastatic neoplasms: a clinicopathologic and morphologic approach.

PubMed

Marchevsky, Alberto M; Gupta, Ruta; Balzer, Bonnie

2010-02-01

The diagnosis of the site of origin of metastatic neoplasms often poses a challenge to practicing pathologists. A variety of immunohistochemical and molecular tests have been proposed for the identification of tumor site of origin, but these methods are no substitute for careful attention to the pathologic features of tumors and their correlation with imaging findings and other clinical data. The current trend in anatomic pathology is to overly rely on immunohistochemical and molecular tests to identify the site of origin of metastatic neoplasms, but this "shotgun approach" is often costly and can result in contradictory and even erroneous conclusions about the site of origin of a metastatic neoplasm. To describe the use of a systematic approach to the evaluation of metastatic neoplasms. Literature review and personal experience. A systematic approach can frequently help to narrow down differential diagnoses for a patient to a few likely tumor sites of origin that can be confirmed or excluded with the use of selected immunohistochemistry and/or molecular tests. This approach involves the qualitative evaluation of the "pretest and posttest probabilities" of various diagnoses before the immunohistochemical and molecular tests are ordered. Pretest probabilities are qualitatively estimated for each individual by taking into consideration the patient's age, sex, clinical history, imaging findings, and location of the metastases. This estimate is further narrowed by qualitatively evaluating, through careful observation of a variety of gross pathology and histopathologic features, the posttest probabilities of the most likely tumor sites of origin. Multiple examples of the use of this systematic approach for the evaluation of metastatic lesions are discussed.

Stochastic and Deterministic Models for the Metastatic Emission Process: Formalisms and Crosslinks.

PubMed

Gomez, Christophe; Hartung, Niklas

2018-01-01

Although the detection of metastases radically changes prognosis of and treatment decisions for a cancer patient, clinically undetectable micrometastases hamper a consistent classification into localized or metastatic disease. This chapter discusses mathematical modeling efforts that could help to estimate the metastatic risk in such a situation. We focus on two approaches: (1) a stochastic framework describing metastatic emission events at random times, formalized via Poisson processes, and (2) a deterministic framework describing the micrometastatic state through a size-structured density function in a partial differential equation model. Three aspects are addressed in this chapter. First, a motivation for the Poisson process framework is presented and modeling hypotheses and mechanisms are introduced. Second, we extend the Poisson model to account for secondary metastatic emission. Third, we highlight an inherent crosslink between the stochastic and deterministic frameworks and discuss its implications. For increased accessibility the chapter is split into an informal presentation of the results using a minimum of mathematical formalism and a rigorous mathematical treatment for more theoretically interested readers.

Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas.

PubMed

Mohanty, Sambit K; Smith, Steven C; Chang, Elena; Luthringer, Daniel J; Gown, Allen M; Aron, Manju; Amin, Mahul B

2014-08-01

New immunohistochemical (IHC) markers of urothelial carcinoma (UCa) and prostatic adenocarcinoma (PCa) have emerged in recent years, yet comparative studies to establish markers remain lacking. We aimed to identify an effective but parsimonious approach for poorly differentiated bladder neck lesions, to establish a best practice panel approach in a setting simulating prospective use. We tested the performance of a panel of IHC markers on whole sections of a consecutive cohort of transurethral resection specimens of poorly differentiated, challenging bladder neck resections (n=36). In the setting of poorly differentiated bladder neck carcinomas, biomarker sensitivities for UCa were as follows: GATA3, 100%; S100P, 88%; p63, 75%; and cytokeratin (CK) 5/6, 56%; specificities of each were 100%. CK7 and CK20 showed sensitivities of 75% and 63%, though these were only 85% and 80% specific. For PCa markers, NKX3.1, p501S, prostate-specific membrane antigen, and androgen receptor (AR) each showed 100% sensitivity, outperforming ERG (35%) and prostate-specific antigen (PSA; 25%). All the prostate histogenesis markers were 100% specific, except for AR, which was positive in 13% of the UCa cases. Novel IHC markers show improved diagnostic performance that enables positive and negative support for identifying histogenesis with the use of as few as two markers for this critical therapeutic distinction. PSA underperforms newer markers. Copyright© by the American Society for Clinical Pathology.

Metastatic potential of melanoma cells is not affected by electrochemotherapy.

PubMed

Todorovic, Vesna; Sersa, Gregor; Mlakar, Vid; Glavac, Damjan; Flisar, Karel; Cemazar, Maja

2011-06-01

Electrochemotherapy is a local treatment combining chemotherapy and application of electric pulses to the tumour. Electrochemotherapy with bleomycin and cisplatin has shown its effectiveness in controlling local tumour growth in the treatment of malignant melanoma. However, the effect of electrochemotherapy on the metastatic potential of tumour cells is not known. Prevention of metastasis is an important aspect of successful treatment; however, it is known that metastasis can be induced by different treatment modalities. Therefore, the aim of this study was to evaluate the effect of electrochemotherapy with cisplatin on the metastatic potential of human malignant melanoma cells. Cells treated by electrochemotherapy with cisplatin were tested for their ability to migrate and invade through Matrigel-coated porous membrane. In addition, RNA was isolated from cells after treatment and differentially expressed genes were investigated by microarray analysis to evaluate the effect of electrochemotherapy with cisplatin on gene expression. There were no significant changes observed in cell migration and invasion of melanoma cells after electrochemotherapy. In addition, there were no changes observed in cell adhesion on Matrigel. Gene expression analysis showed that a very low number of genes were differentially expressed after electrochemotherapy with cisplatin. Two genes, LAMB3 and CD63 involved in cell migration, were both downregulated after electrochemotherapy with cisplatin and the expression of metastasis promoting genes was not increased after electrochemotherapy. Our data suggest that electrochemotherapy does not increase the metastatic behaviour of human melanoma cells.

Ectopic decidua and metastatic squamous carcinoma: presentation in a single pelvic lymph node.

PubMed

Cobb, C J

1988-06-01

The presence of ectopic decidua in pelvic lymph nodes from patients with squamous carcinoma of the cervix makes evaluation for metastatic disease difficult due to the light microscopic similarity between decidua and sheets of squamous epithelial cells. A patient is present in whom decidualized endometriosis was intimately associated with metastatic moderately differentiate squamous carcinoma in a single pelvic lymph node. This phenomenon afforded an excellent opportunity to study the unique morphologic features that distinguish these two entities. A prior report of this kind was not found. In the absence of obvious squamous differentiation (i.e., intercellular bridges, dyskeratosis, and keratin "pearl" formation), as is frequently the case with squamous carcinoma of the cervix, the light microscopic features that are most useful in distinguishing squamous carcinoma from decidua include the presence of well-defined nests of cohesive cells, nuclear hyperchromasia, and cellular pleomorphism.

Platelet-Poor and Platelet-Rich Plasma Stimulate Bone Lineage Differentiation in Periodontal Ligament Stem Cells.

PubMed

Martínez, Constanza E; González, Sergio A; Palma, Verónica; Smith, Patricio C

2016-02-01

Plasma-derived fractions have been used as an autologous source of growth factors; however, limited knowledge concerning their biologic effects has hampered their clinical application. In this study, the authors analyze the content and specific effect of both platelet-rich plasma (PRP) and platelet-poor plasma (PPP) on osteoblastic differentiation using primary cultures of human periodontal ligament stem cells (HPLSCs). The authors evaluated the growth factor content of PRP and PPP using a proteome profiler array and enzyme-linked immunosorbent assay. HPLSCs were characterized by flow cytometry and differentiation assays. The effect of PRP and PPP on HPLSC bone differentiation was analyzed by quantifying calcium deposition after 14 and 21 days of treatment. Albeit at different concentrations, the two fractions had similar profiles of growth factors, the most representative being platelet-derived growth factor (PDGF) isoforms (PDGF-AA, -BB, and -AB), insulin-like growth factor binding protein (IGFBP)-2, and IGFBP-6. Both formulations exerted a comparable stimulus on osteoblastic differentiation even at low doses (2.5%), increasing calcium deposits in HPLSCs. PRP and PPP showed a similar protein profile and exerted comparable effects on bone differentiation. Further studies are needed to characterize and compare the effects of PPP and PRP on bone healing in vivo.

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

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.

[Metastatic breast cancer to the stomach: An uncommon evolution of breast carcinoma].

PubMed

Hild, C; Talha-Vautravers, A; Hoefler, P; Zirabe, S; Bellocq, J-P; Mathelin, C

2014-01-01

Breast carcinoma exceptionally leads to metastatic linitis plastica. Distinguishing a breast cancer metastasis to the stomach from a primary gastric cancer on the basis of clinical and radiological signs is very challenging. Thanks to being cognizant of the previous history of invasive lobular carcinoma and the gastric biopsy followed by immunohistochemical analysis, gastric metastasis can be diagnosed. Despite the use of chemotherapy and hormonal therapy, gastric metastasis remains often associated with poor prognosis. We present a case where gastric biopsy allowed a metastatic breast cancer to the stomach to be diagnosed and we discuss its clinical, diagnostic, pathological and therapeutic particularities. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Multimodality therapy for metastatic sarcomas confined to the lung

PubMed Central

GOLLARD, RUSSELL P.; TURNER, J. FRANCIS

2012-01-01

Metastectomy or resection of sarcomas which have metastasized to the lung from other sites has a long and established history. At present, there are more than forty different drugs with activity in soft tissue sarcomas. A number of sarcomas demonstrate differential sensitivities to chemotherapy and targeted agents. Intimate knowledge of the biological behavior of each distinct type of sarcoma should predicate what treatment or protocol is most suitable. Certain patients might benefit from either neoadjuvant or adjuvant therapy following the resection of metastatic lesions. Much remains to be learned about the differential sensitivities of various sarcomas to different treatment regimens. PMID:23205068

The Gαh-PLCδ1 signaling axis drives metastatic progression in triple-negative breast cancer.

PubMed

Huang, Shang-Pen; Liu, Pei-Yao; Kuo, Chih-Jung; Chen, Chi-Long; Lee, Wei-Jiunn; Tsai, Yu-Hui; Lin, Yuan-Feng

2017-06-02

Distant metastasis of triple-negative breast cancer (TNBC) to other organs, e.g., the lungs, has been correlated with poor survival rates among breast cancer patients. Therefore, the identification of useful therapeutic targets to prevent metastasis or even inhibit tumor growth of TNBC is urgently needed. Gαh is a novel GTP-binding protein and known as an inactive form of calcium-dependent tissue transglutaminase. However, the functional consequences of transamidating and G-protein activities of tissue transglutaminase in promoting cancer metastasis are still controversial. Kaplan-Meier analyses were performed to estimate the prognostic values of Gαh and PLCδ1 by utilizing public databases and performing immunohistochemical staining experiments. Cell-based invasion assays and in vivo lung colony-forming and orthotropic lung metastasis models were established to evaluate the effectiveness of interrupting the protein-protein interaction (PPI) between Gαh and PLCδ1 in inhibiting the invasive ability and metastatic potential of TNBC cells. Here, we showed that the increased level of cytosolic, not extracellular, Gαh is a poor prognostic marker in breast cancer patients and correlates with the metastatic evolution of TNBC cells. Moreover, clinicopathological analyses revealed that the combined signature of high Gαh/PLCδ1 levels indicates worse prognosis in patients with breast cancer and correlates with lymph node metastasis of ER-negative breast cancer. Blocking the PPI of the Gαh/PLCδ1 complex by synthetically myristoylated PLCδ1 peptide corresponding to the Gαh-binding interface appeared to significantly suppress cellular invasiveness in vitro and inhibit lung metastatic colonies of TNBC cells in vivo. This study establishes Gαh/PLCδ1 as a poor prognostic factor for patients with estrogen receptor-negative breast cancers, including TNBCs, and provides therapeutic value by targeting the PPI of the Gαh/PLCδ1 complex to combat the metastatic progression

Albumin expression distinguishes bile duct adenomas from metastatic adenocarcinoma.

PubMed

Moy, Andrea P; Arora, Kshitij; Deshpande, Vikram

2016-09-01

Bile duct adenomas may be difficult to distinguish from metastatic carcinomas, particularly well-differentiated pancreatic ductal adenocarcinoma. Prior studies have evaluated the utility of various immunohistochemical markers, although these markers are notable for low sensitivity and/or specificity. The aim of this study was to investigate the utility of albumin and BRAFV600E expression in distinguishing between metastatic pancreatic adenocarcinoma and bile duct adenoma. We studied 26 bile duct adenomas, three bile duct hamartomas, and 158 pancreatic ductal adenocarcinomas. Branched-chain in-situ hybridization (bISH) for albumin was performed; bISH is based on the branched DNA technology, wherein signal amplification is achieved via a series of sequential steps. Additionally, BRAFV600E immunohistochemistry (IHC) was performed on a subset of cases. Twenty-three of 25 (92%) bile duct adenomas were positive for albumin; 18 (72%) showed diffuse staining, and five showed focal staining (20%), including two challenging examples. Two bile duct hamartomas also stained positively. All pancreatic adenocarcinomas were negative for albumin. Seven of 16 (44%) bile duct adenomas and five of 106 (5%) pancreatic ductal adenocarcinomas were positive for BRAFV600E by IHC. The sensitivity and specificity of expression of albumin, as detected by bISH, for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 92% and 100%, respectively; the sensitivity and specificity of BRAFV600E IHC for distinguishing bile duct adenomas from metastatic pancreatic adenocarcinomas were 43.8% and 95.3%, respectively. Diagnostically challenging examples of bile duct adenoma may be distinguished from metastatic pancreatic adenocarcinoma by the use of albumin bISH. © 2016 John Wiley & Sons Ltd.

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

CYP4A in tumor-associated macrophages promotes pre-metastatic niche formation and metastasis.

PubMed

Chen, X W; Yu, T J; Zhang, J; Li, Y; Chen, H L; Yang, G F; Yu, W; Liu, Y Z; Liu, X X; Duan, C F; Tang, H L; Qiu, M; Wang, C L; Zheng, H; Yue, J; Guo, A M; Yang, J

2017-08-31

Tumor-associated macrophages (TAMs) play an essential role in metastasis. However, what enables TAMs to have a superior capacity to establish pre-metastatic microenvironment in distant organs is unclear. Here we have begun to uncover the effects of cytochrome P450 (CYP) 4A in TAMs on lung pre-metastatic niche formation and metastasis. CYP4A + TAM infiltration was positively associated with metastasis, pre-metastatic niche formation and poor prognosis in breast cancer patients. The pharmacological inhibition of CYP4A reduced lung pre-metastatic niche formation (evidenced by a decrease in vascular endothelial growth factor receptor 1 positive (VEGFR1 + ) myeloid cell recruitment and pro-metastatic protein expression) and metastatic burden, accompanied with TAM polarization away from the M2 phenotype in spontaneous metastasis models of 4T1 breast cancer and B16F10 melanoma. Co-implantation of 4T1 cells with CYP4A10 high macrophages promoted lung pre-metastatic niche formation and metastasis. Depletion of TAMs disrupted lung pre-metastatic niches and thereby prevented metastasis. Treatment with the CM from CYP4A10 high M2 macrophages (M2) increased pre-metastatic niche formation and metastatic burden in the lungs, whereas CYP4A inhibition attenuated these effects. In vitro TAM polarization away from the M2 phenotype induced by CYP4A inhibition decreased VEGFR1 + myeloid cell migration and fibronectin expression, accompanied with downregulation of STAT3 signaling. Conversely, overexpression of CYP4A or exogenous addition of 20-hydroxyeicosatetraenoic acid promoted M2 polarization and cytokine production of macrophages and thereby enhanced migration of VEGFR1 + myeloid cells, which were reversed by siRNA or pharmacological inhibition of STAT3. Importantly, a combined blocking M2 macrophage-derived factors TGF-β, VEGF and SDF-1 abolished VEGFR1 + myeloid cell migration and fibroblast activation induced by CYP4A. In summary, CYP4A in TAMs is crucial for lung pre-metastatic

Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer

PubMed Central

Gentilini, Lucas Daniel; Pérez, Ignacio González; Kotler, Monica Lidia; Chauchereau, Anne; Laderach, Diego Jose; Compagno, Daniel

2017-01-01

Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID:28591719

ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity

PubMed Central

Landreville, Solange; Agapova, Olga A.; Kneass, Zachary T.; Salesse, Christian; Harbour, J. William

2011-01-01

SUMMARY Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1− bulk tumor cells. ABCB1+ cells also exhibited enhanced clonogenicity, anchorage independent growth, tumorigenicity and mitochondrial activity compared to ABCB1− cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1+ cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others, and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma. PMID:21575142

Dedifferentiated Liposarcoma With Rhabdomyosarcomatous Differentiation Producing HCG: A Case Report of a Diagnostic Pitfall.

PubMed

Maryamchik, Elena; Lyapichev, Kirill A; Halliday, Bradford; Rosenberg, Andrew E

2018-03-01

We report a first case of paraneoplastic human chorionic gonadotropin (HCG) production in a dedifferentiated liposarcoma with rhabdosarcomatous differentiation in an 83-year-old man with a retroperitoneal mass, unilateral scrotal enlargement, and a serum HCG level of 843 IU/L. Core biopsy of the retroperitoneal mass revealed rhabdomyosarcoma. Orchiectomy revealed a paratesticular dedifferentiated liposarcoma with rhabdosarcomatous differentiation. Fluorescence in situ hybridization analysis performed on both the retroperitoneal and paratesticular masses revealed amplification of MDM2. The retroperitoneal tumor was interpreted as metastatic dedifferentiated liposarcoma with the dedifferentiated component represented by rhabdomyosarcoma. HCG production is a common feature of testicular germ cell tumors, less common in carcinomas, and extremely rare in sarcomas. Accordingly, sarcomas secreting HCG are a potential diagnostic pitfall, and raise the differential diagnosis of germ cell tumors and a variety of carcinomas. HCG production by carcinomas is a known poor prognostic finding, however the significance of its production in sarcomas is unknown.

SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese metastatic colorectal cancer patients.

PubMed

Mei, Zhu; Shao, Yang W; Lin, Peinan; Cai, Xiaomin; Wang, Biao; Ding, Yan; Ma, Xiangyuan; Wu, Xue; Xia, Yewei; Zhu, Dongqin; Shu, Yongqian; Fu, Zan; Gu, Yanhong

2018-04-27

Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. Patients carrying SMAD4 mutations (SMAD4 mut , n = 8) or NF1 mutations (NF1 mut , n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4 wt , n = 25) (P = 0.0081) or wildtype NF1 (NF1 wt , n = 29) (P = 0.0028), respectively. None of the SMAD4 mut or NF1 mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4 mut and NF1 mut showed the shortest PFS among all the patients. Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.

Socioeconomic Correlates of Gender Differential in Poor Health Status Among Older Adults in India.

PubMed

Pandey, Anamika; Ladusingh, Laishram

2015-10-01

Assessment of the health status of the older adults can go a long way in controlling the disease burden and monitoring the path to healthy aging in India. In the absence of a population-based clinical survey to collect data on morbidities and other health conditions through biomarkers, self-rated health by nationally representative older population is used for understanding factors contributing to the gender differential in health status. Socioeconomic status is the most important factor explaining 59% of the gender gap in self-assessed health among older adults. The vulnerability of older women in terms of educational attainment, occupational status, and economic dependency is responsible for the higher level of poor self-assessed health. The gender gap in self-assessed poor health among older Indian adults, which perpetuates over the life course resulting in severe health disadvantages at old age can be reduced considerably through social empowerment and gender sensitive public policies. © The Author(s) 2013.

Successful resection of metachronous para-aortic, Virchow lymph node and liver metastatic recurrence of rectal cancer.

PubMed

Takeshita, Nobuyoshi; Fukunaga, Toru; Kimura, Masayuki; Sugamoto, Yuji; Tasaki, Kentaro; Hoshino, Isamu; Ota, Takumi; Maruyama, Tetsuro; Tamachi, Tomohide; Hosokawa, Takashi; Asai, Yo; Matsubara, Hisahiro

2015-11-28

A 66-year-old female presented with the main complaint of defecation trouble and abdominal distention. With diagnosis of rectal cancer, cSS, cN0, cH0, cP0, cM0 cStage II, Hartmann's operation with D3 lymph node dissection was performed and a para-aortic lymph node and a disseminated node near the primary tumor were resected. Histological examination showed moderately differentiated adenocarcinoma, pSS, pN3, pH0, pP1, pM1 (para-aortic lymph node, dissemination) fStage IV. After the operation, the patient received chemotherapy with FOLFIRI regimen. After 12 cycles of FOLFIRI regimen, computed tomography (CT) detected an 11 mm of liver metastasis in the postero-inferior segment of right hepatic lobe. With diagnosis of liver metastatic recurrence, we performed partial hepatectomy. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer with cut end microscopically positive. After the second operation, the patient received chemotherapy with TS1 alone for 2 years. Ten months after the break, CT detected a 20 mm of para-aortic lymph node metastasis and a 10 mm of lymph node metastasis at the hepato-duodenal ligament. With diagnosis of lymph node metastatic recurrences, we performed lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as metastatic rectal cancer in para-aortic and hepato-duodenal ligament areas. After the third operation, we started chemotherapy with modified FOLFOX6 regimen. After 2 cycles of modified FOLFOX6 regimen, due to the onset of neutropenia and liver dysfunction, we switched to capecitabine alone and continued it for 6 mo and then stopped. Eleven months after the break, CT detected two swelling 12 mm of lymph nodes at the left supraclavicular region. With diagnosis of Virchow lymph node metastatic recurrence, we started chemotherapy with capecitabine plus bevacizumab regimen. Due to the onset of neutropenia and hand foot syndrome (Grade 3), we managed to

Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the xelbevoct study

PubMed Central

2014-01-01

Background We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset. Methods This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. Results Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. Conclusion The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. Trial registration Trial registration number NCT01203306. PMID:24628963

Evidence of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-PSMA-HBED-CC PET/CT.

PubMed

Verma, Priyanka; Malhotra, Gaurav; Agrawal, Ritesh; Sonavane, Sunita; Meshram, Vilas; Asopa, Ramesh V

2018-06-12

Prostate-specific membrane antigen (PSMA) overexpression is not restricted to prostate cancer, but it has also been demonstrated in gliomas, lung cancer, and in tumor neovasculature. Systematic studies exploring PSMA uptake in thyroid tumors are lacking. The aim of this pilot study was to assess PSMA expression in patients with metastatic differentiated thyroid cancer (mDTC). Ten patients of mDTC harboring 32 lesions (5 men; age range, 38-65 years; mean age, 50 years) underwent prospective evaluation with radioiodine (I), F-FDG PET, and Ga-PSMA-HBED-CC PET scans as per the institution protocol. PSMA expression (SUVmax) was compared with F-FDG and I scan findings in all patients. Lesions were radioiodine avid in 8 patients, whereas 2 were classified as thyroglobulin elevation with negative iodide scintigraphy (TENIS) patients. All patients with iodine-avid metastatic disease showed substantial PSMA uptake. PSMA PET detected 30/32 total lesions (93.75%; SUVmax ranging from 4.86 to 101.81 with median SUVmax of 31.35), whereas FDG PET/CT was positive in 23/32 lesions (81.85%). Twenty-one (70%) of 30 lesions that showed PSMA expression were localized to the bones. PSMA localized a lesion in each of the 2 TENIS patients similar to FDG PET scan. Ga-PSMA-HBED-CC PET/CT is a potentially useful imaging modality in patients of mDTC with most (70%) of PSMA expressing metastasis being localized to the bones. PSMA PET/CT could be useful for identifying patients with limited therapeutic options (eg, TENIS) who might benefit from PSMA-targeted radionuclide therapy.

Fine needle aspiration biopsy of three cases of squamous cell carcinoma presenting as a thyroid mass: cytological findings and differential diagnosis.

PubMed

Rosa, M; Toronczyk, K

2012-02-01

Primary squamous cell carcinomas of the thyroid gland are extremely rare, comprising about 1% of thyroid malignancies. Although squamous cell carcinomas are readily identified as such on aspiration cytology in the majority of cases, the differentiation of primary versus metastatic tumour might not always be easy. Herein, we report three cases of squamous cell carcinomas involving the thyroid gland. Fine needle aspiration cytology (FNAC) was performed in three patients with a thyroid mass using standard guidelines. Smears were stained with Diff-Quik and Papanicolaou stains. Two patients were male and one was female, aged 59, 45 and 35 years, respectively. In all three patients a thyroid mass was present. FNAC smears in all cases showed cytological features of squamous cell carcinoma including keratinization and necrosis. After clinical and cytological correlation, one case appeared to be primary, one case metastatic, and in the third case no additional clinical information or biopsy follow-up was available for further characterization. Because primary squamous cell carcinoma of the thyroid is a rare finding, metastatic squamous cell carcinoma should always be excluded first. Metastatic disease usually presents in the setting of widespread malignancy, therefore a dedicated clinical and radiological investigation is necessary in these cases. In both clinical scenarios the patient's prognosis is poor. © 2010 Blackwell Publishing Ltd.

Histogram analysis of apparent diffusion coefficient maps for the differentiation between lymphoma and metastatic lymph nodes of squamous cell carcinoma in head and neck region.

PubMed

Wang, Yan-Jun; Xu, Xiao-Quan; Hu, Hao; Su, Guo-Yi; Shen, Jie; Shi, Hai-Bin; Wu, Fei-Yun

2018-06-01

Background To clarify the nature of cervical malignant lymphadenopathy is highly important for the diagnosis and differential diagnosis of head and neck tumors. Purpose To investigate the role of first-order apparent diffusion coefficient (ADC) histogram analysis for differentiating lymphoma from metastatic lymph nodes of squamous cell carcinoma (SCC) in the head and neck region. Material and Methods Diffusion-weighted imaging (DWI) data of 67 patients (lymphoma, n = 20; SCC, n = 47) with malignant lymphadenopathy were retrospectively analyzed. The SCC group was divided into nasopharyngeal SCC and non-nasopharyngeal SCC groups. The ADC histogram features (ADC 10 , ADC 25 , ADC mean , ADC median , ADC 75 , ADC 90 , skewness, and kurtosis) were derived and then compared by independent-samples t-test and one-way analysis of variance test, respectively. Receiver operating characteristic curve analyses were employed to investigate diagnostic performance of the significant parameters. Results Lymphoma showed significantly lower ADC mean , ADC median , ADC 75 , and ADC 90 than SCC (all P < 0.05). Setting ADC 90  = 0.719 × 10 -3  mm 2 /s as the threshold value, optimal diagnostic performance was achieved (area under the curve [AUC] = 0.719, sensitivity = 95.7%, specificity = 50.0%). Subgroup analyses showed no significant difference between lymphoma and NPC (all P > 0.05). Lymphoma showed significantly lower ADC 25 , ADC mean , ADC median , ADC 75 , and ADC 90 than non-nasopharyngeal SCC (all P < 0.05). Optimal diagnostic performance (AUC = 0.847, sensitivity = 86.7%, specificity = 80.0%) could be achieved when setting ADC 90  = 0.943 × 10 -3  mm 2 /s as the threshold value. Conclusion Given its limitations, our study has shown that first-order ADC histogram analysis is capable of differentiating lymphoma from metastatic lymph nodes of SCC, especially those of non-nasopharyngeal SCC.

Metastatic basal cell carcinoma: case series and review of the literature.

PubMed

Tang, Simon; Thompson, Stephen; Smee, Robert

2017-05-01

Metastatic basal cell carcinoma is exceedingly uncommon, with a poorly defined natural history, and its incidence, risk factors, patterns of spread, prognosis and potential treatment options are not well understood. This retrospective single institution case series aims to shed light on these issues. Aggressive local management in patients with locoregional disease may result in long-term survivors. © 2016 The Australasian College of Dermatologists.

Identification of Metastatic Tumor Stem Cell

DTIC Science & Technology

2010-09-01

addition to a tumor stem cell , an existence of a metastatic stem cell is predicted. Despite the critical importance of the concept, this idea has not been...isolating stem cell population from a unique set of breast tumor cell lines and by examining their metastatic behavior in an animal model. The overall...will (i) isolate stem - cell population from non-metastatic and metastatic cells of a pair of syngenic breast tumor cell lines, and test their metastatic

c-MET Overexpression in Colorectal Cancer: A Poor Prognostic Factor for Survival.

PubMed

Lee, Su Jin; Lee, Jeeyun; Park, Se Hoon; Park, Joon Oh; Lim, Ho Yeong; Kang, Won Ki; Park, Young Suk; Kim, Seung Tae

2018-03-02

Increased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumor progression and is a new potential drug target for several types of cancers. In the present study, we investigated the incidence of c-MET overexpression and its prognostic significance in patients with colorectal cancer (CRC). We retrospectively reviewed the data from 255 stage IV CRC patients who had results from a c-MET immunohistochemical test at Samsung Medical Center. We explored the relationships between c-MET overexpression and clinicopathological features and survival. Primary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. Among the 255 patients, 39 (15.3%) exhibited c-MET overexpression. There was no significant difference in the prevalence of c-MET overexpression according to primary site, histologic differentiation, molecular markers, or metastatic sites. In a comparison of the tumor response to first-line chemotherapy according to the level of c-MET expression, we found no significant difference in either partial response or disease control rate. In the survival analysis, patients with c-MET overexpression had significantly shorter overall survival (39 vs. 27 months; P = .018) and progression-free survival (PFS) during bevacizumab treatment (10 vs. 7 months; P = .024). c-MET overexpression, which was detected in 39 CRC patients (15.3%) irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment in patients with CRC. Further studies are warranted to elucidate the value of c-MET-targeted therapy in CRC patients. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Reversible inhibition of lysine specific demethylase 1 is a novel anti-tumor strategy for poorly differentiated endometrial carcinoma.

PubMed

Theisen, Emily R; Gajiwala, Snehal; Bearss, Jared; Sorna, Venkataswamy; Sharma, Sunil; Janat-Amsbury, Margit

2014-10-09

Endometrial cancer is the most common gynecologic malignancy. Type II endometrial carcinoma is often poorly differentiated and patients diagnosed with Type II disease (~11%) are disproportionately represented in annual endometrial cancer deaths (48%). Recent genomic studies highlight mutations in chromatin regulators as drivers in Type II endometrial carcinoma tumorigenesis, suggesting the use of epigenetic targeted therapies could provide clinical benefit to these patients. We investigated the anti-tumor efficacy of the LSD1 inhibitor HCI2509 in two poorly differentiated Type II endometrial cancer cell lines AN3CA and KLE. The effects of HCI2509 on viability, proliferation, anchorage-independent growth, global histone methylation, LSD1 target gene induction, cell cycle, caspase activation and TUNEL were assayed. KLE cells were used in an orthotopic xenograft model to assess the anti-tumor activity of HCI2509. Both AN3CA and KLE cells were sensitive to HCI2509 treatment with IC50s near 500 nM for cell viability. Inhibition of LSD1 with HCI2509 caused decreased proliferation and anchorage independent growth in soft agar, elevated global histone methylation, and perturbed the cell cycle in both cell lines. These effects were largely dose-dependent. HCI2509 treatment also caused apoptotic cell death. Orthotopic implantation of KLE cells resulted in slow-growing and diffuse tumors throughout the abdomen. Tumor burden was distributed log-normally. Treatment with HCI2509 resulted 5/9 tumor regressions such that treatment and regressions were significantly associated (p=0.034). Our findings demonstrate the anti-cancer properties of the LSD1 inhibitor HCI2509 on poorly differentiated endometrial carcinoma cell lines, AN3CA and KLE. HCI2509 showed single-agent efficacy in orthotopic xenograft studies. Continued studies are needed to preclinically validate LSD1 inhibition as a therapeutic strategy for endometrial carcinoma.

The Use of Platelet-Rich and Platelet-Poor Plasma to Enhance Differentiation of Skeletal Myoblasts: Implications for the Use of Autologous Blood Products for Muscle Regeneration.

PubMed

Miroshnychenko, Olga; Chang, Wen-Teh; Dragoo, Jason L

2017-03-01

Platelet-rich plasma (PRP) has been used to augment tissue repair and regeneration after musculoskeletal injury. However, there is increasing clinical evidence that PRP does not show a consistent clinical effect. Purpose/Hypothesis: This study aimed to compare the effects of the following non-neutrophil-containing (leukocyte-poor) plasma fractions on human skeletal muscle myoblast (HSMM) differentiation: (1) PRP, (2) modified PRP (Mod-PRP), in which transforming growth factor β1 (TGF-β1) and myostatin (MSTN) were depleted, and (3) platelet-poor plasma (PPP). The hypothesis was that leukocyte-poor PRP would lead to myoblast proliferation (not differentiation), whereas certain modifications of PRP preparations would increase myoblast differentiation, which is necessary for skeletal muscle regeneration. Controlled laboratory study. Blood from 7 human donors was individually processed to simultaneously create leukocyte-poor fractions: PRP, Mod-PRP, PPP, and secondarily spun PRP and Mod-PRP (PRP ss and Mod-PRP ss , respectively). Mod-PRP was produced by removing TGF-β1 and MSTN from PRP using antibodies attached to sterile beads, while a second-stage centrifugal spin of PRP was performed to remove platelets. The biologics were individually added to cell culture groups. Analysis for induction into myoblast differentiation pathways included Western blot analysis, reverse-transcription polymerase chain reaction, and immunohistochemistry, as well as confocal microscopy to assess polynucleated myotubule formation. HSMMs cultured with PRP showed an increase in proliferation but no evidence of differentiation. Western blot analysis confirmed that MSTN and TGF-β1 could be decreased in Mod-PRP using antibody-coated beads, but this modification mildly improved myoblast differentiation. However, cell culture with PPP, PRP ss , and Mod-PRP ss led to a decreased proliferation rate but a significant induction of myoblast differentiation verified by increased multinucleated

Identification of metastatic papillary thyroid carcinoma in FNA specimens using thyroid peroxidase immunohistochemistry.

PubMed

Shield, P W; Crouch, S J; Papadimos, D J; Walsh, M D

2018-06-01

We evaluated immunohistochemical staining for thyroid peroxidase (TPO), a glycoprotein found in the apical plasma membrane of thyroid follicular cells, as a marker for metastatic PTC in FNA samples and compared results with thyroglobulin (Tg) and thyroid transcription factor 1 (TTF1) staining. Cell block sections prepared from 100 FNA specimens were stained with a rabbit monoclonal antibody to TPO (EP159). The FNAs included 64 metastatic malignancies from non-thyroid primary sites, including 18 lung, and 36 cases of thyroid tumours (29 PTC, six cases of medullary thyroid carcinoma and one thyroid anaplastic carcinoma). Thyroid tumours were stained with TTF1 and Tg in addition to TPO. All cases of metastatic lung carcinoma also had TTF-1 staining results. TPO staining was negative in all non-thyroid malignancies. Ninety percent (26/29) of PTC were positive. All positive cases showed strong cytoplasmic staining, although 54% (14/26) showed positivity in less than half of the cells. By comparison, Tg staining of TPC cases was present in 62% and TTF-1 in 100%. In addition to showing higher sensitivity, interpretation of staining results with TPO was generally easier with than Tg. All metastatic lung adenocarcinomas were positive for TTF-1 and TPO negative. The six medullary cancers showed positivity in 17%, 0% and 83% with TPO, Tg and TTF-1, respectively. TPO (mAb EP159) may be a useful addition to immunohistochemical panels for FNA specimens where metastatic PTC is a consideration, particularly in cases where metastatic lung carcinoma features in the differential diagnosis. © 2018 John Wiley & Sons Ltd.

Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell Carcinoma Risk Groups.

PubMed

de Velasco, Guillermo; Miao, Diana; Voss, Martin H; Hakimi, A Ari; Hsieh, James J; Tannir, Nizar M; Tamboli, Pheroze; Appleman, Leonard J; Rathmell, W Kimryn; Van Allen, Eliezer M; Choueiri, Toni K

2016-10-01

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole-exome transcriptome data in renal cell carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by the MSKCC risk group, nor was the expression of cytolytic genes-granzyme A and perforin-or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis revealed that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. Cancer Immunol Res; 4(10); 820-2. ©2016 AACR. ©2016 American Association for Cancer Research.

Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency.

PubMed

Cohen, R; Buhard, O; Cervera, P; Hain, E; Dumont, S; Bardier, A; Bachet, J-B; Gornet, J-M; Lopez-Trabada, D; Dumont, S; Kaci, R; Bertheau, P; Renaud, F; Bibeau, F; Parc, Y; Vernerey, D; Duval, A; Svrcek, M; André, Thierry

2017-11-01

Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs. MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation. Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44). LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Somatostatin receptor imaging in non-(131)I-avid metastatic differentiated thyroid carcinoma for determining the feasibility of peptide receptor radionuclide therapy with (177)Lu-DOTATATE: low fraction of patients suitable for peptide receptor radionuclide therapy and evidence of chromogranin A level-positive neuroendocrine differentiation.

PubMed

Jois, Bhargavi; Asopa, Ramesh; Basu, Sandip

2014-06-01

The aim of the study was to evaluate somatostatin receptor expression in non-I-concentrating metastatic differentiated thyroid carcinoma by Ga-DOTATATE PET-CT/Tc-HYNIC-TOC scintigraphy and to determine the feasibility of Lu-DOTATATE (therapeutic analog) therapy in cases with positive Ga-DOTATATE PET-CT/Tc-HYNIC-TOC scintigraphy. In this research study, 19 patients diagnosed with differentiated thyroid carcinoma with non-iodine-concentrating metastasis with elevated serum thyroglobulin levels, attending thyroid outpatient department for follow-up, underwent Ga-DOTATATE PET-CT/Tc-HYNIC-TOC scan for the evaluation of positivity of somatostatin receptor (SSTR). Based on the visual grading, SSTR-positive lesions were graded into 4 categories (grades I-IV) in comparison with the hepatic uptake on the scan. Patients with grades III and IV uptake in lesions (equal to or more than hepatic uptake on scan) were scheduled for Lu-DOTATATE administration. Posttherapy Lu-DOTATATE scan was undertaken during discharge from the isolation ward. Of the 19 patients studied, 12 patients (63%) showed SSTR-positive lesion expression demonstrating uptake ranging from grade I-IV, and 7 patients (37%) did not demonstrate any tracer uptake. On a lesion-specific analysis, of the total 57 metastatic lesions, 4 lesions (7%) demonstrated grade I tracer uptake, 18 lesions (31%) grade II (less than liver), 2 lesions (3.5%) grade III (equal to liver uptake), and 1 lesion showed grade IV uptake (more than liver). Interestingly, an elevated serum chromogranin A level was documented in 3 of the patients with grades III and IV tumor uptake. A comparison of Ga-DOTATATE PET-CT and Tc-HYNIC-TOC in 4 patients who underwent both the scans demonstrated no significant differences in the tracer concentration in the metastatic lesions in any of the patients on visual grading. Based on the criterion of high tracer uptake and the patient consent, finally 2 of 3 patients were treated with Lu-DOTATATE. On follow

Endothelial-Mesenchymal Transition of Brain Endothelial Cells: Possible Role during Metastatic Extravasation

PubMed Central

Krizbai, István A.; Gasparics, Ákos; Nagyőszi, Péter; Fazakas, Csilla; Molnár, Judit; Wilhelm, Imola; Bencs, Rita; Rosivall, László; Sebe, Attila

2015-01-01

Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-β, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-β1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, β1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-β signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-β-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-β-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring

Metastatic non-gestational choriocarcinoma to the brain: a case report and proposed treatment recommendations.

PubMed

Duong, Jason; Ghanchi, Hammad; Miulli, Dan; Kahlon, Avneet

2018-04-17

Non-gestational choriocarcinoma (NGC) is a rare germ cell tumor, reported less than 0.6% of all gestational tumors, and has a poor prognosis when metastasized. NGC is even less reported with metastasis to the brain. Gestational choriocarcinoma (GC) when metastasized to the brain has a higher morbidity and mortality but has been known to be a chemosensitive and radiosensitive lesion, and NGC is chemoresistant with an even worse prognosis. Currently, there is no consensus for treatment for metastatic NGC to the brain. 66 year-old post-menopausal female presents with left upper extremity weakness more pronounced in her hand, and work up demonstrating a hemorrhagic lesion over the right frontal parietal lobe. Her metastatic work up was negative, leading to a craniotomy for resection of the mass. The pathology was consistent with metastatic gestational choriocarcinoma, non-gestational in origin. Because of its chemosensitive nature, reports of optimal metastatic GC treatment include radiation alone, chemotherapy without radiation, surgical resection, or combined multimodal therapy. No recommendations for NGC metastatic to the brain have been reported. We propose a systematic work up for hemorrhagic brain lesions to include the proposed imaging modalities and serum markers including β-hCG to aid with early diagnosis. With review of literature, we recommend surgical resection with adjuvant therapy for accessible symptomatic metastatic GC and NGC to the brain for optimal patient outcomes. Chemotherapy and radiation alone without surgical resection can be considered for asymptomatic GC metastasis to the brain. Copyright © 2018 Elsevier Inc. All rights reserved.

Evaluation of an inflammation-based prognostic score (GPS) in patients with metastatic breast cancer.

PubMed

Al Murri, A M; Bartlett, J M S; Canney, P A; Doughty, J C; Wilson, C; McMillan, D C

2006-01-30

Prediction of outcome in patients with metastatic breast cancer remains problematical. The present study evaluated the value of an inflammation-based score (Glasgow Prognostic Score, GPS) in patients with metastatic breast cancer. The GPS was constructed as follows: patients with both an elevated C-reactive protein (>10 mg l(-1)) and hypoalbuminaemia (<35 g l(-1)) were allocated a score of 2. Patients in whom only one or none of these biochemical abnormalities was present were allocated a score of 1 or 0, respectively. In total, 96 patients were studied. During follow-up 51 patients died of their cancer. On multivariate analysis of the GPS and treatment received, only the GPS (HR 2.26, 95% CI 1.45-3.52, P<0.001) remained significantly associated with cancer-specific survival. The presence of a systemic inflammatory response (the GPS) appears to be a useful indicator of poor outcome independent of treatment in patients with metastatic breast cancer.

Head and neck cutaneous squamous cell carcinoma metastatic to cervical sublevel IIb lymph nodes occurred from primary sites involving the auricle and adjacent neck.

PubMed

Maher, Nigel Gordon; Hoffman, Gary Russell

2014-03-01

Neck dissections that include sublevel IIb increase the risk of postoperative shoulder dysfunction. The purpose of this investigation was to document the incidence of level IIb metastatic lymphatic spread in a group of patients undergoing neck dissection as part of the surgical management of cutaneous squamous cell carcinoma of the head and neck. A retrospective review of the pathology records taken from 1 surgeon from June 2006 through June 2013 was carried out. The predictor variable was the primary tumor site. The outcome variable was the metastatic nodal involvement according to neck level and sublevel. Secondary variables included T stage, pathologist, tumor depth, and the presence of perineural, perilymphatic, and perivascular invasion. Data analyses were by descriptive statistics. Thirty-six patients with a total of 40 neck dissections met the inclusion criteria. The average primary site tumor depth was 14.7 mm, and there were 16 cases of poorly differentiated squamous cell carcinoma. Sublevel IIb was involved in 7.5% of cases, all of which occurred from lateralized primary sites of the head and neck. Cutaneous squamous cell carcinoma arising from the auricle and neck sites adjacent to sublevel IIb may have increased risk of metastatic involvement of sublevel IIb nodes. Further studies with larger numbers are required to determine the risk of metastasis to sublevel IIb from midline sites of the face. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

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,…

Oncological outcomes of metastatic testicular cancers under centralized management through regional medical network.

PubMed

Inai, Hiromu; Kawai, Koji; Kojima, Takahiro; Joraku, Akira; Shimazui, Toru; Yamauchi, Atsushi; Miyagawa, Tomoaki; Endo, Tsuyoshi; Fukuhara, Yoshiharu; Miyazaki, Jun; Uchida, Katsunori; Nishiyama, Hiroyuki

2013-12-01

To investigate the dose intensity of induction chemotherapy and oncological outcomes of metastatic testicular cancer under centralized management through a regional medical network. We retrospectively analyzed the outcomes of 86 metastatic testicular cancer patients who were given induction chemotherapy at Tsukuba University Hospital and four branch hospitals between January 2000 and November 2010. Principally, management of patients with poor-prognosis disease and patients having risk factors for bleomycin, etoposide and cisplatin were referred to Tsukuba University Hospital before chemotherapy. For high-risk groups, etoposide and cisplatin or etoposide, ifosfamide and cisplatin was used as an alternative to bleomycin, etoposide and cisplatin. Overall, 56 and 30 patients were treated at Tsukuba University Hospital and branch hospitals, respectively. Forty-seven, 18 and 21 patients were classified with good-, intermediate- and poor-prognosis disease, respectively, according to the International Germ Cell Cancer Collaborative Group criteria. Eighteen of the 21 patients (86%) with poor-prognosis disease were treated at Tsukuba University Hospital from the beginning of induction chemotherapy. Induction chemotherapy with a high relative dose intensity was possible in most patients. The average relative dose intensity of each drug was >0.96. Treatment procedures other than induction chemotherapy were efficiently centralized; 74% of post-chemotherapy surgery and all second-line or subsequent chemotherapies were performed at Tsukuba University Hospital. The 5-year overall survival rates of the good-, intermediate- and poor-prognosis groups were 97, 93 and 84%, respectively. Induction chemotherapy with high relative dose intensity, post-chemotherapy surgery and salvage chemotherapy was accomplished efficiently through centralization of management. Oncological outcomes were excellent, especially in patients with poor-prognosis disease, whose 5-year OS reached 84%.

Tumor mutational load and immune parameters across metastatic Renal Cell Carcinoma (mRCC) risk groups

PubMed Central

de Velasco, Guillermo; Miao, Diana; Voss, Martin H.; Hakimi, A. Ari; Hsieh, James J.; Tannir, Nizar M.; Tamboli, Pheroze; Appleman, Leonard J.; Rathmell, W. Kimryn; Van Allen, Eliezer M.; Choueiri, Toni K.

2016-01-01

Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared to patients with favorable or intermediate-risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole exome transcriptome data in RCC patients (n = 54) included in The Cancer Genome Atlas that ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by MSKCC risk group, nor was the expression of cytolytic genes –granzyme A and perforin – or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis found that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. PMID:27538576

Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

PubMed

Hao, Mengze; Zhao, Gang; Du, Xiaoling; Yang, Yun; Yang, Jilong

2016-08-01

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

Theranostics Targeting Metastatic Breast Cancer

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0389 TITLE: Theranostics Targeting Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Kevin Burgess CONTRACTING...ADDRESS. 1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 4. TITLE AND SUBTITLE Theranostics Targeting Metastatic Breast Cancer 5a...safe and effective interventions; (ii) elimination of mortality associated with metastatic breast cancer ; and, (iii) distinguishing aggressive breast

Fatal haemorrhage and neoplastic thrombosis in a captive African lion (Panthera leo) with metastatic testicular sex cord-stromal tumour.

PubMed

Gonzales-Viera, Omar Antonio; Sánchez-Sarmiento, Angélica María; Fernandes, Natália Coelho Couto de Azevedo; Guerra, Juliana Mariotti; Ressio, Rodrigo Albergaria; Catão-Dias, José Luiz

2017-10-13

The study of neoplasia in wildlife species contributes to the understanding of cancer biology, management practices, and comparative pathology. Higher frequencies of neoplasms among captive non-domestic felids have been reported most commonly in aging individuals. However, testicular tumours have rarely been reported. This report describes a metastatic testicular sex cord-stromal tumour leading to fatal haemorrhage and thrombosis in a captive African lion (Panthera leo). During necropsy of a 16-year-old male African lion, the left testicle and spermatic cord were found to be intra-abdominal (cryptorchid), semi-hard and grossly enlarged with multiple pale-yellow masses. Encapsulated haemorrhage was present in the retroperitoneum around the kidneys. Neoplastic thrombosis was found at the renal veins opening into the caudal vena cava. Metastases were observed in the lungs and mediastinal lymph nodes. Histology revealed a poorly differentiated pleomorphic neoplasm comprised of round to polygonal cells and scattered spindle cells with eosinophilic cytoplasm. An immunohistochemistry panel of inhibin-α, Ki-67, human placental alkaline phosphatase, cytokeratin AE1/AE3, cKit, vimentin and S100 was conducted. Positive cytoplasmic immunolabeling was obtained for vimentin and S100. The gross, microscopic and immunohistochemical findings of the neoplasm were compatible with a poorly differentiated pleomorphic sex cord-stromal tumour. Cause of death was hypovolemic shock from extensive retroperitoneal haemorrhage and neoplastic thrombosis may have contributed to the fatal outcome. To our knowledge, this is the first report of sex cord-stromal tumour in non-domestic felids.

TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells.

PubMed

Bartucci, M; Dattilo, R; Moriconi, C; Pagliuca, A; Mottolese, M; Federici, G; Benedetto, A Di; Todaro, M; Stassi, G; Sperati, F; Amabile, M I; Pilozzi, E; Patrizii, M; Biffoni, M; Maugeri-Saccà, M; Piccolo, S; De Maria, R

2015-02-05

Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic.

PubMed

Rose, Darya B; Nellesen, Dave; Neary, Maureen P; Cai, Beilei

2017-04-01

Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic. To assess the 3-year budget impact for a typical US health plan following availability of everolimus for treatment of GI and lung NETs. Methods An economic model was developed that considered two perspectives: an entire health plan and a pharmacy budget. The total budget impact included costs of drug therapies, administration, hospitalizations, physician visits, monitoring, and adverse events (AEs). The pharmacy model only considered drug costs. In a US health plan with 1 million members, the model estimated 66 patients with well-differentiated, non-functional, and advanced or metastatic GI NETs and 20 with lung NETs undergoing treatment each year. Total budget impact in the first through third year after FDA approval ranged from $0.0568-$0.1443 per member per month (PMPM) for GI NETs and from $0.0181-$0.0355 PMPM for lung NETs. The total budget impact was lower than the pharmacy budget impact because it included cost offsets from administration and AE management for everolimus compared with alternative therapies (e.g. chemotherapies). Because GI and lung NETs are rare diseases with limited published data, several assumptions were made that may influence interpretation of results. The budget impact for everolimus was minimal in this rare disease area with a high unmet need, largely due to low disease prevalence. These results should be considered in the context of significant clinical benefits potentially provided by everolimus, including significantly longer progression-free survival (PFS) for advanced GI and lung NET

Serum CA 19-9 as a prognostic factor in patients with metastatic gastric cancer.

PubMed

Jo, Jae-Cheol; Ryu, Min-Hee; Koo, Dong-Hoe; Ryoo, Baek-Yeol; Kim, Hwa Jung; Kim, Tae Won; Choi, Kee Don; Lee, Gin Hyug; Jung, Hwoon-Yong; Yook, Jeong Hwan; Oh, Sung Tae; Kim, Byung Sik; Kim, Jin-Ho; Kang, Yoon-Koo

2013-12-01

To evaluate tumor markers as prognostic factors in patients with metastatic or recurrent gastric cancer receiving first-line chemotherapy. Between January 2000 and December 2008, 1178 patients with metastatic or recurrent gastric cancer were assayed for expression of three serum tumor markers, CA 19-9, CA 72-4 and carcinoembryonic antigen (CEA), prior to the initiation of first-line chemotherapy. Elevated serum concentrations of carbohydrate antigen (CA) 19-9 (>37 U/mL), CA 72-4 (>4 U/mL) and carcinoembryonic antigen (CEA) (>6 ng/mL) were observed in 38, 56 and 33% of patients, respectively. Univariate analysis showed that elevated serum concentration of each of the three markers, CA 19-9 (P = 0.001), CA 72-4 (P = 0.001) and CEA (P = 0.030), was significantly associated with poor patient prognosis. However, multivariate analysis showed that an elevated CA 19-9 concentration only was significantly associated with shorter survival (hazard ratio [HR] 1.22; 95% CI, 1.08-1.37, P = 0.002). In the good risk and moderate risk groups, previously defined by clinical factors alone, survival was significantly lower in patients with elevated CA 19-9 (P < 0.001 and P = 0.021, respectively), but this difference was not observed in the poor-risk group. Elevated serum CA 19-9 concentration in patients with metastatic or recurrent gastric cancer, especially in good or moderate risk groups, is an independent negative predictor of prognosis. © 2012 Wiley Publishing Asia Pty Ltd.

CDX2 immunostaining in primary and metastatic germ cell tumours of the testis.

PubMed

Oz Atalay, Fatma; Aytac Vuruskan, Berna; Vuruskan, Hakan

2016-12-01

Objective To evaluate the immunohistochemical staining pattern of caudal type homeobox 2 (CDX2) protein in germ cell tumours (GCTs) of the testis. Methods This study reassessed archival tissue samples collected from patients diagnosed with primary and metastatic testicular GCTs for CDX2 immunoreactivity using standard immunohistochemical techniques. Positive nuclear immunostaining was evaluated with regard to both the staining intensity and the extent of the staining. Results Tissue sections from primary and metastatic testicular GCTs ( n = 104), germ cell neoplasia in situ (GCNis) ( n = 5) and benign testicles ( n = 15) were analysed. The GCNis and benign testicular tissues showed no immunoreactivity for CDX2. Strong and diffuse staining of CDX2 was demonstrated only in the mature colonic epithelium of teratomas in both primary and metastatic GCTs. CDX2 positivity in other tumours (one pure yolk sac tumour, one yolk sac component of a mixed GCT and one pure seminoma) was infrequent, and was only weak and focal. Conclusions CDX2 immunostaining should be interpreted based on both the staining intensity and the extent of staining so as not to cause misdiagnosis. Teratomas with colonic-type epithelium should be considered in the differential diagnosis if a metastatic tumour with an unknown primary shows prominent CDX2 immunostaining.

Local control of metastatic lung tumors treated with SBRT of 48 Gy in four fractions: in comparison with primary lung cancer.

PubMed

Hamamoto, Yasushi; Kataoka, Masaaki; Yamashita, Motohiro; Shinkai, Tetsu; Kubo, Yoshiro; Sugawara, Yoshifumi; Inoue, Takeshi; Sakai, Shinya; Aono, Shoji; Takahashi, Tadaaki; Semba, Takatoshi; Uwatsu, Kotaro

2010-02-01

The optimal dose of stereotactic body radiotherapy (SBRT) for metastatic lung tumors has not been clarified. Local control rates of metastatic lung tumors treated with SBRT of 48 Gy in four fractions, which is one of the common dose schedules for Stage I primary lung cancer in Japan, were examined. Between 2006 and 2008, 12 metastatic lung tumors (colorectal cancer, 7; others, 5) in 10 patients and 56 lesions of Stage I primary lung cancer (T1, 43; T2, 13) in 52 patients were treated with SBRT of 48 Gy in four fractions at the isocenter. Two-year overall survival rates were 86% for patients with metastatic lung tumors and 96% for patients with Stage I primary lung cancer (P = 0.4773). One- and 2-year local control rates were 48% and 25% for metastatic lung tumors, and 91% and 88% for Stage I primary lung cancer, respectively (P < 0.0001). The local control rates after SBRT of 48 Gy in four fractions were significantly worse in metastatic lung tumors compared with Stage I primary lung cancer. In SBRT, metastatic lung tumors should be clearly differentiated from primary lung cancer and should be given higher doses.

Junctional adhesion molecule-C promotes metastatic potential of HT1080 human fibrosarcoma.

PubMed

Fuse, Chiaki; Ishida, Yuuki; Hikita, Tomoya; Asai, Tomohiro; Oku, Naoto

2007-03-16

The junctional adhesion molecule (JAM) family is a key molecule in a process called transendothelial migration or diapedesis. Here, we report implications of JAM-C in cancer metastasis. We first determined the mRNA expression of JAMs in 19 kinds of cancer cell lines. JAM-C was expressed in most of tumors having potent metastatic properties. Especially in murine K-1735 melanoma cell lines, the highly metastatic sublines (M2 and X21) strongly expressed JAM-C when compared with the poorly metastatic ones (C-10 and C23). Next, we investigated the role of JAM-C in cancer metastasis by using human JAM-C (hJAM-C) gene-transfected HT1080 fibrosarcoma cells. In comparison with mock-transfected HT1080 cells, these cells showed a significant increase in the adhesion to various extracellular substrates and the invasion across a Matrigel-coated membrane. The knockdown of hJAM-C using small interfering RNA resulted in the suppression of both the adhesion and the invasion of HT1080 cells, suggesting that endogenous hJAM-C might be involved in tumor metastasis. Finally, we studied the role of hJAM-C in an in vivo experimental metastatic model. The results showed that the overexpression of hJAM-C in HT1080 cells significantly decreased the life spans of the tumorbearing mice. In contrast, the knockdown of hJAM-C in HT1080 cells suppressed the weight gain of the lungs with metastatic colonies. We conclude that the expression of JAM-C promotes metastasis by enhancing both the adhesion of cancer cells to extracellular matrices and the subsequent invasion.

Metastatic brain cancer: prediction of response to whole-brain helical tomotherapy with simultaneous intralesional boost for metastatic disease using quantitative MR imaging features

NASA Astrophysics Data System (ADS)

Sharma, Harish; Bauman, Glenn; Rodrigues, George; Bartha, Robert; Ward, Aaron

2014-03-01

The sequential application of whole brain radiotherapy (WBRT) and more targeted stereotactic radiosurgery (SRS) is frequently used to treat metastatic brain tumors. However, SRS has side effects related to necrosis and edema, and requires separate and relatively invasive localization procedures. Helical tomotherapy (HT) allows for a SRS-type simultaneous infield boost (SIB) of multiple brain metastases, synchronously with WBRT and without separate stereotactic procedures. However, some patients' tumors may not respond to HT+SIB, and would be more appropriately treated with radiosurgery or conventional surgery despite the additional risks and side effects. As a first step toward a broader objective of developing a means for response prediction to HT+SIB, the goal of this study was to investigate whether quantitative measurements of tumor size and appearance (including first- and second-order texture features) on a magnetic resonance imaging (MRI) scan acquired prior to treatment could be used to differentiate responder and nonresponder patient groups after HT+SIB treatment of metastatic disease of the brain. Our results demonstrated that smaller lesions may respond better to this form of therapy; measures of appearance provided limited added value over measures of size for response prediction. With further validation on a larger data set, this approach may lead to a means for prediction of individual patient response based on pre-treatment MRI, supporting appropriate therapy selection for patients with metastatic brain cancer.

Hyperparathyroidism Mimicking Metastatic Bone Disease: A Case Report and Review of Literature.

PubMed

Gupta, Monica; Singhal, Lalita; Kumar, Akshay

2018-06-01

Multiple osteolytic lesions are usually associated with metastatic involvement of the bone; however, metabolic bone diseases should also be included in the differential diagnosis. In this study, we describe a case of primary hyperparathyroidism (PHPT) with multiple osteolytic lesions that was diagnosed initially as having metastatic bone involvement. The laboratory results showed hypercalcemia and raised alkaline phosphatase along with fibrosis in the bone marrow biopsy with no increase in tumor markers and normal serum protein electrophoresis. The parathyroid hormone levels were high, which pointed toward a diagnosis of PHPT. Sestamibi scan revealed uptake at the level of the left inferior pole of the thyroid gland, which was suggestive of parathyroid adenoma. The possibility of hyperparathyroidism should be kept in mind when a patient presents with multiple osteolytic lesions and hypercalcemia.

A Differential Chemical Element Analysis of the Metal-poor Globular Cluster NGC 6397

NASA Astrophysics Data System (ADS)

Koch, Andreas; McWilliam, Andrew

2011-08-01

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 ~0.1 dex, with opposite signs for the red giant branch (RGB) and TO stars. The α-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. This paper includes data gathered with the 6.5 m Magellan Telescopes located at Las Campanas Observatory, Chile.

TH and DCX mRNAs in peripheral blood and bone marrow predict outcome in metastatic neuroblastoma patients.

PubMed

Yáñez, Yania; Hervás, David; Grau, Elena; Oltra, Silvestre; Pérez, Gema; Palanca, Sarai; Bermúdez, Mar; Márquez, Catalina; Cañete, Adela; Castel, Victoria

2016-03-01

In metastatic neuroblastoma (NB) patients, accurate risk stratification and disease monitoring would reduce relapse probabilities. This study aims to evaluate the independent prognostic significance of detecting tyrosine hydroxylase (TH) and doublecortin (DCX) mRNAs by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) in peripheral blood (PB) and bone marrow (BM) samples from metastatic NB patients. RT-qPCR was performed on PB and BM samples from metastatic NB patients at diagnosis, post-induction therapy and at the end of treatment for TH and DCX mRNAs detection. High levels of TH and DCX mRNAs when detected in PB and BM at diagnosis independently predicted worse outcome in a cohort of 162 metastatic NB. In the subgroup of high-risk metastatic NB, TH mRNA detected in PB remained as independent predictor of EFS and OS at diagnosis. After the induction therapy, high levels of TH mRNA in PB and DCX mRNA in BM independently predicted poor EFS and OS. Furthermore TH mRNA when detected in BM predicted worse EFS. TH mRNA in PB samples at the end of treatment is an independent predictor of worse outcome. TH and DCX mRNAs levels in PB and BM assessed by RT-qPCR should be considered in new pre-treatment risk stratification strategies to reliable estimate outcome differences in metastatic NB patients. In those high-risk metastatic NB, TH and DCX mRNA quantification could be used for the assessment of response to treatment and for early detection of progressive disease or relapses.

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

ClinicalTrials.gov

2017-09-26

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

Anaplastic transformation of metastatic papillary thyroid carcinoma at shoulder mimicking soft tissue sarcoma.

PubMed

Kaushal, Seema; Sharma, Mehar Chand; Mathur, Sandeep R; Rastogi, Shishir; Bal, Chander Shekhar; Chumber, Sunil

2011-01-01

A 52-year-old woman presented with fracture upper end of the left humerus after trivial trauma and aspiration cytology from the lytic lesion in the upper humerus seen on X-ray revealed a metastatic papillary carcinoma from the thyroid. Total thyroidectomy confirmed the papillary carcinoma thyroid. Post-operatively, she was given radioactive iodine (I-131) ablation therapy for 8 years and was asymptomatic during this period; however, for the last 1 year, she has been complaining of swelling in the shoulder, which did not respond to palliative radiotherapy and rapidly increased in size. Disarticulation of the shoulder joint was performed, which showed anaplastic carcinoma on histopathological examination. Anaplastic transformation of papillary carcinoma at the metastatic sites is well documented in the literature and is rare. However, the same has not been reported at the shoulder and from India before. Although soft tissue sarcomas are most common at this site, however, the possibility of anaplastic transformation should be kept in the differential diagnosis of rapidly enlarging painful mass in a known case of metastatic thyroid carcinoma to prevent misdiagnosis.

ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells

PubMed Central

Valabrega, G; Fagioli, F; Corso, S; Madon, E; Brach del Prever, A; Biasin, E; Linari, A; Aglietta, M; Giordano, S

2003-01-01

Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT–PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker. PMID:12569382

Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials.

PubMed

Kanda, Mitsuro; Oba, Koji; Aoyama, Toru; Kashiwabara, Kosuke; Mayanagi, Shuhei; Maeda, Hiromichi; Honda, Michitaka; Hamada, Chikuma; Sadahiro, Sotaro; Sakamoto, Junichi; Saji, Shigetoyo; Yoshikawa, Takaki

2018-04-01

Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. Independent patient data analysis of a pooled database from 3 phase III trials was performed. An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. The treatment regimens of postoperative chemotherapy are now somewhat outdated. Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype

Metastatic breast cancer to the liver with hepatoid features and Hep Par 1 antibody positive mimicking hepatocellular carcinoma.

PubMed

Affleck, Authur; Lyman, William B; Jacobs, W Carl; Livasy, Chad A; Martinie, John B; Iannitti, David A; Vrochides, Dionisios

2018-05-09

The hepatocyte paraffin 1 antibody (Hep Par 1) has a high positive predictive value for differentiating hepatocellular carcinoma from cholangiocarcinoma and metastatic carcinoma. 1 We report a case of metastatic breast cancer to the liver with hepatoid histology and strong positive staining for Hep Par 1 mimicking hepatocellular carcinoma. To our knowledge, primary breast carcinoma staining Hep Par 1 positive has not been reported in the setting of hepatic metastasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

PubMed

Ferrucci, Veronica; de Antonellis, Pasqualino; Pennino, Francesco Paolo; Asadzadeh, Fatemeh; Virgilio, Antonella; Montanaro, Donatella; Galeone, Aldo; Boffa, Iolanda; Pisano, Ida; Scognamiglio, Iolanda; Navas, Luigi; Diana, Donatella; Pedone, Emilia; Gargiulo, Sara; Gramanzini, Matteo; Brunetti, Arturo; Danielson, Laura; Carotenuto, Marianeve; Liguori, Lucia; Verrico, Antonio; Quaglietta, Lucia; Errico, Maria Elena; Del Monaco, Valentina; D'Argenio, Valeria; Tirone, Felice; Mastronuzzi, Angela; Donofrio, Vittoria; Giangaspero, Felice; Picard, Daniel; Remke, Marc; Garzia, Livia; Daniels, Craig; Delattre, Olivier; Swartling, Fredrik J; Weiss, William A; Salvatore, Francesco; Fattorusso, Roberto; Chesler, Louis; Taylor, Michael D; Cinalli, Giuseppe; Zollo, Massimo

2018-05-01

Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.10.1093/brain/awy039_video1awy039media15742053534001.

Metastatic hidradenocarcinoma with demonstration of Her-2/neu gene amplification by fluorescence in situ hybridization: potential treatment implications.

PubMed

Nash, Jason W; Barrett, Terry L; Kies, Merrill; Ross, Merrick I; Sneige, Nour; Diwan, A Hafeez; Lazar, Alexander J F

2007-01-01

A 44-year-old man was referred for a right chest nodule of 3 months duration. A 'benign' nodule had been excised from this location 8 years prior. On examination, palpable nodes were noted in the right axilla. Radiographic studies were significant only for right axillary lymphadenopathy. Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor. Features of a clear cell hidradenoma were noted focally. Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu. Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2. A wide local excision and axillary node dissection was performed. Metastatic tumor involved nine of 28 nodes. Interphase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis. The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic. We believe this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor. In analogy to breast carcinoma, these findings suggest the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.

Differentiating pheochromocytoma from lipid-poor adrenocortical adenoma by CT texture analysis: feasibility study.

PubMed

Zhang, Gu-Mu-Yang; Shi, Bing; Sun, Hao; Jin, Zheng-Yu; Xue, Hua-Dan

2017-09-01

To investigate the feasibility of using CT texture analysis (CTTA) to differentiate pheochromocytoma from lipid-poor adrenocortical adenoma (lp-ACA). Ninety-eight pheochromocytomas and 66 lp-ACAs were included in this retrospective study. CTTA was performed on unenhanced and enhanced images. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) was calculated for texture parameters that were significantly different for the objective. Diagnostic accuracies were evaluated using the cutoff values of texture parameters with the highest AUCs. Compared to lp-ACAs, pheochromocytomas had significantly higher mean gray-level intensity (Mean), entropy, and mean of positive pixels (MPP), but lower skewness and kurtosis on unenhanced images (P < 0.001). On enhanced images, these texture-quantifiers followed a similar trend where Mean, entropy, and MPP were higher, but skewness and kurtosis were lower in pheochromocytomas. Standard deviation (SD) was also significantly higher in pheochromocytomas on enhanced images. Mean and MPP quantified from no filtration on unenhanced CT images yielded the highest AUC of 0.86 ± 0.03 (95% CI 0.81-0.91) at a cutoff value of 34.0 for Mean and MPP, respectively (sensitivity = 79.6%, specificity = 83.3%, accuracy = 81.1%). It was feasible to use CTTA to differentiate pheochromocytoma from lp-ACA.

Survival Gains from First‐Line Systemic Therapy in Metastatic Non‐Small Cell Lung Cancer in the U.S., 1990–2015: Progress and Opportunities

PubMed Central

Goulart, Bernardo H. L.; Ravelo, Arliene; Kolkey, Holli; Ramsey, Scott D.

2017-01-01

Abstract Background. Approximately 190,000 Americans are diagnosed with non‐small cell lung cancer (NSCLC) annually, and about half have metastatic (Stage IV) disease. These patients have historically had poor survival prognosis, but several new therapies introduced since 2000 provide options for improved outcomes. The objectives of this study were to quantify survival gains from 1990, when best supportive care (BSC) only was standard, to 2015 and to estimate the impact of expanded use of systemic therapies in clinically appropriate patients. Materials and Methods. We developed a simulation model to estimate survival gains for patients with metastatic NSCLC from 1990–2015. Survival estimates were derived from major clinical trials and extrapolated to a lifetime horizon. Proportions of patients receiving available therapies were derived from the Surveillance, Epidemiology, and End Results database and a commercial treatment registry. We also estimated gains in overall survival (OS) in scenarios in which systemic therapy use increased by 10% and 30% relative to current use. Results. From 1990–2015, one‐year survival proportion increased by 14.1% and mean per‐patient survival improved by 4.2 months (32,700 population life years). Increasing treated patients by 10% or 30% increased OS by 5.1 months (39,700 population life years) and 6.9 months (53,800 population life years), respectively. Conclusion. Although survival remains poor in metastatic NSCLC relative to other common cancers, meaningful progress in per‐patient and population‐level outcomes has been realized over the past 25 years. These advances can be improved even further by increasing use of systemic therapies in the substantial proportion of patients who are suitable for treatment yet who currently receive BSC only. Implications for Practice. Approximately 93,500 Americans are diagnosed with metastatic non‐small cell lung cancer (NSCLC) annually. Historically, these patients have had poor

Expression of MMP-9 decreases metastatic potential of Chondrosarcoma: an immunohistochemical study.

PubMed

Malcherczyk, Dominik; Heyse, Thomas J; El-Zayat, Bilal F; Kunzke, Vanessa; Moll, Roland; Fuchs-Winkelmann, Susanne; Paletta, Jürgen R J

2018-01-09

Chondrosarcoma is the second most common primary malignant bone tumor. Because of their heterogeneity, with differences in invasive and metastatic behavior, it is important to identify biological markers that will allow for a more accurate estimation of prognosis in patients with these tumors. Matrix metalloproteinases (MMP) play a crucial role in tumor progression, invasion and metastasis. The mechanism of tumor progression dependent of MMPs is complex and influences malignant transformation, angiogenesis and tumor growth at the primary and metastatic sites. The purpose of this study was to investigate immunohistochemicaly the influence of MMP-1, MMP-3, MMP-9 and MMP-13 expression on prognostic parameter in chondrosarcoma. We investigated tissue samples of 28 patients with chondrosarcoma. Immunohistochemical staining to evaluate the expression of MMP-1, MMP-3, MMP-9 and MMP-13 was performed. Subsequently, the expression level was correlated with metastatic potential, histological grading and overall survival in patients with this neoplasm. In consideration of semi quantitative scoring 64% of chondrosarcoma were scored as positive for MMP-1, 46% for MMP-3, 61% for MMP-9. The specimens had shown no expression of MMP-13. High expression of MMP-9 was associated with better histological differentiation, decreased metastatic potential and favourable overall survival. No correlation was found for expression of MMP-1, MMP-3 or MMP-13. MMP-1, MMP-3 and MMP-9 are expressed in chondrosarcoma. Our findings suggest that the expression of MMP-9 is associated with clinical outcome parameters in chondrosarcoma.

[A Case Report of Gastric Carcinoma with Lymphoid Stroma Differentially Diagnosed from Malignant Lymphoma].

PubMed

Yamada, Kazuto; Kosuga, Toshiyuki; Okamoto, Kazuma; Konishi, Hirotaka; Shiozaki, Atsushi; Fujiwara, Hitoshi; Morimura, Ryo; Murayama, Yasutoshi; Kuriu, Yoshiaki; Ikoma, Hisashi; Nakanishi, Masayoshi; Kuroda, Junya; Kishimoto, Mitsuo; Konishi, Eiichi; Otsuji, Eigo

2017-11-01

A 49-year-old man was referred to our hospital for close examination of a submucosal tumor with ulceration located in the upper gastric body. PET-CT showed FDG uptake both in the gastric tumor and an enlarged lymph node. Although routine biopsies and EUS-FNA of this tumor did not demonstrate any malignant findings, he underwent excisional biopsy of the enlarged lymph nodes to rule out malignant lymphoma. Histopathological examination revealed that the excised specimens were metastatic nodes of poorly differentiated carcinoma probably from the known gastric tumor. Subsequently, he underwent total gastrectomy with D2, and histopathological findings confirmed the final diagnosis of gastric carcinoma with lymphoid stroma(GCLS). We report a case of GCLS that was difficult to diagnose.

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.

The management of metastatic radioiodine-refractory differentiated thyroid cancer requires an integrated approach including both directed and systemic therapies.

PubMed

Cooray, Shamil D; Topliss, Duncan J

2017-01-01

A 58-year-old man with metastatic radioiodine-refractory differentiated thyroid cancer (DTC) presented with left thigh and right flank numbness. He had known progressive and widespread bony metastases, for which he received palliative radiotherapy, and multiple bilateral asymptomatic pulmonary metastases. CT scan and MRI of the spine revealed metastases at right T10-L1 vertebrae with extension into the central canal and epidural disease at T10 and T11 causing cord displacement and canal stenosis but retention of spinal cord signal. Spinal surgery was followed by palliative radiotherapy resulting in symptom resolution. Two months later, sorafenib received approval for use in Australia and was commenced and up-titrated with symptomatic management of mild adverse effects. Follow-up CT scan three months after commencement of sorafenib revealed regression of pulmonary metastases but no evident change in most bone metastases except for an advancing lesion eroding into the right acetabulum. The patient underwent a right total hip replacement, intra-lesional curettage and cementing. After six months of sorafenib therapy, CT scanning showed enlarging liver lesions with marked elevation of serum thyroglobulin. Lenvatinib was commenced and sorafenib was ceased. He now has stable disease with a falling thyroglobulin more than 5 years after metastatic radioiodine-refractory DTC was diagnosed. In DTC, 5% of distant metastases become radioiodine-refractory, resulting in a median overall survival of 2.5-3.5 years. Tyrosine kinase inhibitor (TKI) therapy has recently been demonstrated to increase progression-free survival in these patients but poses some unique management issues and is best used as part of an integrated approach with directed therapy. Directed therapies may have greater potential to control localised disease and related symptoms when compared to systemic therapies.Consider TKI therapy in progressive disease where benefits outweigh risks.Active surveillance and

Optical imaging of metabolic adaptability in metastatic and non-metastatic breast cancer

NASA Astrophysics Data System (ADS)

Rebello, Lisa; Rajaram, Narasimhan

2018-02-01

Accurate methods for determining metastatic risk from the primary tumor are crucial for patient survival. Cell metabolism could potentially be used as a marker of metastatic risk. Optical imaging of the endogenous fluorescent molecules nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) provides a non-destructive and label-free method for determining cell metabolism. The optical redox ratio (FAD/FAD+NADH) is sensitive to the balance between glycolysis and oxidative phosphorylation (OXPHOS). We have previously established that hypoxia-reoxygenation stress leads to metastatic potential-dependent changes in optical redox ratio. The objective of this study was to monitor the changes in optical redox ratio in breast cancer cells in response to different periods of hypoxic stress as well various levels of hypoxia to establish an optimal protocol. We measured the optical redox ratio of highly metastatic 4T1 murine breast cancer cells under normoxic conditions and after exposure to 30, 60, and 120 minutes of 0.5% O2. This was followed by an hour of reoxygenation. We found an increase in the optical redox ratio following reoxygenation from hypoxia for all durations. Statistically significant differences were observed at 60 and 120 minutes (p˂0.01) compared with normoxia, implying an ability to adapt to OXPHOS after reoxygenation. The switch to OXPHOS has been shown to be a key promoter of cell invasion. We will present our results from these investigations in human breast cancer cells as well as non-metastatic breast cancer cells exposed to various levels of hypoxia.

Biometric assessment of prostate cancer's metastatic potential.

PubMed

Cooper, C R; Emmett, N; Harris-Hooker, S; Patterson, R; Cooke, D B

1994-01-01

Currently, no protocol exists that can assess the metastatic potential of prostate adenocarcinoma. The reason for this is partly due to the lack of information on cellular changes that result in a tumor cell's becoming metastatic. In this investigation, attempts were made to devise a method that correlated with the metastatic potential of AT-1, Mat-Lu, and Mat-LyLu cell lines of the Dunning R-3327 rat prostatic adenocarcinoma system. To accomplish this, we applied BioQuant biometric parameters, i.e., area, shape factor, and cell motility. AT-1 had a lower shape factor and a greater area as compared with the more highly metastatic Mat-Lu subline. No significant difference in area or shape factor was detected between the AT-1 cell line and the highly metastatic Mat-LyLu line. However, the lowly metastatic AT-1 line had less motility as compared with the Mat-Lu and Mat-LyLu lines. This study revealed that metastatic potential could be partially predicted via area and shape factor and accurately predicted via cell motility.

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma

PubMed Central

Zhang, Shile; Wei, Jun S.; Li, Samuel Q.; Badgett, Tom C.; Song, Young K.; Agarwal, Saurabh; Coarfa, Cristian; Tolman, Catherine; Hurd, Laura; Liao, Hongling; He, Jianbin; Wen, Xinyu; Liu, Zhihui; Thiele, Carol J.; Westermann, Frank; Asgharzadeh, Shahab; Seeger, Robert C.; Maris, John M.; Auvil, Jamie M Guidry; Smith, Malcolm A; Kolaczyk, Eric D; Shohet, Jason; Khan, Javed

2016-01-01

The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p≤0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification. PMID:26683771

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma.

PubMed

Zhang, Shile; Wei, Jun S; Li, Samuel Q; Badgett, Tom C; Song, Young K; Agarwal, Saurabh; Coarfa, Cristian; Tolman, Catherine; Hurd, Laura; Liao, Hongling; He, Jianbin; Wen, Xinyu; Liu, Zhihui; Thiele, Carol J; Westermann, Frank; Asgharzadeh, Shahab; Seeger, Robert C; Maris, John M; Guidry Auvil, Jamie M; Smith, Malcolm A; Kolaczyk, Eric D; Shohet, Jason; Khan, Javed

2016-02-28

The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates that MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p ≤ 0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification. Published by Elsevier Ireland Ltd.

Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

PubMed Central

Aguado, Brian A.; Caffe, Jordan R.; Nanavati, Dhaval; Rao, Shreyas S.; Bushnell, Grace G.; Azarin, Samira M.; Shea, Lonnie D.

2016-01-01

Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche. PMID:26844426

Metastatic rhabdomyosarcoma to the breast.

PubMed

Sheen-Chen, Shyr-Ming; Eng, Hock-Liew; Ko, Sheung-Fat

2005-01-01

Secondary malignancy metastatic to the breast is uncommon, with an incidence of 0.5% to 3% of patients with extramammary malignancy. Although rhabdomyosarcoma is a common aggressive primary malignancy in the pediatric age group, metastatic deposits to the breast rarely occur and are mainly seen in adolescent girls. Here, we report an intriguing, rare adult case with metastasis to the breast from nasal rhabdomyosarcoma. A 31-year-old woman with the complaint of right neck mass noted recently came to this hospital for help. She had a history of nasal malignancy treated with radiotherapy in another hospital three months previously. Physical examination revealed multiple neck masses at bilateral neck areas. Bilateral neck dissection was performed and rhabdomyosarcoma, metastatic to lymph node, was the final diagnosis. One year after operation, the patient felt a large lump in her left breast. Surgical excision was performed and histological analysis was consistent with rhabdomyoblastic origin. Secondary malignancy metastatic to the breast is uncommon, yet this entity does exist. In view of the therapeutic implication, a metastatic breast lesion should not be mistaken as the primary breast carcinoma. Only with the awareness of such a possibility can prompt diagnosis and optimal treatment be achieved.

Group B streptococcal metastatic endophthalmitis.

PubMed

Nagelberg, H P; Petashnick, D E; To, K W; Woodcome, H A

1994-04-15

Reports of invasive Group B Streptococcus infection in adults with underlying medical conditions have been increasing. Ocular infection with this organism is unusual. Metastatic endophthalmitis in adults caused by this organism has been reported rarely and has only been associated with endocarditis. We encountered two cases of Group B streptococcal metastatic endophthalmitis in adults who did not have endocarditis. These cases reflect the increasing incidence of invasive Group B Streptococcus infection with its varying manifestations. Additionally, they emphasize the importance of considering this pathogen as a cause of metastatic endophthalmitis in adults with predisposing illnesses.

Novel metastatic models of esophageal adenocarcinoma derived from FLO-1 cells highlight the importance of E-cadherin in cancer metastasis.

PubMed

Liu, David S; Hoefnagel, Sanne J M; Fisher, Oliver M; Krishnadath, Kausilia K; Montgomery, Karen G; Busuttil, Rita A; Colebatch, Andrew J; Read, Matthew; Duong, Cuong P; Phillips, Wayne A; Clemons, Nicholas J

2016-12-13

There is currently a paucity of preclinical models available to study the metastatic process in esophageal cancer. Here we report FLO-1, and its isogenic derivative FLO-1LM, as two spontaneously metastatic cell line models of human esophageal adenocarcinoma. We show that FLO-1 has undergone epithelial-mesenchymal transition and metastasizes following subcutaneous injection in mice. FLO-1LM, derived from a FLO-1 liver metastasis, has markedly enhanced proliferative, clonogenic, anti-apoptotic, invasive, immune-tolerant and metastatic potential. Genome-wide RNAseq profiling revealed a significant enrichment of metastasis-related pathways in FLO-1LM cells. Moreover, CDH1, which encodes the adhesion molecule E-cadherin, was the most significantly downregulated gene in FLO-1LM compared to FLO-1. Consistent with this, repression of E-cadherin expression in FLO-1 cells resulted in increased metastatic activity. Importantly, reduced E-cadherin expression is commonly reported in esophageal adenocarcinoma and independently predicts poor patient survival. Collectively, these findings highlight the biological importance of E-cadherin activity in the pathogenesis of metastatic esophageal adenocarcinoma and validate the utility of FLO-1 parental and FLO-1LM cells as preclinical models of metastasis in this disease.

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

Diagnosis of metastatic pancreatic mesenchymal tumors by endoscopic ultrasound-guided fine-needle aspiration.

PubMed

Varghese, Linda; Ngae, Min Yi; Wilson, Andrew P; Crowder, Clinton D; Gulbahce, H Evin; Pambuccian, Stefan E

2009-11-01

Involvement of the pancreas by metastatic sarcoma is rare, and can prove challenging to differentiate from sarcomatoid carcinomas which occur more commonly. The endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) technique has been successfully used for the diagnosis of pancreatic carcinomas whether primary or metastatic, and is now considered the most effective noninvasive method for the identification of pancreatic metastases. However, to date very few reports detail the diagnosis of mesenchymal neoplasms by EUS-FNA. Herein, we report a series of four patients who underwent EUS-FNA of the pancreas, where the diagnosis of metastatic sarcoma was made based on morphology and ancillary studies. The cases include metastases of leiomyosarcoma, liposarcoma, alveolar rhabdomyosarcoma, and solitary fibrous tumor. The history of a primary sarcoma of the chest wall, mediastinum, and respectively lower extremity was known for the first three of these patients while in the case of the solitary fibrous tumor a remote history of a paraspinal "hemangiopericytoma" was only elicited after the EUS-FNA diagnosis was made. We conclude that EUS-FNA is efficient and accurate in providing a diagnosis of sarcoma, even in patients without a known primary sarcoma, thus allowing institution of therapy without additional biopsies.

Utility of GATA3 in the differential diagnosis of pheochromocytoma.

PubMed

Perrino, Carmen M; Ho, Alex; Dall, Christopher P; Zynger, Debra L

2017-09-01

GATA3 is a relatively new immunohistochemical marker which shows consistent nuclear expression in a variety of tumours, including breast and urothelial carcinoma. The staining pattern of GATA3 in adrenal lesions is not well established. We aim to describe the expression of GATA3 in adrenal tumours and determine if there is differential staining between pheochromocytoma and adrenal cortical carcinoma. A retrospective search was performed to identify 74 adrenal lesions which were tested immunohistochemically for GATA3 expression. GATA3 was negative in 90% of adrenal cortical carcinoma. In contrast, pheochromocytomas were frequently positive (71%), including benign pheochromocytoma, pheochromocytoma with features concerning for malignancy, malignant (metastatic) pheochromocytoma and composite pheochromocytoma with ganglioneuroma. Metastatic lung adenocarcinoma in the adrenal gland had occasional (36%) expression, while metastatic clear cell renal cell carcinoma in the adrenal gland did not express GATA3. As the most common pitfall in diagnosing adrenal cortical carcinoma is mistaking it for pheochromocytoma or vice versa, GATA3 may be useful in narrowing the differential diagnosis as a part of a panel of immunohistochemical markers. However, occasional GATA3 expression in the most common source of metastases within the adrenal gland, metastatic pulmonary adenocarcinoma, may confound the diagnosis due to the overlapping expression with pheochromocytoma and other carcinomas. © 2017 John Wiley & Sons Ltd.

Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche.

PubMed

Aguado, Brian A; Caffe, Jordan R; Nanavati, Dhaval; Rao, Shreyas S; Bushnell, Grace G; Azarin, Samira M; Shea, Lonnie D

2016-03-01

Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM-coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche. The pre-metastatic niche consists partially of ECM proteins that promote metastatic cell colonization to a target organ. We present a biomaterials-based approach to mimic this niche and identify ECM mediators of colonization. Using murine breast cancer models, we implanted microporous PCL scaffolds to recruit colonizing tumor cells in vivo. As a strategy to modulate colonization, we coated scaffolds with various ECM proteins, including decellularized lung and liver matrix from

Metastatic pattern and DNA ploidy in stage IV breast cancer at initial diagnosis. Relation to response and survival.

PubMed

De Lena, M; Romero, A; Rabinovich, M; Leone, B; Vallejo, C; Machiavelli, M; Cuevas, M; Rodriguez, R; Lacava, J; Perez, J

1993-06-01

Sixty-nine patients with metastatic breast cancer (MBC) at initial diagnosis were analyzed to verify if metastatic pattern and clinical outcome are related to DNA ploidy determined by flow cytometry (FCM). Characteristics of 55 fully evaluable patients were as follows: median age: 61 years; postmenopausal: 75%; bone-only metastases (BM): 60%; extraosseous-only metastases (EM): 40%. Overall response rates (CR + PR) obtained with different chemotherapies and/or hormonal therapies were 58% and 68% for patients with BM and EM, respectively. Sixty percent of specimens resulted aneuploid, and the mean coefficient of variation of the complete series was 5.1%. In the whole group of patients DNA ploidy of primary tumor did not predict the metastatic pattern and had no influence upon response to treatment, duration of response, time to progression, and overall survival. When analyses were carried out according to metastatic pattern, those patients with BM showed similar results. However, within the group with EM, those with diploid tumors presented a significantly better survival (median 18 vs 13 months, p = .04). FCM-DNA analysis seems to identify a subgroup of patients with poor prognosis constituted by those who had aneuploid primary tumors and metastases to extraosseous sites.

Emerging Therapies in Metastatic Prostate Cancer.

PubMed

Sonnenburg, Daniel W; Morgans, Alicia K

2018-04-11

In the last decade, there have been multiple landmark therapeutic advances for the treatment of metastatic prostate cancer, both in the castration-resistant and hormone-sensitive setting. In this review, we highlight recent progress and ongoing trials for metastatic prostate cancer, including advances in chemotherapy, androgen receptor-directed therapy, targeted therapies, and immunotherapy. Several landmark studies for men with metastatic hormone-sensitive prostate cancer demonstrated improvement in overall survival with the addition of docetaxel chemotherapy or abiraterone acetate to standard androgen deprivation therapy. A single-arm phase 2 study of the PARP inhibitor olaparib demonstrated high response rates and more favorable progression-free and overall survival for men with metastatic castration-resistant prostate cancer and DNA repair defects treated with olaparib compared with men without DNA repair defects. Multiple ongoing clinical trials are investigating novel hormonal therapies and combinations of chemotherapy, targeted small molecules, immunotherapy, and radiopharmaceuticals. Progress continues to be made in the treatment of metastatic prostate cancer, and ongoing clinical trials continue to investigate novel agents and approaches to treatment.

Merkel Cell Spinal Metastasis: Management in the Setting of a Poor Prognosis.

PubMed

Goodwin, C Rory; Mehta, Ankit I; Adogwa, Owoicho; Sarabia-Estrada, Rachel; Sciubba, Daniel M

2015-08-01

Study Design Case report. Objective Merkel cell carcinoma is an aggressive neuroendocrine carcinoma with a poor prognosis. Metastatic epidural spinal cord compression (MESCC) is a debilitating disease causing neurologic deficits. The surgical management for MESCC depends on pathology. Methods We report a case of Merkel cell carcinoma of the spine and evaluate the treatment paradigms utilized in the prior reports. Result A 76-year-old man with a history of Merkel cell carcinoma presented with 2-week history of progressive difficulty ambulating and a solitary T5 epidural mass encasing the spinal cord. The patient underwent a T5 corpectomy with cage placement and T3 to T7 posterior fusion with postoperative neurologic improvement and a return to ambulation. Three weeks postoperatively, the patient re-presented with new-onset weakness and widespread metastatic spinal disease with epidural compression at the T8 level. Six weeks postoperatively, he was placed in hospice care. Conclusion Prior reports in the literature demonstrated a poor prognosis for Merkel cell carcinoma metastasis to the spine with survival ranging from 1 to 9 months after diagnosis. Although neurologic decline necessitates a surgical intervention, the assessment of operative benefit should take into account the prognosis associated with the primary tumor subtype.

Management of metastatic renal cell carcinoma patients with poor-risk features: current status and future perspectives.

PubMed

Santoni, Matteo; De Tursi, Michele; Felici, Alessandra; Lo Re, Giovanni; Ricotta, Riccardo; Ruggeri, Enzo Maria; Sabbatini, Roberto; Santini, Daniele; Vaccaro, Vanja; Milella, Michele

2013-06-01

With seven agents approved for renal cell carcinoma within the past few years, there has undoubtedly been progress in treating this disease. However, patients with poor-risk features remain a challenging and difficult-to-treat population, with the mTOR inhibitor, temsirolimus, the only agent approved in the first-line setting. Phase III trial data are still lacking VEGF-pathway inhibitors in patients with poor prognostic features. Poor-risk patients need to be considered as a heterogeneous population. Further understanding of biomarkers can lead to a better selection of patients who may benefit the most from treatment and improvements in prognosis. The presence of poor Karnofsky scores and liver or CNS disease may affect the outcome of these patients much more than other identified factors. This consideration may provide the rationale to further stratify poor-risk patients further subgroups destined to receive either cure or palliation.

Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin

PubMed Central

Todorovic, Vesna; Sersa, Gregor; Mlakar, Vid; Glavac, Damjan; Cemazar, Maja

2012-01-01

Background Electrochemotherapy is a local treatment combining chemotherapy and electroporation and is highly effective treatment approach for subcutaneous tumours of various histologies. Contrary to surgery and radiation, the effect of electrochemotherapy on metastatic potential of tumour cells has not been extensively studied. The aim of the study was to evaluate the effect of electrochemotherapy with bleomycin on the metastatic potential of human melanoma cells in vitro. Materials and methods Viable cells 48 hours after electrochemotherapy were tested for their ability to migrate and invade through Matrigel coated porous membrane. In addition, microarray analysis and quantitative Real-Time PCR were used to detect changes in gene expression after electrochemotherapy. Results Cell migration and invasion were not changed in melanoma cells surviving electrochemotherapy. Interestingly, only a low number of tumourigenesis related genes was differentially expressed after electrochemotherapy. Conclusions Our data suggest that metastatic potential of human melanoma cells is not affected by electrochemotherapy with bleomycin, confirming safe role of electrochemotherapy in the clinics. PMID:22933978

Assessment of the tumourigenic and metastatic properties of SK-MEL28 melanoma cells surviving electrochemotherapy with bleomycin.

PubMed

Todorovic, Vesna; Sersa, Gregor; Mlakar, Vid; Glavac, Damjan; Cemazar, Maja

2012-03-01

Electrochemotherapy is a local treatment combining chemotherapy and electroporation and is highly effective treatment approach for subcutaneous tumours of various histologies. Contrary to surgery and radiation, the effect of electrochemotherapy on metastatic potential of tumour cells has not been extensively studied. The aim of the study was to evaluate the effect of electrochemotherapy with bleomycin on the metastatic potential of human melanoma cells in vitro. Viable cells 48 hours after electrochemotherapy were tested for their ability to migrate and invade through Matrigel coated porous membrane. In addition, microarray analysis and quantitative Real-Time PCR were used to detect changes in gene expression after electrochemotherapy. Cell migration and invasion were not changed in melanoma cells surviving electrochemotherapy. Interestingly, only a low number of tumourigenesis related genes was differentially expressed after electrochemotherapy. Our data suggest that metastatic potential of human melanoma cells is not affected by electrochemotherapy with bleomycin, confirming safe role of electrochemotherapy in the clinics.

Sudden Onset of Brain Metastasis despite the Use of Vemurafenib for Another Metastatic Lesion in Malignant Melanoma Patients.

PubMed

Imafuku, Keisuke; Yoshino, Koji; Yamaguchi, Kei; Tsuboi, Satoshi; Ohara, Kuniaki; Hata, Hiroo

2017-01-01

Vemurafenib is an inhibitor of the BRAF mutation and has been approved by the Food and Drug Administration as a treatment option for patients with unresectable melanoma without brain metastasis. In the literature, vemurafenib has been reported to be also effective against brain metastasis. We encountered 3 cases with brain metastasis on vemurafenib therapy. In these cases, vemurafenib was clinically effective against metastatic lesions other than those in the brain. The brain lesions developed after the metastatic lesion had occurred. Therefore, we assume that the melanomas of the patients acquired resistance against vemurafenib. The brain metastases were treated with the cyberknife. Patients 1 and 2 without LDH elevation are still alive, but patient 3 with abnormal LDH elevation died despite the treatment. We need to carefully follow patients on vemurafenib therapy because brain metastasis can suddenly occur even if the metastatic lesion has decreased clinically. The therapeutic effect of vemurafenib against brain metastasis is poor in cases with LDH elevation.

FDG-PET/CT and FLT-PET/CT for differentiating between lipid-poor benign and malignant adrenal tumours.

PubMed

Nakajo, Masatoyo; Jinguji, Megumi; Fukukura, Yoshihiko; Kajiya, Yoriko; Tani, Atushi; Nakajo, Masayuki; Nakabeppu, Yoshiaki; Arimura, Hiroshi; Nishio, Yoshihiko; Nakamura, Fumihiko; Yoshiura, Takashi

2015-12-01

To compare F-18-fluorodeoxyglucose (FDG) and F-18-fluorothymidine (FLT) PET/CT examinations for differentiating between benign and malignant adrenal tumours. Thirty lipid-poor benign and 11 malignant tumours of 40 patients were included. FDG- and FLT-based indices including visual score, maximum standardized uptake value (SUVmax) and FDG adrenal lesion/liver SUVmax (A/L SUVmax) or FLT adrenal lesion/back muscle SUVmax (A/B SUVmax) ratio were compared between benign and malignant tumours using the Mann-Whitney's U or Wilcoxon signed-rank test, and their diagnostic performances were evaluated by means of the area under the curve (AUC) values derived from the receiver operating characteristic analysis. All indices were significantly higher in malignant than benign tumours on both images (p < 0.05 each). On FDG-PET/CT, the sensitivity, specificity, and accuracy were 91 %, 63 % and 71 % for visual score, 91 %, 67 % and 73 % for SUVmax, and 100 %, 70 % and 78 % for A/L SUVmax ratio, respectively. On FLT-PET/CT, they were 100 %, 97 % and 98 % for visual score, SUVmax and A/B SUVmax ratio, respectively. All FLT indices were significantly higher than those of FDG in AUC (p < 0.05 each). FLT-PET/CT may be superior to FDG-PET/CT in differentiating lipid-poor benign from malignant adrenal tumours because of higher specificity and accuracy. • All FDG indices were significantly higher in malignant than in benign tumours. • All FLT indices were significantly higher in malignant than in benign tumours. • All FLT indices were significantly higher than those of FDG in AUC.

Pleiotropic function of ezrin in human metastatic melanomas.

PubMed

Federici, Cristina; Brambilla, Daria; Lozupone, Francesco; Matarrese, Paola; de Milito, Angelo; Lugini, Luana; Iessi, Elisabetta; Cecchetti, Serena; Marino, Marialucia; Perdicchio, Maurizio; Logozzi, Mariantonia; Spada, Massimo; Malorni, Walter; Fais, Stefano

2009-06-15

The membrane cytoskeleton cross-linker, ezrin, has recently been depicted as a key regulator in the progression and metastasis of several pediatric tumors. Less defined appears the role of ezrin in human adult tumors, especially melanoma. We therefore addressed ezrin involvement in the metastatic phenotype of human adult metastatic melanoma cells. Our results show that cells resected from melanoma metastatic lesions of patients, display marked metastatic spreading capacity in SCID mice organs. Stable transfection of human melanoma cells with an ezrin deletion mutant comprising only 146 N-terminal aminoacids led to the abolishment of metastatic dissemination. In vitro experiments revealed ezrin direct molecular interactions with molecules related to metastatic functions such as CD44, merlin and Lamp-1, consistent with its participation to the formation of phagocitic vacuoles, vesicular sorting and migration capacities of melanoma cells. Moreover, the ezrin fragment capable of binding to CD44 was shorter than that previously reported, and transfection with the ezrin deletion mutant abrogated plasma membrane Lamp-1 recruitment. This study highlights key involvement of ezrin in a complex machinery, which allows metastatic cancer cells to migrate, invade and survive in very unfavorable conditions. Our in vivo and in vitro data reveal that ezrin is the hub of the metastatic behavior also in human adult tumors. Copyright 2008 UICC.

Hilar fat infiltration: A new prognostic factor in metastatic clear cell renal cell carcinoma with first-line sunitinib treatment.

PubMed

Kammerer-Jacquet, Solène-Florence; Brunot, Angelique; Bensalah, Karim; Campillo-Gimenez, Boris; Lefort, Mathilde; Bayat, Sahar; Ravaud, Alain; Dupuis, Frantz; Yacoub, Mokrane; Verhoest, Gregory; Peyronnet, Benoit; Mathieu, Romain; Lespagnol, Alexandra; Mosser, Jean; Edeline, Julien; Laguerre, Brigitte; Bernhard, Jean-Christophe; Rioux-Leclercq, Nathalie

2017-10-01

The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib. In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect. HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival. HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Characteristics of metastasis in the breast from extramammary malignancies.

PubMed

Lee, Se Kyung; Kim, Wan Wook; Kim, Sung Hoon; Hur, Sung Mo; Kim, Sangmin; Choi, Jae Hyuck; Cho, Eun Yoon; Han, Soo Yeon; Hahn, Boo-Kyung; Choe, Jun-Ho; Kim, Jung-Han; Kim, Jee Soo; Lee, Jeong Eon; Nam, Seok Jin; Yang, Jung-Hyun

2010-02-01

Breast metastasis from extramammary neoplasm is rare. We present the cases of metastasis to the breast after review of results in one institute and we want to show the difference of previous report. The surgical and pathology databases of Samsung Medical Center from November 1994 to March 2009 were investigated to identify all patients with a diagnosis of metastasis to the breast. Thirty-three patients with breast metastases from extramammary neoplasm were studied. Gastric carcinoma was most common metastatic origin in this study. There were four cases with microcalcifications in their metastatic lesions. This is the first report of microcalcification of metastatic lesions to the breast from hepatocellular carcinoma and gastric cancer. Pathologic examination and considering known clinical history may be helpful to differentiate the primary breast cancer and metastatic cancer. Metastasis to the breast from an extramammary neoplasm usually indicates disseminated metastatic disease and a poor prognosis. An accurate diagnosis of breast metastases, differentiating primary from metastatic breast carcinoma, is important for proper management.

Significance of sarcopenia as a prognostic factor for metastatic urothelial carcinoma patients treated with systemic chemotherapy.

PubMed

Abe, Hideyuki; Takei, Kohei; Uematsu, Toshitaka; Tokura, Yuumi; Suzuki, Issei; Sakamoto, Kazumasa; Nishihara, Daisaku; Yamaguchi, Yoshiyuki; Mizuno, Tomoya; Nukui, Akinori; Kobayashi, Minoru; Kamai, Takao

2018-04-01

Recently, numerous studies have reported an association between sarcopenia and poor outcomes in various kinds of malignancies. We investigated whether sarcopenia predicts the survival of patients with metastatic urothelial carcinoma who underwent systemic chemotherapy. We reviewed 87 metastatic urothelial carcinoma patients who underwent chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin for cisplatin-unfit patients) between 2007 and 2015. A computed tomography scan prior to chemotherapy was used for evaluating sarcopenia, and we measured three cross-sectional areas of skeletal muscle at the third lumbar vertebra and calculated the skeletal muscle index (SMI), the paraspinal muscle index (PSMI), and the total psoas area (TPA) of each patient. Predictive values of survival were assessed using Cox regression analysis. The median overall survival (OS) was 16 months (95% CI 13.5-18). Although SMI alone was not a significant predictor of shorter OS (P = 0.117) in univariate analysis, SMI stratified by the value of the body mass index (BMI) was a significant predictor of shorter OS in univariate analysis (P = 0.037) and was also an independent predictor of shorter OS in multivariate analysis (P = 0.026). PSMI and TPA were not significant prognostic factors even when stratified by BMI (P = 0.294 and 0.448), respectively. Neither PSMI nor TPA could substitute SMI as a predictor for poor outcomes in metastatic urothelial carcinoma patients treated with systemic chemotherapy in our study. SMI stratified by BMI is a useful predictor of prognosis in these patients.

Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma.

PubMed

Elloul, Sivan; Elstrand, Mari Bukholt; Nesland, Jahn M; Tropé, Claes G; Kvalheim, Gunnar; Goldberg, Iris; Reich, Reuven; Davidson, Ben

2005-04-15

.07). High Snail mRNA expression predicted shorter effusion-free survival (P = 0.008), disease-free survival (P = 0.03), and overall survival (P = 0.008) in patients with breast carcinoma. Transcription factors that regulate E-cadherin were expressed differentially in metastatic ovarian and breast carcinoma. Snail may predict a poor outcome in patients who have breast carcinoma metastatic to effusions. E-cadherin expression generally was conserved in effusions from patients with ovarian carcinoma, but the subset of patients with postulated Sip1-induced repression of this adhesion molecule had a significantly worse outcome. This finding was in agreement with the stronger suppression of E-cadherin by Snail and Sip1 in breast carcinoma effusions, a clinical condition associated with extremely poor survival. (c) 2005 American Cancer Society.

Management of locally advanced and metastatic colon cancer in elderly patients.

PubMed

Kurniali, Peter C; Hrinczenko, Borys; Al-Janadi, Anas

2014-02-28

Colon cancer is the second leading cause of cancer mortality in the United States with a median age at diagnosis of 69 years. Sixty percent are diagnosed over the age of 65 years and 36% are 75 years or older. At diagnosis, approximately 58% of patients will have locally advanced and metastatic disease, for which systemic chemotherapy has been shown to improve survival. Treatment of cancer in elderly patients is more challenging due to multiple factors, including disabling co-morbidities as well as a decline in organ function. Cancer treatment of elderly patients is often associated with more toxicities that may lead to frequent hospitalizations. In locally advanced disease, fewer older patients receive adjuvant chemotherapy despite survival benefit and similar toxicity when compared to their younger counterparts. A survival benefit is also observed in the palliative chemotherapy setting for elderly patients with metastatic disease. When treating elderly patients with colon cancer, one has to consider drug pharmacokinetics and pharmacodynamics. Since chronological age is a poor marker of a patient's functional status, several methods of functional assessment including performance status and activities of daily living (ADL) or instrumental ADL, or even a comprehensive geriatric assessment, may be used. There is no ideal chemotherapy regimen that fits all elderly patients and so a regimen needs to be tailored for each individual. Important considerations when treating elderly patients include convenience and tolerability. This review will discuss approaches to the management of elderly patients with locally advanced and metastatic colon cancer.

Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer

PubMed Central

Kopetz, Scott; Desai, Jayesh; Chan, Emily; Hecht, Joel Randolph; O'Dwyer, Peter J.; Maru, Dipen; Morris, Van; Janku, Filip; Dasari, Arvind; Chung, Woonbook; Issa, Jean-Pierre J.; Gibbs, Peter; James, Brian; Powis, Garth; Nolop, Keith B.; Bhattacharya, Suman; Saltz, Leonard

2015-01-01

Purpose BRAF V600E mutation is seen in 5% to 8% of patients with metastatic colorectal cancer (CRC) and is associated with poor prognosis. Vemurafenib, an oral BRAF V600 inhibitor, has pronounced activity in patients with metastatic melanoma, but its activity in patients with BRAF V600E–positive metastatic CRC was unknown. Patients and Methods In this multi-institutional, open-label study, patients with metastatic CRC with BRAF V600 mutations were recruited to an expansion cohort at the previously determined maximum-tolerated dose of 960 mg orally twice a day. Results Twenty-one patients were enrolled, of whom 20 had received at least one prior metastatic chemotherapy regimen. Grade 3 toxicities included keratoacanthomas, rash, fatigue, and arthralgia. Of the 21 patients treated, one patient had a confirmed partial response (5%; 95% CI, 1% to 24%) and seven other patients had stable disease by RECIST criteria. Median progression-free survival was 2.1 months. Patterns of concurrent mutations, microsatellite instability status, CpG island methylation status, PTEN loss, EGFR expression, and copy number alterations were not associated with clinical benefit. In contrast to prior expectations, concurrent KRAS and NRAS mutations were detected at low allele frequency in a subset of the patients' tumors (median, 0.21% allele frequency) and were apparent mechanisms of acquired resistance in vemurafenib-sensitive patient-derived xenograft models. Conclusion In marked contrast to the results seen in patients with BRAF V600E–mutant melanoma, single-agent vemurafenib did not show meaningful clinical activity in patients with BRAF V600E mutant CRC. Combination strategies are now under development and may be informed by the presence of intratumor heterogeneity of KRAS and NRAS mutations. PMID:26460303

Metastatic Cancer

Cancer.gov

Metastatic cancer is cancer that spreads from its site of origin to another part of the body. Learn how cancer spreads, possible symptoms, common sites where cancer spreads, and how to find out about treatment options.

Integrative Clinical Genomics of Metastatic Cancer

PubMed Central

Robinson, Dan R.; Wu, Yi-Mi; Lonigro, Robert J.; Vats, Pankaj; Cobain, Erin; Everett, Jessica; Cao, Xuhong; Rabban, Erica; Kumar-Sinha, Chandan; Raymond, Victoria; Schuetze, Scott; Alva, Ajjai; Siddiqui, Javed; Chugh, Rashmi; Worden, Francis; Zalupski, Mark M.; Innis, Jeffrey; Mody, Rajen J.; Tomlins, Scott A.; Lucas, David; Baker, Laurence H.; Ramnath, Nithya; Schott, Ann F.; Hayes, Daniel F.; Vijai, Joseph; Offit, Kenneth; Stoffel, Elena M.; Roberts, J. Scott; Smith, David C.; Kunju, Lakshmi P.; Talpaz, Moshe; Cieslik, Marcin; Chinnaiyan, Arul M.

2017-01-01

SUMMARY Metastasis is the primary cause of cancer-related deaths. While The Cancer Genome Atlas (TCGA) has sequenced primary tumor types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here, we perform whole exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing for the identification of gene fusions, pathway activation, and immune profiling. Integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers. PMID:28783718

Working after a metastatic cancer diagnosis: Factors affecting employment in the metastatic setting from ECOG-ACRIN's Symptom Outcomes and Practice Patterns study.

PubMed

Tevaarwerk, Amye J; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary E; Smith, Mary Lou; Cleeland, Charles S; Fisch, Michael J

2016-02-01

Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. A better understanding of how metastatic cancer affects employment is a necessary step toward the development of tools for assisting survivors in this important realm. The ECOG-ACRIN Symptom Outcomes and Practice Patterns study was analyzed to investigate what factors were associated with the employment of 680 metastatic cancer patients. Univariate and multivariate logistic regression analyses were conducted to compare patients stably working with patients no longer working. There were 668 metastatic working-age participants in the analysis: 236 (35%) worked full- or part-time, whereas 302 (45%) had stopped working because of illness. Overall, 58% reported some change in employment due to illness. A better performance status and non-Hispanic white ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis in the multivariate analysis. The disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. A significant percentage of the metastatic patients remained employed; increased symptom burden was associated with a change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working if this is desired. Improvements in symptom control and strategies developed to help address workplace difficulties have promise for improving this aspect of survivorship. © 2015 American Cancer Society.

Importance of Metastatic Lymph Node Ratio in Non-Metastatic, Lymph Node-Invaded Colon Cancer: A Clinical Trial

PubMed Central

Isik, Arda; Peker, Kemal; Firat, Deniz; Yilmaz, Bahri; Sayar, Ilyas; Idiz, Oguz; Cakir, Coskun; Demiryilmaz, Ismail; Yilmaz, Ismayil

2014-01-01

Background The aim of this study was to evaluate the prognostic importance of the metastatic lymph node ratio for stage III colon cancer patients and to find a cut-off value at which the overall survival and disease-free survival change. Material/Methods Patients with pathological stage III colon cancer were retrospectively evaluated for: age; preoperative values of Crp, Cea, Ca 19-9, and Afp; pathologic situation of vascular, perineural, lymphatic, and serosal involvement; and metastatic lymph node ratio values were calculated. Results The study included 58 stage III colon cancer patients: 20 (34.5%) females and 38 (65.5%) males were involved in the study. Multivariate analysis was applied to the following variables to evaluate significance for overall survival and disease-free survival: age, Crp, Cea, perineural invasion, and metastatic lymph node ratio. The metastatic lymph node ratio (<0.25 or ≥0.25) is the only independent variable significant for overall and disease-free survival. Conclusions Metastatic lymph node ratio is an ideal prognostic marker for stage III colon cancer patients, and 0.25 is the cut-off value for prognosis. PMID:25087904

Metastatic pancreatic carcinoma and bronchioloalveolar adenomas in an Egyptian fruit bat (Rousettus aegyptiacus).

PubMed

Cushing, Andrew C; Ossiboff, Robert; Buckles, Elizabeth; Abou-Madi, Noha

2013-09-01

An adult female, intact Egyptian fruit bat (Rousettus aegyptiacus) was presented for lethargy, anorexia, and markedly reduced flying activity. Physical and ultrasound examinations were suggestive of an abdominal mass with free fluid within the abdomen. Based on the poor and deteriorating clinical condition of the animal, euthanasia was elected. Gross necropsy revealed an irregular thickening at the root of the mesentery and a diffusely, dark-red liver with rounded hepatic margins. Histologic examination revealed extensive neoplastic effacement of the pancreas with invasion into the surrounding mesentery and mesenteric lymph nodes and metastatic spread to the liver. Based on the morphology of the neoplastic cells, the involvement of the pancreas, and immunohistochemistry, a diagnosis of metastatic pancreatic carcinoma was made. Additionally, two small neoplasms were identified in the lungs. These masses were distinct from the carcinoma, and their morphology was consistent with bronchioloalveolar adenomas. This is the first known report of either benign pulmonary lesions or pancreatic carcinomas in the order Chiroptera.

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

Imaging Nuclear-Cytoplasmic Dynamics in Primary and Metastatic Colon Cancer in Nude Mice.

PubMed

Hasegawa, Kosuke; Suetsugu, Atsushi; Nakamura, Miki; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Bouvet, Michael; Shimizu, Masahito; Hoffman, Robert M

2016-05-01

Colon cancer frequently results in metastasis to the liver, where it becomes the main cause of death. However, the cell cycle in primary tumors and metastases is poorly understood. We developed a mouse model of liver metastasis using the human colon cancer cell line HCT-116, which expresses green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm (HCT-116-GFP-RFP). HCT-116 GFP-RFP cells were injected into the spleen of nu/nu nude mice. HCT-116-GFP-RFP cells subsequently formed primary tumors in the spleen, as well as metastatic colonies in the liver and retroperitoneum by 28 days after cell transplantation. Using an Olympus FV1000 confocal microscope, it was possible to clearly image mitosis of the dual-colored colon cancer cells in the primary tumor as well as liver and other metastases. Multi-nucleate cancer cells, in addition to mono-nucleate cancer cells and their mitosis, were observed in the primary tumor and metastasis. Multi-nucleate HCT-116-GFP-RFP cells were also observed after culture of the primary and metastatic tumors. A similar ratio of mono-nucleate, multi-nucleate, and mitotic cells grew from the primary and metastatic tumors in culture, suggesting similarity of the nuclear-cytoplasmic dynamics of primary and metastatic cancer cells, further emphasizing the stochastic nature of metastasis. Our results demonstrate a similar heterogeneity of nuclear-cytoplasmic dynamics within primary tumors and metastases, which may be an important factor in the stochastic nature of metastasis. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Osteoradionecrosis of the upper cervical spine after radiation therapy for head and neck cancer: differentiation from recurrent or metastatic disease with MR imaging.

PubMed

Wu, Li-An; Liu, Hon-Man; Wang, Chun-Wei; Chen, Ya-Fang; Hong, Ruey-Long; Ko, Jenq-Yuh

2012-07-01

To compare the magnetic resonance (MR) imaging features of upper cervical spine osteoradionecrosis (ORN) with those of recurrent or metastatic disease after the treatment of head and neck malignancies. This retrospective study was approved by the hospital institutional review board, and the requirement to obtain informed consent was waived. From January 2005 to December 2010, 35 patients who had undergone irradiation of head and neck cancer and who had subsequent C1 or C2 lesions at MR imaging were enrolled. Pathology reports, clinical records, and follow-up MR images were reviewed to classify patients into one of two groups-those with ORN or those with recurrence. The MR imaging characteristics in these patients were evaluated. Statistical significance of intergroup differences was assessed by means of the Pearson χ2 or Fisher exact test for categorical variables and the two-sample t test for continuous variables. ORN was diagnosed in 20 of the 35 patients (57%), and recurrent or metastatic disease was diagnosed in 15 (43%). Ten of the 35 patients (29%) had undergone biopsy of the cervical spine or paraspinal soft tissue. The MR images in the ORN group showed significantly more contiguous involvement of the atlantoaxial or atlanto-occipital bones with intervening joint change (P<.001), more cases of vertebral body collapse (P<.01), more bilateral symmetric involvement of the vertebral body (P<.01), and continuation of vertebral body changes with posterior pharyngeal wall ulceration (P<.01). Posterior arch or other cervical level involvement, paraspinal solid mass, epidural involvement, lateral border cortical destruction, and cervical lymphadenopathy were noted more frequently in the recurrence group than in the ORN group (P=.03, P<.001, P=.02, P<.001, and P<.01, respectively). Various MR imaging characteristics can be used to help differentiate between cervical ORN and recurrent disease. © RSNA, 2012.

Vascular Functional Imaging and Physiological Environment of Hyperplasia, Non-Metastatic and Metastatic Breast Cancer

DTIC Science & Technology

1997-10-01

Specific Aim 1). The overall goal of this research proposal is to use noninvasive Magnetic Resonance (MR) Imaging (I) and Spectroscopy (S) to answer the... spectroscopy in establishing the role of nm23 genes in tumor metabolism and metastatic dissemination. INTRODUCTION Despite continuing advances in the...cellular mechanisms by which the nm23 protein suppresses metastatic phenotypic expression is as yet unknown. Here we have used 3 1P NMR spectroscopy to

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Working after a metastatic cancer diagnosis: factors affecting employment in the metastatic setting from ECOG’s Symptom Outcomes and Practice Patterns (SOAPP) study

PubMed Central

Tevaarwerk, Amye; Lee, Ju-Whei; Terhaar, Abigail; Sesto, Mary; Smith, Mary Lou; Cleeland, Charles; Fisch, Michael

2015-01-01

Background Improved survival for individuals with metastatic cancer accentuates the importance of employment for cancer survivors. Better understanding of how metastatic cancer affects employment is a necessary step towards the development of tools to assist survivors in this important realm. Methods We analyzed the Eastern Cooperative Oncology Group’s “Symptom Outcomes and Practice Patterns (SOAPP)” study to investigate what factors were associated with employment of 680 metastatic cancer patients. Univariable and multivariable logistic regression analyses were conducted to compare patients stably working (Group A) to patients no longer working (Group B). Results There were 668 metastatic working-age participants in our analysis; 236 (35%) worked full or part-time while 302 (45%) stopped working due to illness. Overall, 58% reported some change in employment due to illness. Better performance status and non-Hispanic White ethnicity/race were significantly associated with continuing to work despite a metastatic cancer diagnosis on multivariable analysis. Disease type, time since metastatic diagnosis, number of metastatic sites, location of metastatic disease, and treatment status had no significant impact. Among the potentially modifiable factors, receiving hormonal treatment (if a viable option) and decreasing symptom interference were associated with continuing to work. Conclusions A significant percentage of metastatic patients remain employed; symptom burden was associated with change to no longer working. Modifiable factors resulting in work interference should be minimized so that patients with metastatic disease may continue working, if desired. Improvements in symptom control and strategies developed to help address work place difficulties have promise to improve this aspect of survivorship. PMID:26687819

A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145.

PubMed

Jacob, A N; Kalapurakal, J; Davidson, W R; Kandpal, G; Dunson, N; Prashar, Y; Kandpal, R P

1999-01-01

We have used a modified differential display PCR protocol for isolating 3' restriction fragments of cDNAs specifically expressed or overexpressed in metastatic prostate carcinoma cell line DU145. Several cDNA fragments were identified that matched to milk fat globule protein, UFO/Axl, a receptor tyrosine kinase, human homologue of a Xenopus maternal transcript, laminin and laminin receptor, human carcinoma-associated antigen, and some expressed sequence tags. The transcript for milk fat globule protein, a marker protein shown to be overexpressed in breast tumors, was elevated in DU145 cells. The expression of UFO/Axl, a receptor tyrosine kinase, was considerably higher in DU145 cells as compared to normal prostate cells and prostatic carcinoma cell line PC-3. The overexpression of UFO oncogene in DU145 cells is discussed in the context of prostate cancer metastasis.

Surfactant functionalization induces robust, differential adhesion of tumor cells and blood cells to charged nanotube-coated biomaterials under flow.

PubMed

Mitchell, Michael J; Castellanos, Carlos A; King, Michael R

2015-07-01

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion. Copyright © 2015 Elsevier Ltd. All rights reserved.

Surfactant Functionalization Induces Robust, Differential Adhesion of Tumor Cells and Blood Cells to Charged Nanotube-Coated Biomaterials Under Flow

PubMed Central

Mitchell, Michael J.; Castellanos, Carlos A.; King, Michael R.

2015-01-01

The metastatic spread of cancer cells from the primary tumor to distant sites leads to a poor prognosis in cancers originating from multiple organs. Increasing evidence has linked selectin-based adhesion between circulating tumor cells (CTCs) and endothelial cells of the microvasculature to metastatic dissemination, in a manner similar to leukocyte adhesion during inflammation. Functionalized biomaterial surfaces hold promise as a diagnostic tool to separate CTCs and potentially treat metastasis, utilizing antibody and selectin-mediated interactions for cell capture under flow. However, capture at high purity levels is challenged by the fact that CTCs and leukocytes both possess selectin ligands. Here, a straightforward technique to functionalize and alter the charge of naturally occurring halloysite nanotubes using surfactants is reported to induce robust, differential adhesion of tumor cells and blood cells to nanotube-coated surfaces under flow. Negatively charged sodium dodecanoate-functionalized nanotubes simultaneously enhanced tumor cell capture while negating leukocyte adhesion, both in the presence and absence of adhesion proteins, and can be utilized to isolate circulating tumor cells regardless of biomarker expression. Conversely, diminishing nanotube charge via functionalization with decyltrimethylammonium bromide both abolished tumor cell capture while promoting leukocyte adhesion. PMID:25934290

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kang, Chung-Jan; Head and Neck Oncology Group, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan; Lin, Chien-Yu

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%),more » 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.« less

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

2018-01-19

Poorly Differentiated Malignant 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.)

Tumor-educated mesenchymal stem cells promote pro-metastatic phenotype

PubMed Central

Passaro, Nunzia; Zannetti, Antonella

2017-01-01

Multipotent mesenchymal stem cells (MSCs) are recruited into tumor microenvironment in response to multiple signals produced by cancer cells. Molecules involved in their homing to tumors are the same inflammatory mediators produced by injured tissues: chemokines, cytokines and growth factors. When MSCs arrive into the tumor microenvironment these are “educated” to have pro-metastatic behaviour. Firstly, they promote cancer immunosuppression modulating both innate and adaptive immune systems. Moreover, tumor associated-MSCs trans-differentiating into cancer-associated fibroblasts can induce epithelial-mesenchymal-transition program in tumor cells. This process determinates a more aggressive phenotype of cancer cells by increasing their motility and invasiveness and favoring their dissemination to distant sites. In addition, MSCs are involved in the formation and modelling of pre-metastatic niches creating a supportive environment for colonization of circulating tumor cells. The development of novel therapeutic approaches targeting the different functions of MSCs in promoting tumor progression as well as the mechanisms underlying their activities could enhance the efficacy of conventional and immune anti-cancer therapies. Furthermore, many studies report the use of MSCs engineered to express different genes or as vehicle to specifically deliver novel drugs to tumors exploiting their strong tropism. Importantly, this approach can enhance local therapeutic efficacy and reduce the risk of systemic side effects. PMID:29069870

Utility of immunohistochemistry in distinguishing primary adenocarcinomas from metastatic breast carcinomas in the gastrointestinal tract.

PubMed

O'Connell, Fionnuala P; Wang, Helen H; Odze, Robert D

2005-03-01

Breast carcinoma often metastasizes to the gastrointestinal tract, especially the stomach, where it is frequently difficult to distinguish from a primary gastric carcinoma. To evaluate the utility of immunohistochemical stains in differentiating primary gastric carcinomas from metastatic breast carcinomas. Mucosal biopsy specimens from 47 adenocarcinomas involving the gastrointestinal tract (28 primary gastric carcinomas and 19 metastatic breast carcinomas) and 16 control cases of primary breast carcinomas without metastasis were immunohistochemically stained for estrogen receptor protein (ER), progesterone receptor protein (PR), gross cystic disease fluid protein (GCDFP), human epidermal growth factor receptor 2 protein, cytokeratin (CK) 5/6, CK/7, CK/20, a panel of mucin glycoprotein antigens (MUC2, MUC3, MUC5AC, and MUC6), monoclonal antibody DAS-1, and caudal-type homeobox transcription factor CDX2 and compared between primary and metastatic adenocarcinomas. Highly significant proportions of metastatic breast carcinomas were positive for ER (72%), PR (33%), GCDFP (78%), and CK5/6 (61%) compared with primary gastric carcinomas (ER, 0%; PR, 0%; GCDFP, 0%; and CK5/6, 14%) (P < .001, P = .002, P < .001, and P = .004, respectively). Of these immunostains, ER, PR, and GCDFP were 100% specific. Primary breast tumors and their metastases showed a similar phenotypic profile. In contrast, primary gastric carcinomas showed significantly higher proportions of cases that stained with CK20 (50%), MUC2 (54%), MUC5AC (71%), MUC6 (39%), DAS-1 (43%), and CDX2 (67%) compared with metastatic breast carcinomas (CK20, 0%; MUC2, 24%; MUC5AC, 6%; MUC6, 0%; DAS-1, 0%; and CDX2, 0%) (P = .001, P = .01, P < .001, P = .02, P = .009, and P < .001, respectively). No significant differences were observed with regard to any of the other immunostains (human epidermal growth factor receptor 2 protein, CK7, and MUC3) between the patient groups. Estrogen receptor protein, PR, GCDFP, CK5/6, CK20

CD147 and matrix-metalloproteinase-2 expression in metastatic and non-metastatic uveal melanomas.

PubMed

Lüke, Julia; Vukoja, Vlatka; Brandenbusch, Tim; Nassar, Khaled; Rohrbach, Jens Martin; Grisanti, Salvatore; Lüke, Matthias; Tura, Aysegül

2016-06-03

Extracellular matrix remodelling regulated by matrix-metalloproteinase (MMP) inducer (CD147) is a crucial process during tumor cell invasion and regulation of blood supply. In this study, we evaluated the correlation of CD147 and MMP-2 expression with major prognostic factors for uveal melanoma and the development of metastasis. The expression of CD147 and MMP-2 was analyzed in 49 samples of uveal melanomas. Triple immunofluorescence stainings using markers against glial cells (GFAP), endothelial cells (CD34) and macrophages (CD68) were performed to further analyse the exact localisation of CD147 and MMP-2 positivity. In 28 cases clinical metastatic disease were found. The remaining 21 cases showed no signs of metastatic disease for an average follow-up of 10 years. Correlation analysis (Pearson correlation) was performed to analyse the association of CD147 and MMP-2 expression with known prognostic factors, vasculogenic mimicry (VM), the mature vasculature (von Willebrand Factor) and tumor induced angiogenesis (by means of Endoglin expression). CD147 and MMP-2 were expressed in 47 (96.0 %) of the uveal melanomas. CD147 up-regulation was significantly correlated with a higher MMP-2 expression. The overall expression analysis revealed no significant difference in the metastatic (p = 0.777) and non-metastatic subgroup (p = 0.585). No correlation of CD147 expression and any system of blood supply was evident. In the non-metastatic sub-group a significant correlation of clustered CD147 positive cells with largest basal diameter (p = 0.039), height (p = 0.047) and TNM-stage (p = 0.013) was evident. These data may indicate that CD147 regulates MMP-2 expression in uveal melanoma cells.

Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

NASA Astrophysics Data System (ADS)

Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

2017-09-01

Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

Epidemiology and therapies for metastatic sarcoma

PubMed Central

Amankwah, Ernest K; Conley, Anthony P; Reed, Damon R

2013-01-01

Sarcomas are cancers arising from the mesenchymal layer that affect children, adolescents, young adults, and adults. Although most sarcomas are localized, many display a remarkable predilection for metastasis to the lungs, liver, bones, subcutaneous tissue, and lymph nodes. Additionally, many sarcoma patients presenting initially with localized disease may relapse at metastatic sites. While localized sarcomas can often be cured through surgery and often radiation, controversies exist over optimal management of patients with metastatic sarcoma. Combinations of chemotherapy are the most effective in many settings, and many promising new agents are under active investigation or are being explored in preclinical models. Metastatic sarcomas are excellent candidates for novel approaches with additional agents as they have demonstrated chemosensitivity and affect a portion of the population that is motivated toward curative therapy. In this paper, we provide an overview on the common sarcomas of childhood (rhabdomyosarcoma), adolescence, and young adults (osteosarcoma, Ewing sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumor) and older adults (leiomyosarcoma, liposarcoma, and undifferentiated high grade sarcoma) in terms of the epidemiology, current therapy, promising therapeutic directions and outcome with a focus on metastatic disease. Potential advances in terms of promising therapy and biologic insights may lead to more effective and safer therapies; however, more clinical trials and research are needed for patients with metastatic sarcoma. PMID:23700373

Trastuzumab and survival of patients with metastatic breast cancer.

PubMed

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without

Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer.

PubMed

Turner, Tia H; Alzubi, Mohammad A; Sohal, Sahib S; Olex, Amy L; Dozmorov, Mikhail G; Harrell, J Chuck

2018-03-12

Basal-like breast cancers are aggressive and often metastasize to vital organs. Treatment is largely limited to chemotherapy. This study aims to characterize the efficacy of cancer therapeutics in vitro and in vivo within the primary tumor and metastatic setting, using patient-derived xenograft (PDX) models. We employed two basal-like, triple-negative PDX models, WHIM2 and WHIM30. PDX cells, obtained from mammary tumors grown in mice, were treated with twelve cancer therapeutics to evaluate their cytotoxicity in vitro. Four of the effective drugs-carboplatin, cyclophosphamide, bortezomib, and dacarbazine-were tested in vivo for their efficacy in treating mammary tumors, and metastases generated by intracardiac injection of tumor cells. RNA sequencing showed that global gene expression of PDX cells grown in the mammary gland was similar to those tested in culture. In vitro, carboplatin was cytotoxic to WHIM30 but not WHIM2, whereas bortezomib, dacarbazine, and cyclophosphamide were cytotoxic to both lines. Yet, these drugs were ineffective in treating both primary and metastatic WHIM2 tumors in vivo. Carboplatin and cyclophosphamide were effective in treating WHIM30 mammary tumors and reducing metastatic burden in the brain, liver, and lungs. WHIM2 and WHIM30 metastases showed distinct patterns of cytokeratin and vimentin expression, regardless of treatment, suggesting that different tumor cell subpopulations may preferentially seed in different organs. This study highlights the utility of PDX models for studying the efficacy of therapeutics in reducing metastatic burden in specific organs. The differential treatment responses between two PDX models of the same intrinsic subtype, in both the primary and metastatic setting, recapitulates the challenges faced in treating cancer patients and highlights the need for combination therapies and predictive biomarkers.

Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid-stimulated migration of murine osteosarcoma LM8 cells.

PubMed

Kubohara, Yuzuru; Komachi, Mayumi; Homma, Yoshimi; Kikuchi, Haruhisa; Oshima, Yoshiteru

2015-08-07

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), -2, and -3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5-20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC50 values of 5.5, 4.6, and 4.2 μM, respectively. On the other hand, the IC50 values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. Copyright © 2015 Elsevier Inc. All rights reserved.

Image-based Multilevel Subdivision of M1 Category in TNM Staging System for Metastatic Nasopharyngeal Carcinoma.

PubMed

Shen, Lujun; Li, Wang; Wang, Siyang; Xie, Guofeng; Zeng, Qi; Chen, Chen; Shi, Feng; Zhang, Ying; Wu, Ming; Shu, Wanhong; Pan, Changchuan; Xia, Yunfei; Wu, Peihong

2016-09-01

Purpose To establish an image-based M1 category subdivision system for personalized prognosis prediction and treatment planning in patients with metastatic nasopharyngeal carcinoma (NPC). Materials and Methods A total of 1172 patients with metachronous metastasic NPC were retrospectively enrolled (the dataset is from Sun Yat-sen University Cancer Center for derivation, and the combined datasets are from Guangzhou Medical University Cancer Center and the Fifth Affiliated Hospital of Sun Yat-sen University for validation). The Ethics Committee of the three centers approved this study. A general subdivision system of the M1 category was established on the basis of the most influential metastatic features for overall survival (OS). The following multilevel subdivision system for precise subdivision of the M1 category was designed: M [number of locations]-Location [number of lesions], with B indicating bone, L indicating the lung, H indicating the liver, and N indicating a node. The correlation of the M1 subdivisions with OS was determined with Cox regression. The best treatment response was assessed with Response Evaluation Criteria in Solid Tumors 1.1 guidelines and modified Response Evaluation Criteria in Solid Tumors criteria. Results Multivariate analysis in the derivation cohort showed that the number of metastatic lesions (multiple or single), the number of metastatic locations (multiple or single), liver involvement, and bone involvement were independent prognostic factors for OS. In general, subdividing the cohort by the number of metastatic lesions and the number of metastatic locations resulted in three subcategories of differential OS: M1a, a single lesion in a single organ or location; M1b, multiple lesions in a single organ or location; and M1c, metastases in multiple locations (for M1b vs M1a, hazard ratio [HR] = 2.28, 95% confidence interval [CI]: 1.71, 3.05; for M1c vs M1a, HR = 3.65, 95% CI: 2.75, 4.85); these subdivisions were externally validated

The Impact of Metastatic Spinal Tumor Location on 30-Day Perioperative Mortality and Morbidity After Surgical Decompression.

PubMed

Hussain, Awais K; Vig, Khushdeep S; Cheung, Zoe B; Phan, Kevin; Lima, Mauricio C; Kim, Jun S; Kaji, Deepak A; Arvind, Varun; Cho, Samuel Kang-Wook

2018-06-01

A retrospective cohort study from 2011 to 2014 was performed using the American College of Surgeons National Surgical Quality Improvement Program database. The purpose of this study was to assess the impact of tumor location in the cervical, thoracic, or lumbosacral spine on 30-day perioperative mortality and morbidity after surgical decompression of metastatic extradural spinal tumors. Operative treatment of metastatic spinal tumors involves extensive procedures that are associated with significant complication rates and healthcare costs. Past studies have examined various risk factors for poor clinical outcomes after surgical decompression procedures for spinal tumors, but few studies have specifically investigated the impact of tumor location on perioperative mortality and morbidity. We identified 2238 patients in the American College of Surgeons National Surgical Quality Improvement Program database who underwent laminectomy for excision of metastatic extradural tumors in the cervical, thoracic, or lumbosacral spine. Baseline patient characteristics were collected from the database. Univariate and multivariate regression analyses were performed to examine the association between spinal tumor location and 30-day perioperative mortality and morbidity. On univariate analysis, cervical spinal tumors were associated with the highest rate of pulmonary complications. Multivariate regression analysis demonstrated that cervical spinal tumors had the highest odds of multiple perioperative complications. However, thoracic spinal tumors were associated with the highest risk of intra- or postoperative blood transfusion. In contrast, patients with metastatic tumors in the lumbosacral spine had lower odds of perioperative mortality, pulmonary complications, and sepsis. Tumor location is an independent risk factor for perioperative mortality and morbidity after surgical decompression of metastatic spinal tumors. The addition of tumor location to existing prognostic scoring

Well-differentiated neuroendocrine tumors in skin: Terminology and diagnostic utility of cytokeratin 5/6 and p63.

PubMed

Panse, Gauri; Cowper, Shawn E; Leffell, David J; Pulitzer, Melissa; Ko, Christine J

2017-06-01

Well-differentiated neuroendocrine tumors (WDNETs) in skin include metastases from visceral primary sites and very uncommonly, primary cutaneous carcinoid tumors. Cutaneous WDNET may present a diagnostic challenge and in particular can be mistaken for a benign skin adnexal tumor. In contrast to cutaneous adnexal tumors, metastatic adenocarcinomas to the skin are cytokeratin 5/6 (CK5/6) and p63 negative in the majority of cases. It is unclear if failure to stain with CK5/6 and p63 would be helpful in differentiating WDNETs from cutaneous adnexal neoplasms. We reviewed 10 cases of cutaneous WDNETs (8 cases of metastatic disease and 2 presumed primary carcinoid tumors of the skin) and performed immunohistochemical stains for CK5/6 and p63 on all cases. All 10 cases were negative with both CK5/6 and p63. Negative staining for CK5/6 and p63 can be helpful to distinguish WDNETs from cutaneous adnexal neoplasms. It is important to consider WDNETs in the differential diagnosis of cutaneous adnexal neoplasms as low-grade tumors may be the first sign of aggressive metastatic disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

[The drug of the month: everolimus (Afinitor) for the treatment of metastatic breast cancer].

PubMed

Jerusalem, G; Rorive, A; Collignon, J

2014-09-01

Sequential endocrine treatments are recommended for estrogen receptor (ER) positive human epidermal growth factor receptor 2 (HER 2) negative metastatic breast cancers except in the case of symptomatic visceral disease. However, patients who suffer from disease progression while receiving a non-steroidal aromatase inhibitor (NSAI) have a very poor prognosis with standard endocrine therapy alone. Recently, based onthe results of the BOLERO 2 trial, the mammalian target of rapamycin (mTOR) inhibitor everolimus, combined with exemestane, a steroidal aromatase inhibitor, has been approved in Europe and the US for patients suffering from ER positive HER2 negative advanced breast cancer previously treated by a NSAI. The median progression-free survival (PFS) increased from 3.2 to 7.8 months in patients receiving everolimus and exemestane compared to placebo and exemestane. The magnitude of benefit was consistent in all pre-specified subgroups. Side effects were manageable and the quality of life was at least maintained. Everolimus has also beenrecently studied in HER2 positive locally advanced or metastatic disease in heavily pretreated patients (BOLERO 3 trial). This trial met its primary endpoint. The median PFS was increased in patients receiving trastuzumab, vinorelbine and everolimus compared to patients receiving trastuzumab, vinorelbine and placebo. We review pharmacological data and side effects of the drug. We also review the most important clinical trials leading to reimbursement of everolimus in metastatic breast cancer.

On the Antiquity of Cancer: Evidence for Metastatic Carcinoma in a Young Man from Ancient Nubia (c. 1200BC)

PubMed Central

Binder, Michaela; Roberts, Charlotte; Spencer, Neal; Antoine, Daniel; Cartwright, Caroline

2014-01-01

Cancer, one of the world’s leading causes of death today, remains almost absent relative to other pathological conditions, in the archaeological record, giving rise to the conclusion that the disease is mainly a product of modern living and increased longevity. This paper presents a male, young-adult individual from the archaeological site of Amara West in northern Sudan (c. 1200BC) displaying multiple, mainly osteolytic, lesions on the vertebrae, ribs, sternum, clavicles, scapulae, pelvis, and humeral and femoral heads. Following radiographic, microscopic and scanning electron microscopic (SEM) imaging of the lesions, and a consideration of differential diagnoses, a diagnosis of metastatic carcinoma secondary to an unknown soft tissue cancer is suggested. This represents the earliest complete example in the world of a human who suffered metastatic cancer to date. The study further draws its strength from modern analytical techniques applied to differential diagnoses and the fact that it is firmly rooted within a well-documented archaeological and historical context, thus providing new insights into the history and antiquity of the disease as well as its underlying causes and progression. PMID:24637948

Third-line Targeted Therapy in Metastatic Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

PubMed

Wells, J Connor; Stukalin, Igor; Norton, Craig; Srinivas, Sandy; Lee, Jae Lyun; Donskov, Frede; Bjarnason, Georg A; Yamamoto, Haru; Beuselinck, Benoit; Rini, Brian I; Knox, Jennifer J; Agarwal, Neeraj; Ernst, D Scott; Pal, Sumanta K; Wood, Lori A; Bamias, Aristotelis; Alva, Ajjai S; Kanesvaran, Ravindran; Choueiri, Toni K; Heng, Daniel Y C

2017-02-01

The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment decisions. This study examined the use of third-line therapy in a large international population. To evaluate the use and efficacy of targeted therapy in a third-line setting. Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated

Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology.

PubMed

Walker, Steven M; Knight, Laura A; McCavigan, Andrena M; Logan, Gemma E; Berge, Viktor; Sherif, Amir; Pandha, Hardev; Warren, Anne Y; Davidson, Catherine; Uprichard, Adam; Blayney, Jaine K; Price, Bethanie; Jellema, Gera L; Steele, Christopher J; Svindland, Aud; McDade, Simon S; Eden, Christopher G; Foster, Chris; Mills, Ian G; Neal, David E; Mason, Malcolm D; Kay, Elaine W; Waugh, David J; Harkin, D Paul; Watson, R William; Clarke, Noel W; Kennedy, Richard D

2017-10-01

Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in

Differential prevalence of established risk factors for poor cessation outcomes among smokers by level of social anxiety.

PubMed

Watson, Noreen L; Heffner, Jaimee L; McClure, Jennifer B; Mull, Kristen E; Bricker, Jonathan B

2017-03-01

Despite clear associations between social anxiety (SA), high prevalence of smoking, and cessation failure, little is known about factors contributing to these relationships. Moreover, the extent to which smokers with moderate SA represent an at-risk group of smokers is also unknown. This study examined the extent to which established risk factors for poor cessation (eg, sociodemographic, smoking history, mental health comorbidity) are prevalent among smokers with low, moderate, and high levels of SA. Participants (N = 2,637) were adult smokers from a web-based smoking cessation trial. Nineteen characteristics considered risk factors for poor cessation outcomes were assessed at baseline. Those associated with social anxiety were subsequently compared by SA level. Regression models indicated that 10/19 risk factors were associated with SA. Compared to smokers with low SA, those with moderate and high SA endorsed 4/10 and 10/10 risk factors as more prevalent or severe, respectively. Compared to smokers with low SA, High SA was associated with greater sociodemographic risk factors, while both moderate and high SA was associated with more severe mental health symptoms. Smokers with moderate and high levels of SA endorse more risk factors for poor cessation outcomes than those with low levels of SA, particularly mental health symptoms. These factors may help explain the differential smoking outcomes of socially anxious smokers. Results suggest that smokers with both moderate and high levels of SA would likely benefit from cessation interventions that address and consider these risk factors. (Am J Addict 2017;26:176-182). © 2017 American Academy of Addiction Psychiatry.

Differential Prevalence of Established Risk Factors for Poor Cessation Outcomes among Smokers by Level of Social Anxiety

PubMed Central

Watson, Noreen L.; Heffner, Jaimee L.; McClure, Jennifer B.; Mull, Kristen E.; Bricker, Jonathan B.

2017-01-01

Background and Objectives Despite clear associations between social anxiety (SA), high prevalence of smoking, and cessation failure, little is known about factors contributing to these relationships. Moreover, the extent to which smokers with moderate SA represent an at-risk group of smokers is also unknown. This study examined the extent to which established risk factors for poor cessation (e.g., sociodemographic, smoking history, mental health comorbidity) are prevalent among smokers with low, moderate, and high levels of SA. Methods Participants (N = 2,637) were adult smokers from a web-based smoking cessation trial. Nineteen characteristics considered risk factors for poor cessation outcomes were assessed at baseline. Those associated with social anxiety were subsequently compared by SA level. Results Regression models indicated that 10/19 risk factors were associated with SA. Compared to smokers with low SA, those with moderate and high SA endorsed 4/10 and 10/10 risk factors as more prevalent or severe, respectively. Compared to smokers with low SA, High SA was associated with greater sociodemographic risk factors, while both moderate and high SA was associated with more severe mental health symptoms. Conclusions and Scientific Significance Smokers with moderate and high levels of SA endorse more risk factors for poor cessation outcomes than those with low levels of SA, particularly mental health symptoms. These factors may help explain the differential smoking outcomes of socially anxious smokers. Results suggest that smokers with both moderate and high levels of SA would likely benefit from cessation interventions that address and consider these risk factors. PMID:28191916

Prognostic significance of pattern and burden of metastatic disease in patients with stage 4 neuroblastoma: A study from the International Neuroblastoma Risk Group database.

PubMed

Morgenstern, Daniel A; London, Wendy B; Stephens, Derek; Volchenboum, Samuel L; Simon, Thorsten; Nakagawara, Akira; Shimada, Hiroyuki; Schleiermacher, Gudrun; Matthay, Katherine K; Cohn, Susan L; Pearson, Andrew D J; Irwin, Meredith S

2016-09-01

Neuroblastoma is a childhood cancer with remarkably divergent tumour behaviour and the presence of metastatic disease is a powerful predictor of adverse outcome. However, the importance of the involvement of specific metastatic sites or overall metastatic burden in determining outcome has not been fully explored. We analysed data from the International Neuroblastoma Risk Group database for 2250 patients with stage 4 disease treated from 1990 to 2002. Metastatic burden was assessed using a 'metastatic site index' (MSI), a score based on the number of metastatic systems involved. Overall, involvement of bone marrow, bone, lung, central nervous system, or other sites was associated with worse outcome. For patients aged ≥18 months, involvement of liver had the greatest impact on outcome and was associated with tumour MYCN amplification and adrenal primary and lung metastases. Increased MSI was associated with worse outcome and higher baseline ferritin/lactate dehydrogenase. We explored the impact of initial treatment approach on these associations. Limiting the analysis to patients allocated to protocols including stem cell transplant (SCT), there was no longer an association of outcome with metastatic involvement of any individual system or increasing MSI. Thus, treatment escalation with SCT (and the addition of differentiating agents to maintenance therapy) appears to have provided maximal benefit to patients with greatest metastatic disease burden. These findings underscore the importance of examining prognostic factors in the context of specific treatments since the addition of new therapies may change or even negate the predictive impact of a particular variable. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

Nogueira, Jeronimo A; Ono-Nita, Suzane K; Nita, Marcelo E; de Souza, Marcelo M T; do Carmo, Eliane P; Mello, Evandro S; Scapulatempo, Cristovan; Paranaguá-Vezozzo, Denise C; Carrilho, Flair J; Alves, Venancio A F

2009-06-26

Ser-249 TP53 mutation (249(Ser)) 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 249(Ser) mutation in HCC from patients in Brazil. We studied 74 HCC formalin fixed paraffin blocks samples of patients whom underwent surgical resection in Brazil. 249(Ser) mutation was analyzed by RFLP and DNA sequencing. HBV DNA presence was determined by Real-Time PCR. 249(Ser) 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 249(Ser) 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 249(Ser) mutation (OR = 2.415, 95% CI = 1.001 - 5.824, p = 0.05). The mean size of 249(Ser) HCC tumor was 9.4 cm versus 5.5 cm on wild type HCC (p = 0.012). HBV DNA detection was not related to 249(Ser) mutation. Our results indicate that 249(Ser) mutation is a HCC important factor of carcinogenesis in Brazil and it is associated to large and poorly differentiated tumors.

Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy

PubMed Central

Ghorayeb, Nada El; Rondeau, Geneviève; Latour, Mathieu; Cohade, Christian; Olney, Harold; Lacroix, André; Perrotte, Paul; Sabourin, Alexis; Mazzuco, Tania L; Bourdeau, Isabelle

2016-01-01

Abstract Mitotane has been used for more than 5 decades as therapy for adrenocortical carcinoma (ACC). However its mechanism of action and the extent of tumor response remain incompletely understood. To date no cases of rapid and complete remission of metastatic ACC with mitotane monotherapy has been reported. A 52-year-old French Canadian man presented with metastatic disease 2 years following a right adrenalectomy for stage III nonsecreting ACC. He was started on mitotane which was well tolerated despite rapid escalation of the dose. The patient course was exceptional as he responded to mitotane monotherapy after only few months of treatment. Initiation of chemotherapy was not needed and he remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years. A germline heterozygous TP53 exon 4 polymorphism c.215C>G (p. Pro72Arg) was found. Immunohistochemical stainings for IGF-2 and cytoplasmic β-catenin were positive. Advanced ACC is an aggressive disease with poor prognosis and the current therapeutic options remain limited. These findings suggest that mitotane is a good option for the treatment of metastatic ACC and might result in rapid complete remission in selected patients. PMID:27043680

Distinguishing between Poor/Dysfunctional Parenting and Child Emotional Maltreatment

ERIC Educational Resources Information Center

Wolfe, David A.; McIsaac, Caroline

2011-01-01

Objective: This paper was intended to distinguish between poor parenting and child emotional maltreatment (CEM), to inform child welfare and public health policymakers of the need for differentiated responses. Methods: Scientific literature was integrated with current practice and assumptions relating to poor/dysfunctional parenting and child…

Case for diagnosis. Metastatic Crohn's disease*

PubMed Central

Gontijo, João Renato Vianna; Leidenz, Franciele Antonieta Bianchi; de Sousa, Maria Silvia Laborne Alves

2016-01-01

Metastatic Crohn's disease is a rare skin manifestation, defined by granulomatous skin lesions that are discontinuous to the affected gastrointestinal tract and histopathologically resembling inflammatory bowel lesions. Up to 44% of patients with Crohn's disease have cutaneous manifestations, of which metastatic lesions are the least common. We present a case of an adolescent with refractory Crohn's disease and persistent papules and plaques on the skin. PMID:27579756

Uncovering cancer cell behavioral phenotype in 3-D in vitro metastatic landscapes

NASA Astrophysics Data System (ADS)

Liu, Liyu; Sun, Bo; Duclos, Guillaume; Kam, Yoonseok; Gatenby, Robert; Stone, Howard; Austin, Robert

2012-02-01

One well-known fact is that cancer cell genetics determines cell metastatic potentials. However, from a physics point of view, genetics as cell properties cannot directly act on metastasis. An agent is needed to unscramble the genetics first before generating dynamics for metastasis. Exactly this agent is cell behavioral phenotype, which is rarely studied due to the difficulties of real-time cell tracking in in vivo tissue. Here we have successfully constructed a micro in vitro environment with collagen based Extracellular Matrix (ECM) structures for cell 3-D metastasis. With stable nutrition (glucose) gradient inside, breast cancer cell MDA-MB-231 is able to invade inside the collagen from the nutrition poor site towards the nutrition rich site. Continuous confocal microscopy captures images of the cells every 12 hours and tracks their positions in 3-D space. The micro fluorescent beads pre-mixed inside the ECM demonstrate that invasive cells have altered the structures through mechanics. With the observation and the analysis of cell collective behaviors, we argue that game theory may exist between the pioneering cells and their followers in the metastatic cell group. The cell collaboration may explain the high efficiency of metastasis.

Extracellular vesicles for personalized therapy decision support in advanced metastatic cancers and its potential impact for prostate cancer.

PubMed

Soekmadji, Carolina; Corcoran, Niall M; Oleinikova, Irina; Jovanovic, Lidija; Ramm, Grant A; Nelson, Colleen C; Jenster, Guido; Russell, Pamela J

2017-10-01

The use of circulating tumor cells (CTCs) and circulating extracellular vesicles (EVs), such as exosomes, as liquid biopsy-derived biomarkers for cancers have been investigated. CTC enumeration using the CellSearch based platform provides an accurate insight on overall survival where higher CTC counts indicate poor prognosis for patients with advanced metastatic cancer. EVs provide information based on their lipid, protein, and nucleic acid content and can be isolated from biofluids and analyzed from a relatively small volume, providing a routine and non-invasive modality to monitor disease progression. Our pilot experiment by assessing the level of two subpopulations of small EVs, the CD9 positive and CD63 positive EVs, showed that the CD9 positive EV level is higher in plasma from patients with advanced metastatic prostate cancer with detectable CTCs. These data show the potential utility of a particular EV subpopulation to serve as biomarkers for advanced metastatic prostate cancer. EVs can potentially be utilized as biomarkers to provide accurate genotypic and phenotypic information for advanced prostate cancer, where new strategies to design a more personalized therapy is currently the focus of considerable investigation. © 2017 Wiley Periodicals, Inc.

Metastatic pheochromocytoma: clinical, genetic, and histopathologic characteristics

PubMed Central

Zelinka, Tomáš; Musil, Zdeněk; Dušková, Jaroslava; Burton, Deborah; Merino, Maria J; Milosevic, Dragana; Widimský, Jiří; Pacak, Karel

2011-01-01

Background Pheochromocytomas are tumors arising from chromaffin tissue located in the adrenal medulla associated with typical symptoms and signs which may occasionally develop metastases, which are defined as the presence of tumor cells at sites where these cells are not found. This retrospective analysis was focused on clinical, genetic, and histopathologic characteristics of primary metastatic versus primary benign pheochromocytomas. Materials and methods We identified 41 subjects with metastatic pheochromocytoma and 108 subjects with apparently benign pheochromocytoma. We assessed dimension and biochemical profile of the primary tumor, age at presentation, and time to develop metastases. Results Subjects with metastatic pheochromocytoma presented at a significantly younger age (41.4±14.7 vs. 50.2±13.7 years; P<0.001), with larger primary tumors (8.38±3.27 cm vs. 6.18±2.75 cm; P<0.001) and secreted more frequently norepinephrine (95.1% vs. 83.3 %; P=0.046) compared to subjects with apparently benign pheochromocytomas. No significant differences were found in the incidence of genetic mutations in both groups of subjects (25.7 % in the metastatic group and 14.7 % in the benign group; P=0.13). From available histopathologic markers of potential malignancy, only necrosis occurred more frequently in subjects with metastatic pheochromocytoma (27.6 % vs. 0 %; P<0.001). The median time to develop metastases was 3.6 years with the longest interval 24 years. Conclusions In conclusion, regardless of a genetic background, the size of a primary pheochromocytoma and age of its first presentation are two independent risk factors associated with the development of metastatic disease. PMID:21692797

Zn{sup 2+} induces apoptosis in human highly metastatic SHG-44 glioma cells, through inhibiting activity of the voltage-gated proton channel Hv1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yifan; Zhang, Shangrong; Li, Shu Jie, E-mail: shujieli@nankai.edu.cn

Highlights: •Hv1 is expressed in highly metastatic glioma cell. •Zn{sup 2+} ions induces apoptosis in highly metastatic glioma cells. •Zn{sup 2+} ions markedly inhibit proton secretion. •Zn{sup 2+} ions reduce the gelatinase activity. •Inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth. -- Abstract: In contrast to the voltage-gated K{sup +} channels, the voltage-gated proton channel Hv1 contains a voltage-sensor domain but lacks a pore domain. Here, we showed that Hv1 is expressed in the highly metastatic glioma cell SHG-44, but lowly in the poorly metastatic glioma cell U-251. Inhibition of Hv1 activity by 140more » μM zinc chloride induces apoptosis in the human highly metastatic glioma cells. Zn{sup 2+} ions markedly inhibit proton secretion, and reduce the gelatinase activity in the highly metastatic glioma cells. In vivo, the glioma tumor sizes of the implantation of the SHG-44 xenografts in nude mice that were injected zinc chloride solution, were dramatically smaller than that in the controlled groups. The results demonstrated that the inhibition of Hv1 activity via Zn{sup 2+} ions can effectively retard the cancer growth and suppress the cancer metastasis by the decrease of proton extrusion and the down-regulation of gelatinase activity. Our results suggest that Zn{sup 2+} ions may be used as a potential anti-glioma drug for glioma therapy.« less

Zebrafish sp7 mutants show tooth cycling independent of attachment, eruption and poor differentiation of teeth.

PubMed

Kague, E; Witten, P E; Soenens, M; Campos, C L; Lubiana, T; Fisher, S; Hammond, C; Brown, K Robson; Passos-Bueno, M R; Huysseune, A

2018-03-15

The capacity to fully replace teeth continuously makes zebrafish an attractive model to explore regeneration and tooth development. The requirement of attachment bone for the appearance of replacement teeth has been hypothesized but not yet investigated. The transcription factor sp7 (osterix) is known in mammals to play an important role during odontoblast differentiation and root formation. Here we study tooth replacement in the absence of attachment bone using sp7 zebrafish mutants. We analysed the pattern of tooth replacement at different stages of development and demonstrated that in zebrafish lacking sp7, attachment bone is never present, independent of the stage of tooth development or fish age, yet replacement is not interrupted. Without bone of attachment we observed abnormal orientation of teeth, and abnormal connection of pulp cavities of predecessor and replacement teeth. Mutants lacking sp7 show arrested dentinogenesis, with non-polarization of odontoblasts and only a thin layer of dentin deposited. Osteoclast activity was observed in sp7 mutants; due to the lack of bone of attachment, remodelling was diminished but nevertheless present along the pharyngeal bone. We conclude that tooth replacement is ongoing in the sp7 mutant despite poor differentiation and defective attachment. Without bone of attachment tooth orientation and pulp organization are compromised. Copyright © 2018 Elsevier Inc. All rights reserved.

Laparoscopic cholecystectomy for melanoma metastatic to the gallbladder: is it an adequate surgical procedure? Report of a case and review of the literature.

PubMed

Marone, Ugo; Caracò, Corrado; Losito, Simona; Daponte, Antonio; Chiofalo, Maria Grazia; Mori, Stefano; Cerra, Rocco; Pezzullo, Luciano; Mozzillo, Nicola

2007-12-11

Only 2% to 4% of patients with melanoma will be diagnosed with gastrointestinal metastasis during the course of their disease. The most common sites of gastrointestinal metastases from melanoma include the small bowel (35%-67%), colon (9%-15%) and stomach (5%-7%), with a median survival of 6-10 months after surgery, and 18% survival at five years. Metastatic melanoma to the gallbladder is extremely rare and it is associated with a very poor prognosis. We report a case of a 54-year old man presented to observation with diagnosis of 6.1 mm thick, Clark's level IV, ulcerated melanoma of the trunk, developing in the course of the disease metastatic involvement of the gallbladder as first site of recurrence, treated by laparoscopic cholecystectomy. To date only few cases of patients with metastatic melanoma of the gallbladder treated by this surgical procedure have been reported in literature. Gallbladder metastasis represents a rare event as a first site of recurrence. It must be considered a possible expression of systemic disease also despite radiological absence of other metastatic lesions. Laparoscopic approach has a possible therapeutic role, but open surgery has also a concomitant diagnostic purpose because gives the possibility of manual exploration of abdominal cavity, useful particularly to reveal bowel metastatic lesions, not easily identifiable by preoperative imaging examinations.

Laparoscopic cholecystectomy for melanoma metastatic to the gallbladder: is it an adequate surgical procedure? Report of a case and review of the literature

PubMed Central

Marone, Ugo; Caracò, Corrado; Losito, Simona; Daponte, Antonio; Chiofalo, Maria Grazia; Mori, Stefano; Cerra, Rocco; Pezzullo, Luciano; Mozzillo, Nicola

2007-01-01

Background Only 2% to 4% of patients with melanoma will be diagnosed with gastrointestinal metastasis during the course of their disease. The most common sites of gastrointestinal metastases from melanoma include the small bowel (35%–67%), colon (9%–15%) and stomach (5%–7%), with a median survival of 6–10 months after surgery, and 18% survival at five years. Metastatic melanoma to the gallbladder is extremely rare and it is associated with a very poor prognosis. Case presentation We report a case of a 54-year old man presented to observation with diagnosis of 6.1 mm thick, Clark's level IV, ulcerated melanoma of the trunk, developing in the course of the disease metastatic involvement of the gallbladder as first site of recurrence, treated by laparoscopic cholecystectomy. To date only few cases of patients with metastatic melanoma of the gallbladder treated by this surgical procedure have been reported in literature. Conclusion Gallbladder metastasis represents a rare event as a first site of recurrence. It must be considered a possible expression of systemic disease also despite radiological absence of other metastatic lesions. Laparoscopic approach has a possible therapeutic role, but open surgery has also a concomitant diagnostic purpose because gives the possibility of manual exploration of abdominal cavity, useful particularly to reveal bowel metastatic lesions, not easily identifiable by preoperative imaging examinations. PMID:18072972

Direct effects of mitochondrial dysfunction on poor bone health in Leigh syndrome.

PubMed

Kato, Hiroki; Han, Xu; Yamaza, Haruyoshi; Masuda, Keiji; Hirofuji, Yuta; Sato, Hiroshi; Pham, Thanh Thi Mai; Taguchi, Tomoaki; Nonaka, Kazuaki

2017-11-04

Mitochondrial diseases are the result of aberrant mitochondrial function caused by mutations in either nuclear or mitochondrial DNA. Poor bone health has recently been suggested as a symptom of mitochondrial diseases; however, a direct link between decreased mitochondrial function and poor bone health in mitochondrial disease has not been demonstrated. In this study, stem cells from human exfoliated deciduous teeth (SHED) were isolated from a child with Leigh syndrome (LS), a mitochondrial disease, and the effects of decreased mitochondrial function on poor bone health were analyzed. Compared with control SHED, LS SHED displayed decreased osteoblastic differentiation and calcium mineralization. The intracellular and mitochondrial calcium levels were lower in LS SHED than in control SHED. Furthermore, the mitochondrial activity of LS SHED was decreased compared with control SHED both with and without osteoblastic differentiation. Our results indicate that decreased osteoblast differentiation potential and osteoblast function contribute to poor bone health in mitochondrial diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Longitudinal 3.0T MRI analysis of changes in lymph node volume and apparent diffusion coefficient in an experimental animal model of metastatic and hyperplastic lymph nodes.

PubMed

Klerkx, Wenche M; Geldof, Albert A; Heintz, A Peter; van Diest, Paul J; Visser, Fredy; Mali, Willem P; Veldhuis, Wouter B

2011-05-01

To perform a longitudinal analysis of changes in lymph node volume and apparent diffusion coefficient (ADC) in healthy, metastatic, and hyperplastic lymph nodes. Three groups of four female Copenhagen rats were studied. Metastasis was induced by injecting cells with a high metastatic potential in their left hind footpad. Reactive nodes were induced by injecting Complete Freund Adjuvant (CFA). Imaging was performed at baseline and at 2, 5, 8, 11, and 14 days after tumor cell injection. Finally, lymph nodes were examined histopathologically. The model was highly efficient in inducing lymphadenopathy: subcutaneous cell or CFA inoculation resulted in ipsilateral metastatic or reactive popliteal lymph nodes in all rats. Metastatic nodal volumes increased exponentially from 5-7 mm(3) at baseline to 25 mm(3) at day 14, while the control node remained 5 mm(3). The hyperplastic nodes showed a rapid volume increase reaching a plateau at day 6. The ADC of metastatic nodes significantly decreased (range 13%-32%), but this decrease was also seen in reactive nodes. Metastatic and hyperplastic lymph nodes differed in terms of enlargement patterns and ADC changes. Enlarged reactive or malignant nodes could not be differentiated based on their ADC values. Copyright © 2011 Wiley-Liss, Inc.

Minimizing metastatic risk in radiotherapy fractionation schedules

NASA Astrophysics Data System (ADS)

Badri, Hamidreza; Ramakrishnan, Jagdish; Leder, Kevin

2015-11-01

Metastasis is the process by which cells from a primary tumor disperse and form new tumors at distant anatomical locations. The treatment and prevention of metastatic cancer remains an extremely challenging problem. This work introduces a novel biologically motivated objective function to the radiation optimization community that takes into account metastatic risk instead of the status of the primary tumor. In this work, we consider the problem of developing fractionated irradiation schedules that minimize production of metastatic cancer cells while keeping normal tissue damage below an acceptable level. A dynamic programming framework is utilized to determine the optimal fractionation scheme. We evaluated our approach on a breast cancer case using the heart and the lung as organs-at-risk (OAR). For small tumor α /β values, hypo-fractionated schedules were optimal, which is consistent with standard models. However, for relatively larger α /β values, we found the type of schedule depended on various parameters such as the time when metastatic risk was evaluated, the α /β values of the OARs, and the normal tissue sparing factors. Interestingly, in contrast to standard models, hypo-fractionated and semi-hypo-fractionated schedules (large initial doses with doses tapering off with time) were suggested even with large tumor α/β values. Numerical results indicate the potential for significant reduction in metastatic risk.

Non-cytotoxic differentiation treatment of renal cell cancer

PubMed Central

Negrotto, Soledad; Hu, Zhenbo; Alcazar, Oscar; Ng, Kwok Peng; Triozzi, Pierre; Lindner, Daniel; Rini, Brian; Saunthararajah, Yogen

2013-01-01

Current drug therapy for metastatic renal cell cancer (RCC) results in temporary disease control but not cure, necessitating continued investigation into alternative mechanistic approaches. Drugs that inhibit chromatin-modifying enzymes involved in transcription repression (chromatin-relaxing drugs) could have a role, by inducing apoptosis, and/or through differentiation pathways. At low doses, the cytosine analogue decitabine can be used to deplete DNA methyl-transferase 1 (DNMT1), modify chromatin and alter differentiation without causing apoptosis (cytotoxicity). Non-cytotoxic regimens of decitabine were evaluated for in vitro and in vivo efficacy against RCC cell lines, including a p53 mutated RCC cell line developed from a patient with treatment refractory metastatic RCC. The cell-division permissive mechanism of action, absence of early apoptosis or DNA damage, increase in expression of HNF4α (a key driver associated with the mesenchymal to epithelial transition), decrease in mesenchymal marker expression, increase in epithelial marker expression, and late increase in cyclin dependent kinase inhibitor CDKN1B (p27) protein, was consistent with differentiation-mediated cell cycle exit. In vivo blood counts and animal weights were consistent with minimal toxicity of therapy. The distinctive mechanism of action of a dose and schedule of decitabine designed for non-cytotoxic depletion of DNMT1 suggests a potential role in treating RCC. PMID:21303982

Three-dimensional Optical Coherence Tomography for Optical Biopsy of Lymph Nodes and Assessment of Metastatic Disease

PubMed Central

John, Renu; Adie, Steven G.; Chaney, Eric J.; Marjanovic, Marina; Tangella, Krishnarao V.; Boppart, Stephen A.

2013-01-01

Background Numerous techniques have been developed for localizing lymph nodes before surgical resection and for their histological assessment. Nondestructive high-resolution transcapsule optical imaging of lymph nodes offers the potential for in situ assessment of metastatic involvement, potentially during surgical procedures. Methods Three-dimensional optical coherence tomography (3-D OCT) was used for imaging and assessing resected popliteal lymph nodes from a preclinical rat metastatic tumor model over a 9-day time-course study after tumor induction. The spectral-domain OCT system utilized a center wavelength of 800 nm, provided axial and transverse resolutions of 3 and 12 µm, respectively, and performed imaging at 10,000 axial scans per second. Results OCT is capable of providing high-resolution labelfree images of intact lymph node microstructure based on intrinsic optical scattering properties with penetration depths of ~1–2 mm. The results demonstrate that OCT is capable of differentiating normal, reactive, and metastatic lymph nodes based on microstructural changes. The optical scattering and structural changes revealed by OCT from day 3 to day 9 after the injection of tumor cells into the lymphatic system correlate with inflammatory and immunological changes observed in the capsule, precortical regions, follicles, and germination centers found during histopathology. Conclusions We report for the first time a longitudinal study of 3-D transcapsule OCT imaging of intact lymph nodes demonstrating microstructural changes during metastatic infiltration. These results demonstrate the potential of OCT as a technique for intraoperative, real-time in situ 3-D optical biopsy of lymph nodes for the intraoperative staging of cancer. PMID:22688663

Radiosurgery for metastatic disease at the craniocervical junction.

PubMed

Tuchman, Alexander; Yu, Cheng; Chang, Eric L; Kim, Paul E; Rusch, Mairead C; Apuzzo, Michael L J

2014-12-01

Metastatic disease of the craniovertebral junction (CVJ) can cause pain, cranial nerve deficits, occipitocervical instability, or brainstem/spinal cord compression if left untreated. Many patients with metastasis in this region have a high burden of systemic disease and short life expectancy, making them poor candidates for aggressive surgical resections and fusion procedures. Traditionally, symptom palliation and local disease control in these patients has been achieved through conventional radiation therapy. Stereotactic radiosurgery (SRS) has the advantage of precisely delivering radiation to a target in fewer fractions. To our knowledge, we report the results of the largest series of patients with CVJ metastasis treated with stereotactic radiosurgery. We performed a retrospective review of 9 consecutive patients with 10 tumors of the CVJ treated with SRS at the Keck Medical Center of the University of Southern California. Two tumors were treated with Gamma Knife, whereas the other 8 received CyberKnife. The median marginal dose was 20 Gy (16-24 Gy) over 1-5 fractions. Point maximal dose to the brainstem or spinal cord ranged between 8 and 18.9 Gy. Median survival was 4 months (1-51 months). Five of six patients presenting with pain had at least partial symptom resolution. No patient went on to require surgical decompression or fusion, and there were no complications directly related to SRS. In well-selected patients, SRS for metastatic lesions of the CVJ has a low risk for complications or treatment failure, while achieving a high rate of palliation of pain symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

[Efficacy and safety of TS-1 monotherapy for advanced/metastatic breast cancer - an observational study by the Kumamoto Breast Cancer Cooperative Group(KBCCG)].

PubMed

Yamamoto, Yutaka; Nishimura, Reiki; Tanigawa, Tomio; Kawano, Ichiro; Hayashi, Kyoji; Kuramoto, Masafumi; Yamamoto-Ibusuki, Mutsuko; Iwase, Hirotaka

2014-10-01

TS-1, an oral fluoropyrimidine, is known to be effective for the treatment of various carcinomas including advanced/metastatic breast cancer.The Kumamoto Breast Cancer Cooperative Group(KBCCG)conducted an observational study, wherein, the efficacy and safety of TS-1 monotherapy was analyzed in 35 patients with recurrent or metastatic breast cancer.The median time to cancer progression was 3.7 months, overall response rate was 12%, and clinical benefit rate was 32%. Adverse events were observed in 27 patients(77%), and adverse events of Grade >3 were observed in 7 patients(20%). The rate of treatment-related Grade 3 and 4 adverse events increased, and was associated with poor levels of creatinine clearance(Ccr)ie <60mL/min.This study suggests that TS-1 monotherapy can potentially be used as a salvage treatment for advanced/metastatic breast cancer owing to its safety and efficacy.Measuring the level of Ccr before TS-1 therapy should be considered to avoid severe adverse events.

Population-based estimates of survival and cost for metastatic melanoma.

PubMed

McCarron, C E; Ernst, S; Cao, J Q; Zaric, G S

2015-10-01

Fewer than half of all patients with metastatic melanoma survive more than 1 year. Standard treatments have had little success, but recent therapeutic advances offer the potential for an improved prognosis. In the present study, we used population-based administrative data to establish real-world baseline estimates of survival outcomes and costs against which new treatments can be compared. Data from administrative databases and patient registries were used to find a cohort of patients with metastatic melanoma in Ontario. To identify individuals most likely to receive new treatments, we focused on patients eligible for second-line treatment. The identified cohort had two characteristics: no surgical resection beyond primary skin excision, and receipt of first-line systemic therapy. Patient characteristics, Kaplan-Meier survival curves, and mean costs are reported. Of the 33,585 patients diagnosed with melanoma in Ontario from 1 January 1991 to 31 December 2010, 278 met the study inclusion criteria. Average age was 63 years, and 62% of the patients were men. Overall survival was estimated to be 19%, 12%, and 6% at 12, 24, and 60 months respectively. Mean survival time was 11.5 months, and mean cost was $30,685. Our baseline estimates indicate that survival outcomes are poor and costs are high for patients receiving standard treatment. Understanding the relative improvement accruing from any new treatment requires a comparison with the existing standard of care.

FRMD4A upregulation in human squamous cell carcinoma promotes tumor growth and metastasis and is associated with poor prognosis.

PubMed

Goldie, Stephen J; Mulder, Klaas W; Tan, David Wei-Min; Lyons, Scott K; Sims, Andrew H; Watt, Fiona M

2012-07-01

New therapeutic strategies are needed to improve treatment of head and neck squamous cell carcinoma (HNSCC), an aggressive tumor with poor survival rates. FRMD4A is a human epidermal stem cell marker implicated previously in epithelial polarity that is upregulated in SCC cells. Here, we report that FRMD4A upregulation occurs in primary human HNSCCs where high expression levels correlate with increased risks of relapse. FRMD4A silencing decreased growth and metastasis of human SCC xenografts in skin and tongue, reduced SCC proliferation and intercellular adhesion, and stimulated caspase-3 activity and expression of terminal differentiation markers. Notably, FRMD4A attenuation caused nuclear accumulation of YAP, suggesting a potential role for FRMD4A in Hippo signaling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan caused nuclear depletion of FRMD4A, nuclear accumulation of YAP and reduced SCC growth and metastasis. Together, our findings suggest FRMD4A as a novel candidate therapeutic target in HNSCC based on the key role in metastatic growth we have identified. ©2012 AACR.

Quantitative characterization of metastatic disease in the spine. Part I. Semiautomated segmentation using atlas-based deformable registration and the level set method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hardisty, M.; Gordon, L.; Agarwal, P.

2007-08-15

Quantitative assessment of metastatic disease in bone is often considered immeasurable and, as such, patients with skeletal metastases are often excluded from clinical trials. In order to effectively quantify the impact of metastatic tumor involvement in the spine, accurate segmentation of the vertebra is required. Manual segmentation can be accurate but involves extensive and time-consuming user interaction. Potential solutions to automating segmentation of metastatically involved vertebrae are demons deformable image registration and level set methods. The purpose of this study was to develop a semiautomated method to accurately segment tumor-bearing vertebrae using the aforementioned techniques. By maintaining morphology of anmore » atlas, the demons-level set composite algorithm was able to accurately differentiate between trans-cortical tumors and surrounding soft tissue of identical intensity. The algorithm successfully segmented both the vertebral body and trabecular centrum of tumor-involved and healthy vertebrae. This work validates our approach as equivalent in accuracy to an experienced user.« less

Loss of GPER identifies new targets for therapy among a subgroup of ERα-positive endometrial cancer patients with poor outcome

PubMed Central

Krakstad, C; Trovik, J; Wik, E; Engelsen, I B; Werner, H M J; Birkeland, E; Raeder, M B; Øyan, A M; Stefansson, I M; Kalland, K H; Akslen, L A; Salvesen, H B

2012-01-01

Background: The G protein-coupled oestrogen receptor, GPER, has been suggested as an alternative oestrogen receptor. Our purpose was to investigate the potential of GPER as a prognostic and predictive marker in endometrial carcinoma and to search for new drug candidates to improve treatment of aggressive disease. Materials and method: A total of 767 primary endometrial carcinomas derived from three patient series, including an external dataset, were studied for protein and mRNA expression levels to investigate and validate if GPER loss identifies poor prognosis and new targets for therapy in endometrial carcinoma. Gene expression levels, according to ERα/GPER status, were used to search the connectivity map database for small molecular inhibitors with potential for treatment of metastatic disease for receptor status subgroups. Results: Loss of GPER protein is significantly correlated with low GPER mRNA, high FIGO stage, non-endometrioid histology, high grade, aneuploidy and ERα loss (all P-values ⩽0.05). Loss of GPER among ERα-positive patients identifies a subgroup with poor prognosis that until now has been unrecognised, with reduced 5-year survival from 93% to 76% (P=0.003). Additional loss of GPER from primary to metastatic lesion counterparts further supports that loss of GPER is associated with disease progression. Conclusion: These results support that GPER status adds clinically relevant information to ERα status in endometrial carcinoma and suggest a potential for new inhibitors in the treatment of metastatic endometrial cancers with ERα expression and GPER loss. PMID:22415229

Metastatic Complications from Staphylococcus intermedius, a Zoonotic Pathogen

PubMed Central

Sree, Aruna; Tirrell, Sandra; Torres, Brenda; Rothman, Alan L.

2012-01-01

Metastatic infection is an infrequent complication of non-Staphylococcus aureus staphylococcal infection. Here we report a case of bloodstream infection due to Staphylococcus intermedius. To our knowledge, ours is the only known case of metastatic infection with S. intermedius. PMID:22170938

Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors.

PubMed

Anaka, Matthew; Hudson, Christopher; Lo, Pu-Han; Do, Hongdo; Caballero, Otavia L; Davis, Ian D; Dobrovic, Alexander; Cebon, Jonathan; Behren, Andreas

2013-10-11

Intratumoral heterogeneity is a major obstacle for the treatment of cancer, as the presence of even minor populations that are insensitive to therapy can lead to disease relapse. Increased clonal diversity has been correlated with a poor prognosis for cancer patients, and we therefore examined genetic, transcriptional, and functional diversity in metastatic melanoma. Amplicon sequencing and SNP microarrays were used to profile somatic mutations and DNA copy number changes in multiple regions from metastatic lesions. Clonal genetic and transcriptional heterogeneity was also assessed in single cell clones from early passage cell lines, which were then subjected to clonogenicity and drug sensitivity assays. MAPK pathway and tumor suppressor mutations were identified in all regions of the melanoma metastases analyzed. In contrast, we identified copy number abnormalities present in only some regions in addition to homogeneously present changes, suggesting ongoing genetic evolution following metastatic spread. Copy number heterogeneity from a tumor was represented in matched cell line clones, which also varied in their clonogenicity and drug sensitivity. Minor clones were identified based on dissimilarity to the parental cell line, and these clones were the most clonogenic and least sensitive to drugs. Finally, treatment of a polyclonal cell line with paclitaxel to enrich for drug-resistant cells resulted in the adoption of a gene expression profile with features of one of the minor clones, supporting the idea that these populations can mediate disease relapse. Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma.

Intratumoral genetic heterogeneity in metastatic melanoma is accompanied by variation in malignant behaviors

PubMed Central

2013-01-01

Background Intratumoral heterogeneity is a major obstacle for the treatment of cancer, as the presence of even minor populations that are insensitive to therapy can lead to disease relapse. Increased clonal diversity has been correlated with a poor prognosis for cancer patients, and we therefore examined genetic, transcriptional, and functional diversity in metastatic melanoma. Methods Amplicon sequencing and SNP microarrays were used to profile somatic mutations and DNA copy number changes in multiple regions from metastatic lesions. Clonal genetic and transcriptional heterogeneity was also assessed in single cell clones from early passage cell lines, which were then subjected to clonogenicity and drug sensitivity assays. Results MAPK pathway and tumor suppressor mutations were identified in all regions of the melanoma metastases analyzed. In contrast, we identified copy number abnormalities present in only some regions in addition to homogeneously present changes, suggesting ongoing genetic evolution following metastatic spread. Copy number heterogeneity from a tumor was represented in matched cell line clones, which also varied in their clonogenicity and drug sensitivity. Minor clones were identified based on dissimilarity to the parental cell line, and these clones were the most clonogenic and least sensitive to drugs. Finally, treatment of a polyclonal cell line with paclitaxel to enrich for drug-resistant cells resulted in the adoption of a gene expression profile with features of one of the minor clones, supporting the idea that these populations can mediate disease relapse. Conclusion Our results support the hypothesis that minor clones might have major consequences for patient outcomes in melanoma. PMID:24119551

Targeting nodal in conjunction with dacarbazine induces synergistic anticancer effects in metastatic melanoma.

PubMed

Hardy, Katharine M; Strizzi, Luigi; Margaryan, Naira V; Gupta, Kanika; Murphy, George F; Scolyer, Richard A; Hendrix, Mary J C

2015-04-01

Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDA-approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma. ©2015 American Association for Cancer Research.

Fluorodeoxyglucose--positive internal mammary lymph node in breast cancer patients with silicone implants: is it always metastatic cancer?

PubMed

Soudack, Michalle; Yelin, Alon; Simansky, David; Ben-Nun, Alon

2013-07-01

Patients with breast cancer following mastectomy and silicone implant reconstruction may have enlarged internal mammary lymph nodes with pathological uptake on positron emission tomography with (18)F-fluorodeoxyglucose. This lymphadenopathy is usually considered as metastatic in nature, but has also been reported to be related to other conditions, including silicon migration. The purpose of this study was to determine the rate of metastatic disease in this unique group of patients. A retrospective comparative study of 12 female patients with breast cancer with silicone implants referred for biopsy due to isolated internal mammary lymph node fluorodeoxyglucose uptake on positron emission tomography. Five patients (41.6%) had histological findings related to silicone (n = 4) or non-specific inflammation (n = 1). The remaining 7 (58.3%) had histological evidence of cancer recurrence. There was no significant difference in the fluorodeoxyglucose-standardized uptake value between the two groups. Fluorodeoxyglucose-positive mammary lymph nodes in patients with breast cancer following silicone implant reconstruction may be due to metastatic deposits, non-specific inflammation or silicone migration. Clinical and imaging characteristics are insufficient in differentiating between these conditions. Biopsy is recommended prior to initiation of further treatment.

Management of metastatic renal cell carcinoma in the era of targeted therapies.

PubMed

Webber, K; Cooper, A; Kleiven, H; Yip, D; Goldstein, D

2011-08-01

Metastatic renal cell cancer is associated with poor prognosis and survival and is resistant to conventional chemotherapy. Therapeutic targeting of molecular pathways for tumour angiogenesis and other specific activation mechanisms offers improved tumour response and prolonged survival. To conduct a retrospective audit of metastatic renal cell carcinoma patients treated with targeted therapies. Data were extracted from clinical records of patients undergoing targeted treatment between 2005 and 2009 at two hospital sites. Data collected included pathology, systemic therapy class, toxicity and survival. Univariate and multivariate survival analyses were performed. Sixty-one patients were treated with 102 lines of therapy with a median overall survival (OS) of 23 months, median time to failure of first-line treatment (TTF1) of 10 months and median time to failure of second-line treatment (TTF2) of 5.2 months. Time from first diagnosis to treatment >12 months was significantly associated with improved OS, longer TTF1, TTF2 and response to first-line anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGF TKI) therapy. Variables associated with tumour biology, natural history and the systemic inflammatory response were associated with improved OS and TTF1. Development of hypertension was predictive of anti-VEGF TKI outcome. Toxicities were as expected for each drug class.   Survival and toxicity outcomes from two Australian sites are comparable to published data. The adverse event profile differs to conventional chemotherapy. Clinicians caring for patients with metastatic renal cancer will need to become familiar with these toxicities and their management as these agents enter widespread use. © 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.

Bone marrow invasion in multiple myeloma and metastatic disease.

PubMed

Vilanova, J C; Luna, A

2016-04-01

Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. Copyright © 2015 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Metastatic cancer stem cells: from the concept to therapeutics.

PubMed

Liao, Wen-Ting; Ye, Ya-Ping; Deng, Yong-Jian; Bian, Xiu-Wu; Ding, Yan-Qing

2014-01-01

Metastatic cancer stem cells (MCSCs) refer to a subpopulation of cancer cells with both stem cell properties and invasion capabilities that contribute to cancer metastasis. MCSCs have capability of self-renewal, potentials of multiple differentiation and development and/or reconstruction of cancer tissues. As compared with stationary cancer stem cells, MCSCs are capable of invasion to normal tissues such as vasculatures, resistance to chemo- and/or radio-therapies, escape from immune surveillance, survival in circulation and formation of metastasis. MCSCs are derived from invasive cancer stem cells (iCSCs) due to the plasticity of cancer stem cells, which is one of the characteristics of cancer cell heterogeneity. Both stages of iCSCs and MSCSs are the potential therapeutic targets for cancer metastasis in the future strategies of personalized cancer therapy.

In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer

NASA Astrophysics Data System (ADS)

Lizotte, P. H.; Wen, A. M.; Sheen, M. R.; Fields, J.; Rojanasopondist, P.; Steinmetz, N. F.; Fiering, S.

2016-03-01

Nanotechnology has tremendous potential to contribute to cancer immunotherapy. The ‘in situ vaccination’ immunotherapy strategy directly manipulates identified tumours to overcome local tumour-mediated immunosuppression and subsequently stimulates systemic antitumour immunity to treat metastases. We show that inhalation of self-assembling virus-like nanoparticles from cowpea mosaic virus (CPMV) reduces established B16F10 lung melanoma and simultaneously generates potent systemic antitumour immunity against poorly immunogenic B16F10 in the skin. Full efficacy required Il-12, Ifn-γ, adaptive immunity and neutrophils. Inhaled CPMV nanoparticles were rapidly taken up by and activated neutrophils in the tumour microenvironment as an important part of the antitumour immune response. CPMV also exhibited clear treatment efficacy and systemic antitumour immunity in ovarian, colon, and breast tumour models in multiple anatomic locations. CPMV nanoparticles are stable, nontoxic, modifiable with drugs and antigens, and their nanomanufacture is highly scalable. These properties, combined with their inherent immunogenicity and demonstrated efficacy against a poorly immunogenic tumour, make CPMV an attractive and novel immunotherapy against metastatic cancer.

Sapanisertib or Pazopanib Hydrochloride in Treating Patients With Locally Advanced or Metastatic Sarcoma

ClinicalTrials.gov

2018-06-20

High Grade Sarcoma; Metastatic Leiomyosarcoma; Metastatic Malignant Peripheral Nerve Sheath Tumor; Metastatic Synovial Sarcoma; Metastatic Undifferentiated Pleomorphic Sarcoma; Myxofibrosarcoma; Recurrent Leiomyosarcoma; Recurrent Malignant Peripheral Nerve Sheath Tumor; Recurrent Synovial Sarcoma; Recurrent Undifferentiated Pleomorphic Sarcoma; Uterine Corpus Leiomyosarcoma

Bowenoid epidermotropic metastatic squamous cell carcinoma.

PubMed

Ihm, C W; Park, S L; Sung, S Y; Lee, I S

1996-10-01

Epidermotropic metastatic squamous cell carcinoma produced full-thickness cellular atypia of bowenoid carcinoma in situ or vulvar intraepithelial neoplasia, grade 3 (VIN 3), in a 73-year-old woman who had past history of uterine cervical carcinoma. The presence of intravascular tumor cell nests and areas showing smooth continuity of the malignant squamous cell nodules with the adjoining benign epidermis supported the possibility of the epidermotropic metastasis. To our knowledge, metastatic epidermotropic squamous carcinoma clinicopathologically simulating primary Bowen's disease has not been reported.

Fine-Needle Aspiration of Metastatic Central Type Primitive Neuroectodermal Tumors in Patients with a Germ Cell Tumor.

PubMed

Chen, Shaoxiong; Idrees, Muhammad; Lin, Jingmei; Wu, Howard H

2017-01-01

Central type primitive neuroectodermal tumors (PNET) are some of the most frequent somatic type tumors derived from germ cell tumors and can metastasize. We studied the cytomorphological features of metastatic central type PNET by fine-needle aspiration (FNA). A computerized search of our laboratory information system was performed for the 9-year period from 2005 through 2014 to identify all cytology cases in which a diagnosis of metastatic central type PNET had been rendered. A total of 5 FNA cases were collected and direct smears were reexamined. All patients had a history of testicular or ovarian germ cell tumors. Direct smears displayed single and clusters of atypical round to oval cells with scant to moderate cytoplasm. Abundant naked nuclei were present in Diff-Quik-stained smears with mild to marked crushed artifacts and nuclear molding. Tumor cells showed fine granular chromatin, nuclear size variation (up to 1:3), and one or more small nucleoli. Pseudorosettes (Homer Wright-like rosette) were noticed in 1 case. Tumor cells were commonly positive for synaptophysin. Metastatic PNET can be reliably diagnosed by FNA. Differential diagnoses include Ewing sarcoma/peripheral PNET, alveolar rhabdomyosarcoma, neuroblastoma, etc. It is important to be familiar with this entity to avoid diagnostic pitfalls. © 2017 S. Karger AG, Basel.

Fulminant hepatic failure due to metastatic choroidal melanoma

PubMed Central

Escobar-Valdivia, Emmanuel; Monreal-Robles, Roberto; Delgado-García, Guillermo; Hernández-Velazquez, Badir

2017-01-01

Background: Acute liver failure (ALF) as a consequence of metastatic disease is extremely uncommon. The liver is the most commonly affected organ by metastatic disease, but only a few cases of ALF in the setting of metastatic choroidal melanoma have been reported. Case Presentation: We describe the case of a 47-year-old man with right upper quadrant pain, progressive jaundice, and unintentional weight loss. He also reported that he had experienced reduced left visual acuity which progressed to blindness over 2 months. On physical examination, we found a pigmented scleral lesion in the left eye. He had a coagulopathy and, during his hospital stay, he also developed encephalopathy. The diagnosis of ALF was therefore established and was later attributed to metastatic uveal melanoma. In addition, we briefly review the relevant literature. Conclusion: Liver metastasis should be kept in mind when assessing abnormal liver function tests in patients with uveal malignant melanoma. PMID:28503286

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

PubMed Central

Gerlini, Gianni; Tun-Kyi, Adrian; Dudli, Christa; Burg, Günter; Pimpinelli, Nicola; Nestle, Frank O.

2004-01-01

CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n = 10) but not in primary melanoma lesions (n = 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor. PMID:15579430

Surgery of metastatic anal sac adenocarcinoma in five dogs.

PubMed

Hobson, Howard Phil; Brown, Marjorie Raquel; Rogers, Kenita S

2006-04-01

To identify survival and morbidity information after surgery for metastases from apocrine gland anal sac adenocarcinomas (AGACA). Retrospective study. Five dogs with AGACA. Medical records of dogs that had surgery for treatment of metastatic AGACA between 1993 and 2003 were reviewed. Criteria for inclusion required that dogs had lymphadenectomy, with or without further debulking, as part of their treatment for metastatic AGACA and that the tissue was histologically confirmed as consistent with the primary AGACA. Signalment, history, physical examination findings, clinicopathologic data, imaging findings, surgical complications, number of surgeries, survival times, and cause of death were recorded. All dogs had a complete blood count, serum biochemical profile, serum electrolytes, 3-projection thoracic radiographs, abdominal radiographs and/or abdominal ultrasonography, and histologic confirmation of metastatic AGACA invading the regional lymph nodes and caudal abdomen. No surgical complications occurred. Three dogs were euthanatized; median survival, 20.6 months. One dog was alive for 19 months postoperatively. One dog had 5 sequential surgical procedures: 1 iliac lymphadenectomy and 4 debulking procedures of metastatic neoplastic tissue around and dorsal to the iliac vessels extending into the pelvic cavity, and was alive 54 months after initial surgery. Dogs with anal sac adenocarcinoma metastases to the iliac lymph nodes can experience long-term survival after surgical excision of the metastatic lesion. Lymphadenectomy may afford long-term survival to patients with metastatic anal sac adenocarcinoma.

Impact of Surgical Resection of the Primary Tumor on Overall Survival in Patients With Metastatic Pheochromocytoma or Sympathetic Paraganglioma.

PubMed

Roman-Gonzalez, Alejandro; Zhou, Shouhao; Ayala-Ramirez, Montserrat; Shen, Chan; Waguespack, Steven G; Habra, Mouhammed A; Karam, Jose A; Perrier, Nancy; Wood, Christopher G; Jimenez, Camilo

2018-07-01

To determine whether primary tumor resection in patients with metastatic pheochromocytoma or paraganglioma (PPG) is associated with longer overall survival (OS). Patients with metastatic PPG have poor survival outcomes. The impact of surgical resection of the primary tumor on OS is not known. We retrospectively studied patients with metastatic PPG treated at the University of Texas, MD Anderson Cancer Center from January 2000 through January 2015. Kaplan-Meier analysis with log-rank tests was used to compare OS among patients undergoing primary tumor resection and patients not treated surgically. Propensity score method was applied to adjust for selection bias using demographic, clinical, biochemical, genetic, imaging, and pathologic information. A total of 113 patients with metastatic PPG were identified. Eighty-nine (79%) patients had surgery and 24 (21%) patients did not. Median OS was longer in patients who had surgery than in patients who did not [148 months, 95% confidence interval (CI) 112.8-183.2 months vs 36 months, 95% CI 27.2-44.8 months; P < 0.001].Fifty-three (46%) patients had synchronous metastases; of these patients, those who had surgery had longer OS than those who did not (85 months, 95% CI 64.5-105.4 months vs 36 months, 95% CI 29.7-42.3 months; P < 0.001). Patients who had surgery had a similar ECOG performance status to the ones who did not (P = 0.1798, two sample t test; P = 0.2449, Wilcoxon rank sum test). Univariate and propensity score analysis confirmed that patients treated with surgery had longer OS than those not treated surgically irrespective of age, race, primary tumor size and location, number of metastatic sites, and genetic background (log-rank P < 0.001).In patients with hormonally active tumors (70.8%), the symptoms of catecholamine excess improved after surgery. However, the tumor burden was a more important determinant of OS than hormonal secretion. Primary tumor resection in patients with metastatic PPG appeared to be

Cutaneous metastatic tuberculous abcess in a patient with cervico-mediastinal lymphatic tuberculosis.

PubMed

Dekeyzer, S; Moerman, F; Callens, S; Vandekerckhove, L

2013-01-01

Metastatic tuberculous abcess or tuberculous gumma is a rare form of cutaneous tuberculosis resulting from haematogenous spread from a non-cutaneous tuberculous focus. A 26-year old patient of Pakistani origin presented at our clinic with an abcess on his right thigh that had slowly grown over a period of two months to a total size of 30 cm. Based on clinical findings, microbiology, CT thigh and CT chest, our patient was diagnosed with a tuberculous abcess and cervico-mediastinal tuberculous lymphadenitis. Antituberculosis drugs were initiated. Cutaneous tuberculosis should be included in the differential diagnosis of chronic cutaneous abcesses, especially in patients from tuberculosis endemic nations.

Systemic treatment and primary tumor location in patients with metastatic colorectal cancer.

PubMed

Antoniou, Efstathios; Andreatos, Nikolaos; Margonis, Georgios A; Papalois, Apostolos; Wang, Jaeyun; Damaskos, Christos; Garmpis, Nikolaos; Buettner, Stefan; Deshwar, Amar; Pappas, Vasilios; Weiss, Matthew J; Pawlik, Timothy M; Pikoulis, Emmanouel

2017-01-01

Tumor location (right-sided vs. left-sided) is known to exert a significant influence on the prognosis of primary colorectal cancer (CRC). Given the genetic continuity between primary and metastatic lesions, we aimed to summarize the existing literature on the prognostic implications of primary tumor site as well as to examine the response to chemotherapy by primary tumor location in patients with metastatic CRC (mCRC). A structured review of the literature was performed between 6/1/2016-7/1/2016 using the Pubmed database. Original research articles published between 1/1/2000- 07/01/2016 were considered eligible. The primary endpoints were overall survival (OS)/ progression free survival (PFS) and response to systemic treatment in patients with mCRC. Eleven studies were included. Tumor site was a strong independent predictor of worse OS/PFS in 9 studies, with right-sided tumors having worse prognosis in all cases. Furthermore, 6 studies demonstrated an inferior response to systemic treatment or worse prognosis following the administration of specific regimens among patients with right-sided cancers. As such, there is significant evidence that right-sided lesions are associated with poor outcomes and resistance to systemic treatment. Consequently, primary tumor location should be a consideration, when the administration of systemic therapy is contemplated in mCRC.

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma

PubMed Central

Glenn, Sean T.; Jones, Craig A.; Sexton, Sandra; LeVea, Charles M.; Caraker, Susan M.; Hajduczok, George; Gross, Kenneth W.

2014-01-01

Efforts to model human pancreatic neuroendocrine tumors (PanNET) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene while classically associated with expression in the kidney is also expressed in many other extra-renal tissues including the pancreas. To induce tumorigenesis within renin specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon, furthermore an increased level of glucagon is found in the serum identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to lymph nodes and liver, mimicking human disease and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides a unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying co-operating mutations that are necessary for progression of disease. PMID:24292676

Conditional deletion of p53 and Rb in the renin-expressing compartment of the pancreas leads to a highly penetrant metastatic pancreatic neuroendocrine carcinoma.

PubMed

Glenn, S T; Jones, C A; Sexton, S; LeVea, C M; Caraker, S M; Hajduczok, G; Gross, K W

2014-12-11

Efforts to model human pancreatic neuroendocrine tumors (PanNETs) in animals have been moderately successful, with minimal evidence for glucagonomas or metastatic spread. The renin gene, although classically associated with expression in the kidney, is also expressed in many other extrarenal tissues including the pancreas. To induce tumorigenesis within rennin-specific tissues, floxed alleles of p53 and Rb were selectively abrogated using Cre-recombinase driven by the renin promoter. The primary neoplasm generated is a highly metastatic islet cell carcinoma of the pancreas. Lineage tracing identifies descendants of renin-expressing cells as pancreatic alpha cells despite a lack of active renin expression in the mature pancreas. Both primary and metastatic tumors express high levels of glucagon; furthermore, an increased level of glucagon is found in the serum, identifying the pancreatic cancer as a functional glucagonoma. This new model is highly penetrant and exhibits robust frequency of metastases to the lymph nodes and the liver, mimicking human disease, and provides a useful platform for better understanding pancreatic endocrine differentiation and development, as well as islet cell carcinogenesis. The use of fluorescent reporters for lineage tracing of the cells contributing to disease initiation and progression provides an unique opportunity to dissect the timeline of disease, examining mechanisms of the metastatic process, as well as recovering primary and metastatic cells for identifying cooperating mutations that are necessary for progression of disease.

Prognostic significance of preimmunotherapy serum CA27.29 (MUC-1) mucin level after active specific immunotherapy of metastatic adenocarcinoma patients.

PubMed

MacLean, G D; Reddish, M A; Longenecker, B M

1997-01-01

The TRUQUANT BR radioimmunoassay, which uses monoclonal antibody B27.29 to quantitate CA27.29 mucin antigen (MUC-1 gene product) in serum, has recently received Food and Drug Administration approval for predicting recurrent breast cancer in patients with stage II and III disease. The purpose of this study was to determine whether the new radioimmunoassay for serum MUC-1 has prognostic significance for patients with metastatic adenocarcinoma receiving active specific immunotherapy (ASI). Using 40 U/ml as the upper limit of "normal," patients with metastatic breast and ovarian cancer with a preimmunotherapy serum CA27.29 mucin > 40 U/ml (CA27.29 Hi patients) had a poorer survival than CA27.29 Lo patients (< or = 40 U/ml) after ASI. There was no significant correlation between preimmunotherapy CA27.29 serum levels and measurable tumor burden. The preimmunotherapy CA27.29 serum level was a predictor of poor survival of metastatic colorectal and pancreatic cancer patients independent of other prognostic factors. There seemed to be two populations of pancreatic cancer patients, separated at 60 U/ml serum CA27.29 (CA27.29 Hi versus Lo patients). A CA27.29 serum level of 22 U/ml separated patients with CA27.29 Hi vs. Lo colorectal cancer. Patients with CA27.29 Lo colorectal and pancreatic cancer survived longer after ASI compared with patients with CA27.29 Hi colorectal and pancreatic cancer, respectively. We suggest that various CA27.29 serum levels define poor prognosis patients (CA27.29 Hi secretors) versus good prognosis patients (CA27.29 Lo secretors) for different cancer types.

Advantages of concurrent biochemotherapy modified by decrescendo interleukin-2, granulocyte colony-stimulating factor, and tamoxifen for patients with metastatic melanoma.

PubMed

O'Day, S J; Gammon, G; Boasberg, P D; Martin, M A; Kristedja, T S; Guo, M; Stern, S; Edwards, S; Fournier, P; Weisberg, M; Cannon, M; Fawzy, N W; Johnson, T D; Essner, R; Foshag, L J; Morton, D L

1999-09-01

Concurrent biochemotherapy results in high response rates but also significant toxicity in patients with metastatic melanoma. We attempted to improve its efficacy and decrease its toxicity by using decrescendo dosing of interleukin-2 (IL-2), posttreatment granulocyte colony-stimulating factor (G-CSF), and low-dose tamoxifen. Forty-five patients with poor prognosis metastatic melanoma were treated at a community hospital inpatient oncology unit affiliated with the John Wayne Cancer Institute (Santa Monica, CA) between July 1995 and September 1997. A 5-day modified concurrent biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo IL-2, interferon alfa-2b, and tamoxifen was repeated at 21-day intervals. G-CSF was administered beginning on day 6 for 7 to 10 days. The overall response rate was 57% (95% confidence interval, 42% to 72%), the complete response rate was 23%, and the partial response rate was 34%. Complete remissions were achieved in an additional 11% of patients by surgical resection of residual disease after biochemotherapy. The median time to progression was 6.3 months and the median duration of survival was 11.4 months. At a maximum follow-up of 36 months (range, 10 to 36 months), 32% of patients are alive and 14% remain free of disease. Decrescendo IL-2 dosing and administration of G-CSF seemed to reduce toxicity, length of hospital stay, and readmission rates. No patient required intensive care unit monitoring, and there were no treatment-related deaths. The data from this study indicate that the modified concurrent biochemotherapy regimen reduces the toxicity of concurrent biochemotherapy with no apparent decrease in response rate in patients with poor prognosis metastatic melanoma.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

The Differential Contribution of the Innate Immune System to a Good Pathological Response in the Breast and Axillary Lymph Nodes Induced by Neoadjuvant Chemotherapy in Women with Large and Locally Advanced Breast Cancers

PubMed Central

Verma, Chandan; Eremin, Jennifer M.; Cowley, Gerard; Ilyas, Mohammad; Satthaporn, Sukchai; Eremin, Oleg

2017-01-01

The tumour microenvironment consists of malignant cells, stroma, and immune cells. The role of adaptive immunity in inducing a pathological complete response (pCR) in breast cancer with neoadjuvant chemotherapy (NAC) is well studied. The contribution of innate immunity, however, is poorly documented. Breast tumours and axillary lymph nodes (ALNs) from 33 women with large and locally advanced breast cancers (LLABCs) undergoing NAC were immunohistochemically assessed for tumour-infiltrating macrophages (TIMs: M1 and M2), neutrophils (TINs), and dendritic cells (TIDCs) using labelled antibodies and semiquantitative methods. Patients' blood neutrophils (n = 108), DCs (mDC1 and pDC), and their costimulatory molecules (n = 30) were also studied. Pathological results were classified as pCR, good (GPR) or poor (PRR). In breast and metastatic ALNs, high levels of CD163+ TIMs were significantly associated with a pCR. In blood, high levels of neutrophils were significantly associated with pCR in metastatic ALNs, whilst the % of mDC1 and pDC and expression of HLA-DR, mDC1 CD40, and CD83 were significantly reduced. NAC significantly reduced tumour DCs but increased blood DCs. PPRs to NAC had significantly reduced HLA-DR, CD40, and CD86 expression. Our study demonstrated novel findings documenting the differential but important contributions of innate immunity to pCRs in patients with LLABCs undergoing NAC. PMID:28913366

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients

PubMed Central

Radvanyi, Laszlo G.; Bernatchez, Chantale; Zhang, Minying; Fox, Patricia S.; Miller, Priscilla; Chacon, Jessica; Wu, Richard; Lizee, Gregory; Mahoney, Sandy; Alvarado, Gladys; Glass, Michelle; Johnson, Valen E.; McMannis, John D.; Shpall, Elizabeth; Prieto, Victor; Papadopoulos, Nicholas; Kim, Kevin; Homsi, Jade; Bedikian, Agop; Hwu, Wen-Jen; Patel, Sapna; Ross, Merrick I.; Lee, Jeffrey E.; Gershenwald, Jeffrey E.; Lucci, Anthony; Royal, Richard; Cormier, Janice N.; Davies, Michael A.; Mansaray, Rahmatu; Fulbright, Orenthial J.; Toth, Christopher; Ramachandran, Renjith; Wardell, Seth; Gonzalez, Audrey; Hwu, Patrick

2012-01-01

Purpose Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing Phase II clinical trial testing the efficacy of ACT using TIL in metastatic melanoma patients and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL followed by two cycles of high-dose (HD) IL-2 therapy. The effects of patient clinical features and the phenotypes of the T-cells infused on clinical response were determined. Results Overall, 15/31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC), with two patients (6.5%) having a complete response. Progression-free survival of >12 months was observed for 9/15 (60%) of the responding patients. Factors significantly associated with objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T-cells in the infusion product, a more differentiated effector phenotype of the CD8+ population and a higher frequency of CD8+ T-cells co-expressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in telomere lengths of TIL between responders and non-responders was identified. Conclusion These results indicate that immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in metastatic melanoma patients and that CD8+ T-cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. PMID:23032743

MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis

PubMed Central

Musa, Julian; Aynaud, Marie-Ming; Mirabeau, Olivier; Delattre, Olivier; Grünewald, Thomas GP

2017-01-01

Limitless cell proliferation, evasion from apoptosis, dedifferentiation, metastatic spread and therapy resistance: all these properties of a cancer cell contribute to its malignant phenotype and affect patient outcome. MYBL2 (alias B-Myb) is a transcription factor of the MYB transcription factor family and a physiological regulator of cell cycle progression, cell survival and cell differentiation. When deregulated in cancer cells, MYBL2 mediates the deregulation of these properties. In fact, MYBL2 is overexpressed and associated with poor patient outcome in numerous cancer entities. MYBL2 and players of its downstream transcriptional network can be used as prognostic and/or predictive biomarkers as well as potential therapeutic targets to offer less toxic and more specific anti-cancer therapies in future. In this review, we summarize current knowledge on the physiological roles of MYBL2 and highlight the impact of its deregulation on cancer initiation and progression. PMID:28640249

High-grade poorly differentiated neuroendocrine carcinoma of the breast with low oncotype Dx recurrence score: A case report.

PubMed

Munoz-Zuluaga, Carlos A; Kotiah, Sandy; Studeman, Kimberley D

2017-01-01

Primary neuroendocrine carcinoma of the breast (NECB) is a rare malignant tumor with controversial biological behavior and a lack of data guiding treatment decisions due to its scarcity. Cancer gene-expression profiling tests provide a better indication of clinical prognosis and help determine the best clinical management versus the traditional clinical and pathological parameters. This is a report of a NECB with a genetic assay that showed a low-risk tumor despite high-grade and poorly differentiated histopathological features. Patient outcomes correlate with the low risk classification without the need for adjuvant chemotherapy despite the standard clinical-pathologic approach. Analysis of cancer related genes expression and outcomes in historical NECB may elucidate new insight of this rare disease.

Targeting Nodal in Conjunction with Dacarbazine Induces Synergistic Anti-cancer Effects in Metastatic Melanoma

PubMed Central

Hardy, Katharine M.; Strizzi, Luigi; Margaryan, Naira V.; Gupta, Kanika; Murphy, George F.; Scolyer, Richard A.; Hendrix, Mary J.C.

2015-01-01

Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent Dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently FDA approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain if targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Implications Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma. PMID:25767211

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.

Constraining cosmic scatter in the Galactic halo through a differential analysis of metal-poor stars

NASA Astrophysics Data System (ADS)

Reggiani, Henrique; Meléndez, Jorge; Kobayashi, Chiaki; Karakas, Amanda; Placco, Vinicius

2017-12-01

Context. The chemical abundances of metal-poor halo stars are important to understanding key aspects of Galactic formation and evolution. Aims: We aim to constrain Galactic chemical evolution with precise chemical abundances of metal-poor stars (-2.8 ≤ [Fe/H] ≤ -1.5). Methods: Using high resolution and high S/N UVES spectra of 23 stars and employing the differential analysis technique we estimated stellar parameters and obtained precise LTE chemical abundances. Results: We present the abundances of Li, Na, Mg, Al, Si, Ca, Sc, Ti, V, Cr, Mn, Co, Ni, Zn, Sr, Y, Zr, and Ba. The differential technique allowed us to obtain an unprecedented low level of scatter in our analysis, with standard deviations as low as 0.05 dex, and mean errors as low as 0.05 dex for [X/Fe]. Conclusions: By expanding our metallicity range with precise abundances from other works, we were able to precisely constrain Galactic chemical evolution models in a wide metallicity range (-3.6 ≤ [Fe/H] ≤ -0.4). The agreements and discrepancies found are key for further improvement of both models and observations. We also show that the LTE analysis of Cr II is a much more reliable source of abundance for chromium, as Cr I has important NLTE effects. These effects can be clearly seen when we compare the observed abundances of Cr I and Cr II with GCE models. While Cr I has a clear disagreement between model and observations, Cr II is very well modeled. We confirm tight increasing trends of Co and Zn toward lower metallicities, and a tight flat evolution of Ni relative to Fe. Our results strongly suggest inhomogeneous enrichment from hypernovae. Our precise stellar parameters results in a low star-to-star scatter (0.04 dex) in the Li abundances of our sample, with a mean value about 0.4 dex lower than the prediction from standard Big Bang nucleosynthesis; we also study the relation between lithium depletion and stellar mass, but it is difficult to assess a correlation due to the limited mass range. We

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

PubMed

Dong, Baijun; Fan, Liancheng; Wang, Yanqing; Chi, Chenfei; Ma, Xiaowei; Wang, Rui; Cai, Wen; Shao, Xiaoguang; Pan, Jiahua; Zhu, Yinjie; Shangguan, Xun; Xin, Zhixiang; Hu, Jianian; Xie, Shaowei; Kang, Xiaonan; Zhou, Lixin; Xue, Wei

2017-05-01

To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of m

Prevalence and Treatment Patterns of Physical Impairments in Patients With Metastatic Breast Cancer

PubMed Central

Cheville, Andrea L.; Troxel, Andrea B.; Basford, Jeffrey R.; Kornblith, Alice B.

2014-01-01

Purpose Physical impairments cause profound functional declines in patients with cancer. Although common rehabilitation measures can address many impairments, the extent of their delivery is unknown. We studied these issues by quantifying physical impairments in patients with metastatic breast cancer and by assessing how they are addressed. Patients and Methods A consecutive sample of 163 community-dwelling patients with metastatic breast cancer was stratified by Karnofsky performance score and administered the Medical Outcomes Study Physical Function Subscale and the Older Americans Resource Study Activities of Daily Living subscales. Cancer-related physical impairments were identified through a physical examination, the 6-Minute Walk Test, and the Functional Independence Measure Mobility Subscale. Patients were questioned regarding the nature, type, and setting of treatments for impairments. Physical rehabilitation needs were determined through a consensus process involving physiatrists and physical/occupational therapists specializing in cancer. Results Ninety-two percent of patients (150 of 163) had at least one physical impairment. Among 530 identified impairments, 484 (92%) required a physical rehabilitation intervention and 469 (88%) required physical therapy (PT) and/or occupational therapy (OT). Only 30% of impairments requiring rehabilitation services and 21% of those requiring PT/OT received treatment. Impairments detected during hospitalization were overwhelmingly more likely to receive a rehabilitation intervention (odds ratio [OR] = 87.9; 95% CI, 28.5 to 271.4), and PT/OT (OR = 558.8; 95% CI, 187.0 to 1,669.6). Low socioeconomic and minority status were significantly associated with nontreatment. Conclusion Remediable physical impairments were prevalent and poorly addressed among patients with metastatic breast cancer, drastically so in the outpatient setting. Undertreatment was particularly prominent among minority and socioeconomically disadvantaged

Circulating tumor cells in metastatic breast cancer: timing of blood extraction for analysis.

PubMed

Martín, Miguel; García-Sáenz, José Angel; Maestro De las Casas, Maria Luisa; Vidaurreta, Marta; Puente, Javier; Veganzones, Silvia; Rodríguez-Lajusticia, Laura; De la Orden, Virginia; Oliva, Belén; De la Torre, Julio-César; López-Tarruella, Sara; Casado, Antonio; Sastre, Javier; Díaz-Rubio, Eduardo

2009-10-01

Circulating tumor cells (CTCs) can be detected in the peripheral blood of around 50% of patients with metastatic breast cancer. Their numbers are an independent predictor of the patient's progression-free survival (PFS) and of overall survival (OS). However, to date, none of the studies carried out with the most commonly used system of CTC determination (the CellSearch System, approved by the US Food and Drug Administration) has examined the intra-patient variation in CTC numbers, a variation that could impact on prognosis assessment. To evaluate possible circadian variations in the number of CTCs in patients with breast cancer a pilot study was conducted in which these cells were quantified 12 h apart (at 8:00 a.m. and 8:00 p.m. of the same day) in a cohort of hospitalized patients with metastatic breast cancer. Out of the 58 patients included in the study, 51 were evaluable. No statistically significant differences between day-time and night-time CTC numbers were observed (p=0.8427, Wilcoxon matched pair test). Only two of the patients were classified in different prognostic categories in the morning and night determinations (5 or more CTCs=poor prognosis group; <5 CTCs=good prognosis group). The prognostic classification of the remaining 49 patients was the same at 8:00 a.m. and 8:00 p.m. The number of peripheral blood CTCs in metastatic breast cancer patients is not significantly different at 8:00 a.m. from that at 8:00 p.m. and, as such, indicates a lack of circadian rhythm with respect to CTC numbers in these patients.

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

ClinicalTrials.gov

2018-06-28

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

Differential expression of c-Met between primary and metastatic sites in clear-cell renal cell carcinoma and its association with PD-L1 expression.

PubMed

Lalani, Aly-Khan A; Gray, Kathryn P; Albiges, Laurence; Callea, Marcella; Pignon, Jean-Christophe; Pal, Soumitro; Gupta, Mamta; Bhatt, Rupal S; McDermott, David F; Atkins, Michael B; Woude, G F Vande; Harshman, Lauren C; Choueiri, Toni K; Signoretti, Sabina

2017-11-28

In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0-300): intensity of c-Met staining (0-3) x % of positive cells (0-100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.

Control of Metastatic Progression by microRNA Regulatory Networks

PubMed Central

Pencheva, Nora; Tavazoie, Sohail F.

2015-01-01

Aberrant microRNA (miRNA) expression is a defining feature of human malignancy. Specific miRNAs have been identified as promoters or suppressors of metastatic progression. These miRNAs control metastasis through divergent or convergent regulation of metastatic gene pathways. Some miRNA regulatory networks govern cell-autonomous cancer phenotypes, while others modulate the cell-extrinsic composition of the metastatic microenvironment. The use of small RNAs as probes into the molecular and cellular underpinnings of metastasis holds promise for the identification of candidate genes for potential therapeutic intervention. PMID:23728460

WITHDRAWN: Systemic treatments for metastatic cutaneous melanoma.

PubMed

Crosby, Tom; Fish, Reg; Coles, Bernadette; Mason, Malcolm

2018-02-07

Systemic therapies for metastatic cutaneous melanoma, the most aggressive of all skin cancers, remain disappointing. Few lasting remissions are achieved and the therapeutic aim remains one of palliation.Many agents are used alone or in combination with varying degrees of toxicity and cost. It is unclear whether evidence exists to support these complex regimens over best supportive care / placebo. To review the benefits from the use of systemic therapies in metastatic cutaneous melanoma compared to best supportive care/placebo, and to establish whether a 'standard' therapy exists which is superior to other treatments. Randomised controlled trials were identified from the MEDLINE, EMBASE and CCTR/CENTRAL databases. References, conference proceedings, and Science Citation Index/Scisearch were also used to locate trials. Cancer registries and trialists were also contacted. Randomised controlled trials of adults with histologically proven metastatic cutaneous melanoma in which systemic anti-cancer therapy was compared with placebo or supportive care. Study selection was performed by two independent reviewers. Data extraction forms were used for studies which appeared to meet the selection criteria and, where appropriate, full text articles were retrieved and reviewed independently. No randomised controlled trials were found comparing a systemic therapy with placebo or best supportive care in metastatic cutaneous melanoma. There is no evidence from randomised controlled clinical trials to show superiority of systemic therapy over best supportive care / placebo in the treatment of malignant cutaneous melanoma.Given that patients with metastatic melanoma frequently receive systemic therapy, it is our pragmatic view that a future systematic review could compare any systemic treatment, or combination of treatments, to single agent dacarbazine.

Fine needle aspiration biopsy diagnosis of metastatic neoplasms of the breast. A three-case report

PubMed Central

Raquel, Garza-Guajardo; Nora, Mendez-Olvera; Pablo, Flores-Gutierrez Juan; Silvia, Hernandez-Martinez; Michelle, Candanosa-Mc Cann; Jesús, Ancer-Rodriguez; Oralia, Barboza-Quintana

2005-01-01

Metastases to the breast are unusual lesions that make up approximately 2% of all malignant mammary neoplasms and may mimic both benign and malignant primary neoplasms from a clinical point of view, as well as in imaging studies. Arriving at a correct diagnosis is therefore essential in order to establish appropriate management. We present three cases of metastatic neoplasms diagnosed through fine needle aspiration biopsy and immunocytochemistry. The cytological diagnoses were: medulloblastoma in an 18-year-old woman, melanoma in a 26-year-old man, and an exceptional case of ovarian sarcoma originating from a granulosa cell tumor with metastases to both breasts. A metastatic disease should be considered in the differential diagnosis of a palpable mass in the breast, especially if there is a history of an extramammary malignant neoplasm. Fine needle aspiration biopsy is the method of choice for the management of these cases. Whenever possible the exam of the material obtained should be compared to the previous biopsy, which is usually enough to arrive at a correct diagnosis, thus preventing unnecessary surgical procedures. PMID:16174298

Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid–stimulated migration of murine osteosarcoma LM8 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kubohara, Yuzuru, E-mail: ykuboha@juntendo.ac.jp; Department of Health Science, Juntendo University Graduate School of Health and Sports Science, Inzai 270-1695; Komachi, Mayumi

Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), −2, and −3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5–20 μM) dose-dependently suppressed LPA-induced cell migration with associated IC{sub 50} values of 5.5, 4.6, andmore » 4.2 μM, respectively. On the other hand, the IC{sub 50} values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 μM, respectively, in LM8 cells, and >20, 14.8, and 4.3 μM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. - Highlights: • LPA induces cell migration (invasion) in murine osteosarcoma LM8 cells. • DIFs are novel lead anti-tumor agents found in Dictyostelium discoideum. • We examined the effects of DIF derivatives on LPA-induced LM8 cell migration in vitro. • Some of the DIF derivatives inhibited LPA-induced LM8 cell migration.« less

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

PubMed

Weber, Matthias M; Fottner, Christian

2018-01-01

Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited. Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load. © 2018 S. Karger GmbH, Freiburg.

Differentiation of brain abscesses from glioblastomas and metastatic brain tumors: comparisons of diagnostic performance of dynamic susceptibility contrast-enhanced perfusion MR imaging before and after mathematic contrast leakage correction.

PubMed

Toh, Cheng Hong; Wei, Kuo-Chen; Chang, Chen-Nen; Ng, Shu-Hang; Wong, Ho-Fai; Lin, Ching-Po

2014-01-01

To compare the diagnostic performance of dynamic susceptibility contrast-enhanced perfusion MRI before and after mathematic contrast leakage correction in differentiating pyogenic brain abscesses from glioblastomas and/or metastatic brain tumors. Cerebral blood volume (CBV), leakage-corrected CBV and leakage coefficient K2 were measured in enhancing rims, perifocal edema and contralateral normal appearing white matter (NAWM) of 17 abscesses, 19 glioblastomas and 20 metastases, respectively. The CBV and corrected CBV were normalized by dividing the values in the enhancing rims or edema to those of contralateral NAWM. For each study group, a paired t test was used to compare the K2 of the enhancing rims or edema with those of NAWM, as well as between CBV and corrected CBV of the enhancing rims or edema. ANOVA was used to compare CBV, corrected CBV and K2 among three lesion types. The diagnostic performance of CBV and corrected CBV was assessed with receiver operating characteristic (ROC) curve analysis. The CBV and correction CBV of enhancing rim were 1.45±1.17 and 1.97±1.01 for abscesses, 3.85±2.19 and 4.39±2.33 for glioblastomas, and 2.39±0.90 and 2.97±0.78 for metastases, respectively. The CBV and corrected CBV in the enhancing rim of abscesses were significantly lower than those of glioblastomas and metastases (P = 0.001 and P = 0.007, respectively). In differentiating abscesses from glioblastomas and metastases, the AUC values of corrected CBV (0.822) were slightly higher than those of CBV (0.792). Mathematic leakage correction slightly increases the diagnostic performance of CBV in differentiating pyogenic abscesses from necrotic glioblastomas and cystic metastases. Clinically, DSC perfusion MRI may not need mathematic leakage correction in differentiating abscesses from glioblastomas and/or metastases.

Metastatic serous carcinoma presenting as inflammatory carcinoma over the breast-Report of two cases and literature review.

PubMed

Panse, Gauri; Bossuyt, Veerle; Ko, Christine J

2018-03-01

Non-mammary metastases involving breast are rare and most commonly involve the breast parenchyma. Infrequently, metastasis from an extramammary primary site presents as inflammatory carcinoma over the breast. Diagnosis of such lesions can be challenging, especially in patients with coexisting primary breast carcinoma. Few such cases have been described in literature; however, none of the previously reported cases had a prior history of primary breast carcinoma. We present 2 patients with history of breast carcinoma and serous carcinoma of ovarian/peritoneal origin that presented with inflammatory carcinoma over the breast. Biopsies from breast tissue showed atypical cells in the dermis forming cords and papillary structures. Histopathologic differential diagnosis included infiltrating ductal carcinoma of breast origin and metastatic serous carcinoma. Immunohistochemical studies showed that the tumor cells were positive for markers of ovarian origin such as PAX-8 and CA-125 and negative for breast markers such as GATA-3, thus supporting the diagnosis. In summary, we describe the unusual presentation of metastatic serous carcinoma as inflammatory carcinoma over breast and discuss the diagnostic challenges in patients with coexisting primary breast and ovarian malignancies. We also review the morphologic features of tumors of breast and ovarian origin and the immunohistochemical stains to differentiate these 2 entities. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cetuximab in the treatment of metastatic mucoepidermoid carcinoma of the salivary glands: A case report and review of literature

PubMed Central

Grisanti, Salvatore; Amoroso, Vito; Buglione, Michela; Rosati, Anna; Gatta, Roberto; Pizzocaro, Claudio; Ferrari, Vittorio D; Marini, Giovanni

2008-01-01

Introduction Patients with metastatic mucoepidermoid carcinoma of salivary glands have a poor outcome. The epidermal growth factor receptor protein is overexpressed in approximately 70% of mucoepidermoid carcinoma patients and may represent a therapeutic target. However, whether treatment with anti-epidermal growth factor receptor agents is effective is unclear and clinical trials are difficult due to the rarity of the disease. Here we assessed the activity of cetuximab in mucoepidermoid carcinoma on a molecular basis. Case presentation We present the case of a 40-year old Caucasian man with a mucoepidermoid carcinoma of the major salivary glands who developed distant bone and visceral metastases despite platinum-based chemotherapy. Epidermal growth factor receptor was overexpressed and fluorescence in situ hybridization analysis demonstrated a chromosome 7 polysomy. The patient was treated with the monoclonal antibody cetuximab in combination with cisplatin. After 11 doses of cetuximab, the patient developed brain metastases but evidence of response was documented at all extracranial metastatic sites. Conclusion This case report indicates that cetuximab can be active in mucoepidermoid carcinoma and may restore sensitivity to cisplatin in platinum-treated patients. Cetuximab does not cross the blood brain barrier and may select a metastatic clone to home the central nervous system while responding at other sites. PMID:18826647

Effects of different concentrations of Platelet-rich Plasma and Platelet-Poor Plasma on vitality and differentiation of autologous Adipose tissue-derived stem cells.

PubMed

Felthaus, Oliver; Prantl, Lukas; Skaff-Schwarze, Mona; Klein, Silvan; Anker, Alexandra; Ranieri, Marco; Kuehlmann, Britta

2017-01-01

Autologous fat grafts and adipose-derived stem cells (ASCs) can be used to treat soft tissue defects. However, the results are inconsistent and sometimes comprise tissue resorption and necrosis. This might be due to insufficient vascularization. Platelet-rich plasma (PRP) is a source of concentrated autologous platelets. The growth factors and cytokines released by platelets can facilitate angiogenesis. The simultaneous use of PRP might improve the regeneration potential of fat grafts. The optimal ratio has yet to be elucidated. A byproduct of PRP preparation is platelet-poor plasma (PPP). In this study we investigated the influence of different concentrations of PRP on the vitality and differentiation of ASCs. We processed whole blood with the Arthrex Angel centrifuge and isolated ASCs from the same donor. We tested the effects of different PRP and PPP concentrations on the vitality using resazurin assays and the differentiation of ASCs using oil-red staining. Both cell vitality and adipogenic differentiation increase to a concentration of 10% to 20% PRP. With a PRP concentration of 30% cell vitality and differentiation decrease. Both PRP and PPP can be used to expand ASCs without xenogeneic additives in cell culture. A PRP concentration above 20% has inhibitory effects.

[Clinical and pathologic observation of uveal metastatic carcinoma].

PubMed

Cong, C X; Lin, J Y; Wang, L H

2016-10-11

Objective: To observe the clinical and pathological features of uveal metastatic carcinoma. Methods: It was a retrospective case series study. The clinical manifestation, growth pattern, tumor types and relative pathological features of 13 patients visiting from January 1980 to December 2014 with uveal metastatic carcinoma in Tianjin Eye Hospital were analyzed retrospectively. Results: There were 13 cases, 6 cases of male and 7 of female. Age was from 37.0 to 66.0 years old. The mean age was 52.1 years old. all cases were monocular. There were 5 cases with right eye and 8 cases with left eye. Among 13 cases, 10 tumors were in posterior choroid, one tumor was in anterior choroid and ciliary body, 2 tumors were in the iris. There were 5 patients with lung cancer, 4 patients with breast cancer, 1 patient with prostate cancer, 1 patient with thyroid cancer and 1 patient with esophageal cancer. The primary tumor wasn't found in 1 patient. The rapid decrease of visual acuity showed in 10 patients with posterior choroidal metastatic carcinoma, 8 of them accompanied with extensive retinal detachment and 6 of them had secondary glaucoma. The multiple gray-white nodule or pink cauliflower mass on the papillary margin of iris were showed respectively in 2 patients with iris metastatic carcinoma. The pathological examination found that posterior choroidal metastatic carcinoma mainly located in temporal or nasal side choroids in 10 cases, among them, local or diffuse flat choroidal masses showed in 6cases, extensive mass involving choroid and ciliary body showed in 1 case, large nodular or globular choroidal mass showed in 2 cases, choroidal mass surrounded the optic disc in 1 case, optic nerve invasion showed in 3 cases and extraocular or orbital invasion showed in 3 cases. The scleral and subconjunctival invasion showed in 1 case of anterior choroid and ciliary body metastatic carcinoma. Conclusions: Uveal metastatic carcinoma manifested various growth pattern, the rapid

Suppression of adhesion-induced protein tyrosine phosphorylation decreases invasive and metastatic potentials of B16-BL6 melanoma cells by protein tyrosine kinase inhibitor genistein.

PubMed

Yan, C; Han, R

1997-01-01

Protein tyrosine kinase (PTK) appears to be involved in the activation of signaling during cell attachment to and spreading on extracellular matrix (ECM) in the metastatic cascade. To verify the assumption that PTK inhibitors might impair ECM signaling and prevent cancer metastasis, the highly metastatic B16-BL6 mouse melanoma cells were exposed to the PTK inhibitor genistein for 3 days. The ability of the cells to invade through reconstituted basement membrane (Matrigel) and to establish experimental pulmonary metastatic foci in C57BL/6 mice decreased after genistein exposure. The genistein-treated cells were also prevented from attaching to Matrigel and spread extremely poorly on the ECM substratum. Immunoblot analysis showed that tyrosine phosphorylation of a 125-kD protein in response to cell spreading on Matrigel was suppressed in the genistein-treated cells. Adhesion-induced protein tyrosine phosphorylation represents the earlier and specific event in the activation of ECM signaling, so this result implied ECM signaling was impaired in the treated cells. With immunofluorescence microscopy, the adhesion-induced tyrosine phosphorylated proteins were located at the pericytoplasms of well-spread cells, but not at the periphery of poorly spread genistein-treated cells. Therefore, this paper suggests that genistein might impair ECM signaling and subsequently prevent cancer cells from spreading well and invading or establishing metastasis through the suppression of adhesion-induced protein tyrosine phosphorylation. PTKs and adhesion-induced protein tyrosine phosphorylation might play a role in the control of invasion and metastasis.

Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

PubMed Central

Czarnecka, Anna M.; Lewicki, Sławomir; Helbrecht, Igor; Brodaczewska, Klaudia; Koch, Irena; Zdanowski, Robert; Król, Magdalena; Szczylik, Cezary

2016-01-01

Background Recent advancement in cancer research has shown that tumors are highly heterogeneous, and multiple phenotypically different cell populations are found in a single tumor. Cancer development and tumor growth are driven by specific types of cells—stem cell-like cancer cells (SCLCCs)—which are also responsible for metastatic spread and drug resistance. This research was designed to verify the presence of SCLCCs in renal cell cancer cell lines. Subsequently, we aimed to characterize phenotype and cell biology of CD105+ cells, defined previously as renal cell carcinoma tumor-initiating cells. The main goal of the project was to describe the gene-expression profile of stem cell-like cancer cells of primary tumor and metastatic origin. Materials and Methods Real-time PCR analysis of stemness genes (Oct-4, Nanog and Ncam) and soft agar colony formation assay were conducted to check the stemness properties of renal cell carcinoma (RCC) cell lines. FACS analysis of CD105+ and CD133+ cells was performed on RCC cells. Isolated CD105+ cells were verified for expression of mesenchymal markers—CD24, CD146, CD90, CD73, CD44, CD11b, CD19, CD34, CD45, HLA-DR and alkaline phosphatase. Hanging drop assay was used to investigate CD105+ cell-cell cohesion. Analysis of free-floating 3D spheres formed by isolated CD105+ was verified, as spheres have been hypothesized to contain undifferentiated multipotent progenitor cells. Finally, CD105+ cells were sorted from primary (Caki-2) and metastatic (ACHN) renal cell cancer cell lines. Gene-expression profiling of sorted CD105+ cells was performed with Agilent’s human GE 4x44K v2 microarrays. Differentially expressed genes were further categorized into canonical pathways. Network analysis and downstream analysis were performed with Ingenuity Pathway Analysis. Results Metastatic RCC cell lines (ACHN and Caki-1) demonstrated higher colony-forming ability in comparison to primary RCC cell lines. Metastatic RCC cell lines harbor

Integrative Genome Comparison of Primary and Metastatic Melanomas

PubMed Central

Feng, Bin; Nazarian, Rosalynn M.; Bosenberg, Marcus; Wu, Min; Scott, Kenneth L.; Kwong, Lawrence N.; Xiao, Yonghong; Cordon-Cardo, Carlos; Granter, Scott R.; Ramaswamy, Sridhar; Golub, Todd; Duncan, Lyn M.; Wagner, Stephan N.; Brennan, Cameron; Chin, Lynda

2010-01-01

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes. PMID:20520718

Dynamic Contrast-enhanced Magnetic Resonance Imaging for Differentiating Between Primary Tumor, Metastatic Node and Normal Tissue in Head and Neck Cancer.

PubMed

Chen, Liangliang; Ye, Yufeng; Chen, Hanwei; Chen, Shihui; Jiang, Jinzhao; Dan, Guo; Huang, Bingsheng

2018-06-01

To study the difference of the Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) parameters among the primary tumor, metastatic node and peripheral normal tissue of head and neck cancer. Consecutive newly-diagnosed head and neck cancer patients with nodal metastasis between December 2010 and July 2013 were recruited, and 25 patients (8 females; 24~63,mean 43±11 years old) were enrolled. DCE-MRI was performed in the primary tumor region including the regional lymph nodes on a 3.0-T MRI system. Three quantitative parameters: Ktrans (volume transfer constant), ve (volume fraction of extravascular extracellular space) and kep (the rate constant of contrast transfer) were calculated for the largest node. A repeated-measure ANOVA with a Greenhouse-Geisser correction and post hoc tests using the Bonferroni correction were used to evaluate the differences in Ktrans, ve and kep among primary tumors, metastatic nodes and normal tissue. The values of both Ktrans and ve of normal tissue differed significantly from those of nodes (both P < 0.001) and primary tumors (both P < 0.001) respectively, while no significant differences of Ktrans and ve were observed between nodes and primary tumors (P = 0.075 and 0.365 respectively). The kep values of primary tumors were significantly different from those of nodes (P = 0.001) and normal tissue (P = 0.002), while no significant differences between nodes and normal tissue (P > 0.999). The DCE-MRI parameters were different in the tumors, metastatic nodes and normal tissue in head and neck cancer. These findings may be useful in the characterization of head and neck cancer.

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

PubMed Central

Li, Lin Z.

2012-01-01

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

Phase II trial of irinotecan plus cisplatin in patients with recurrent or metastatic squamous carcinoma of the head and neck.

PubMed

Gilbert, Jill; Cmelak, Anthony; Shyr, Yu; Netterville, James; Burkey, Brian B; Sinard, Robert J; Yarbrough, Wendall G; Chung, Christine H; Aulino, Joseph M; Murphy, Barbara A

2008-07-01

Patients with recurrent or metastatic HNC have a poor response and survival with currently available chemotherapy agents. Thus, new agents are needed. The authors report the results of a phase II trial of irinotecan and cisplatin in patients with metastatic or recurrent HNC. Patients were treated with irinotecan 65 mg/m2 IV over 90 minutes and cisplatin 30 mg/m2 were administered intravenously weekly for four weeks, followed by a two week rest. However, after 17 patients were treated with weekly irinotecan at a dose of 65 mg/m2, toxicity analysis demonstrated the poor tolerance of that dose in this patient population. Thus, the protocol was amended, and irinotecan was dose reduced to a starting dose of 50 mg/m2. Twenty-three additional patients were treated with this dose. Forty patients were enrolled on study between February 2002 and April 2006, 17 patients at the first dose level and 23 patients at the amended dose level. Overall, 12 of 17 patients (71%) treated with irinotecan 65 mg/m2 experienced clinically significant grade 3 or 4 toxicity. Twelve patients required dose reductions. Toxicity was reduced but 17% of patients still experienced grade 3 or 4 toxicity on the lower irinotecan dose. The response rate was 35% for patients treated at irinotecan 65 mg/m2 and 22% for patients treated at 50 mg/m2. No complete responses were noted. The combination of irinotecan and cisplatin is efficacious in a poor prognosis group of patients but toxicity is substantial. (Copyright) 2008 American Cancer Society.

Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system: a potential target for anti-PD-1/PD-L1 therapy.

PubMed

Roberts, Jordan A; Gonzalez, Raul S; Das, Satya; Berlin, Jordan; Shi, Chanjuan

2017-12-01

Poorly differentiated neuroendocrine carcinoma of the digestive system has a dismal prognosis with limited treatment options. This study aimed to investigate expression of the PD-1/PD-L1 pathway in these tumors. Thirty-seven patients with a poorly differentiated neuroendocrine carcinoma of the digestive system were identified. Their electronic medical records, pathology reports, and pathology slides were reviewed for demographics, clinical history, and pathologic features. Tumor sections were immunohistochemically labeled for PD-1 and PD-L1, and expression of PD-1 and PD-L1 on tumor and tumor-associated immune cells was analyzed and compared between small cell and large cell neuroendocrine carcinomas. The mean age of patients was 61 years old with 18 men and 19 women. The colorectum (n=20) was the most common primary site; other primary sites included the pancreaticobiliary system, esophagus, stomach, duodenum, and ampulla. Expression of PD-1 was detected on tumor cells (n=6, 16%) as well as on tumor-associated immune cells (n=23, 63%). The 6 cases with PD-1 expression on tumor cells also had the expression on immune cells. Expression of PD-L1 was visualized on tumor cells in 5 cases (14%) and on tumor-associated immune cells in 10 cases (27%). There was no difference in PD-1 and PD-L1 expression between small cell and large cell neuroendocrine carcinomas. In conclusion, PD-1/PD-L1 expression is a frequent occurrence in poorly differentiated neuroendocrine carcinomas of the digestive system. Checkpoint blockade targeting the PD-1/PD-L1 pathway may have a potential role in treating patients with this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

GATA3 staining in primary cutaneous apocrine cribriform carcinoma: Usefulness to differentiate it from breast cancer metastasis.

PubMed

Llamas-Velasco, Mar; Pérez-Gónzalez, Yosmar C; Daudén, Esteban; Rütten, Arno

2018-05-01

Primary cutaneous apocrine cribriform carcinoma (PCACC) is a rare tumor, clinically appearing as a solitary nodule, mostly involving extremities of females and this lesion usually raises a differential diagnosis with metastatic cribriform carcinomas, especially breast cancer. To study GATA3 expression in a series of 14 primary cutaneous cribriform carcinomas and to test its usefulness to differentiate this tumor from metastatic breast cancer. We retrieved 14 cases with PCACC (each from a different patient) from the files of the authors. Cases were dated from 1994 to 2014. We also evaluated 6 cases of cutaneous breast cancer metastasis RESULTS: No PCACCs expressed GATA3. Breast cancer metastases expressed GATA3 in 100% of our studied cases. Even though GATA3 expression has been reported in many benign and malignant adnexal tumors (mostly of sebaceous, follicular, and apocrine differentiation), as well as in many other neoplasms, GATA3 staining to differentiate PCACC from skin breast cancer metastasis has a high negative predictive value. A positive GATA3 staining in this context should permit one to rule out PCACC with a high level of confidence. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PubMed

Pham, M N; Apolo, A B; De Santis, M; Galsky, M D; Leibovich, B C; Pisters, L L; Siefker-Radtke, A O; Sonpavde, G; Steinberg, G D; Sternberg, C N; Tagawa, S T; Weizer, A Z; Woods, M E; Milowsky, M I

2017-03-01

To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Fracture risk assessment: improved evaluation of vertebral integrity among metastatic cancer patients to aid in surgical decision-making

NASA Astrophysics Data System (ADS)

Augustine, Kurt E.; Camp, Jon J.; Holmes, David R.; Huddleston, Paul M.; Lu, Lichun; Yaszemski, Michael J.; Robb, Richard A.

2012-03-01

Failure of the spine's structural integrity from metastatic disease can lead to both pain and neurologic deficit. Fractures that require treatment occur in over 30% of bony metastases. Our objective is to use computed tomography (CT) in conjunction with analytic techniques that have been previously developed to predict fracture risk in cancer patients with metastatic disease to the spine. Current clinical practice for cancer patients with spine metastasis often requires an empirical decision regarding spinal reconstructive surgery. Early image-based software systems used for CT analysis are time consuming and poorly suited for clinical application. The Biomedical Image Resource (BIR) at Mayo Clinic, Rochester has developed an image analysis computer program that calculates from CT scans, the residual load-bearing capacity in a vertebra with metastatic cancer. The Spine Cancer Assessment (SCA) program is built on a platform designed for clinical practice, with a workflow format that allows for rapid selection of patient CT exams, followed by guided image analysis tasks, resulting in a fracture risk report. The analysis features allow the surgeon to quickly isolate a single vertebra and obtain an immediate pre-surgical multiple parallel section composite beam fracture risk analysis based on algorithms developed at Mayo Clinic. The analysis software is undergoing clinical validation studies. We expect this approach will facilitate patient management and utilization of reliable guidelines for selecting among various treatment option based on fracture risk.

[Secondary tumors of the gastrointestinal tract].

PubMed

Langner, C

2012-02-01

Metastatic involvement of the gastrointestinal tract is rare and may cause considerable difficulties with respect to differential diagnosis. The gastrointestinal tract may either be affected by direct invasion, intraperitoneal dissemination or hematogenous cancer spread, the latter most often originating from malignant melanoma, breast and lung carcinomas. Metastatic deposits primarily develop within the submucosa. Secondary involvement of the mucosa typically leads to centrally depressed and/or ulcerated (volcano-like) nodular lesions. In histology, lack of a mucosal in situ component favors diagnosis of metastasis, whereas presence of an adenomatous precursor lesion is regarded to be characteristic of primary tumors. This concept, however, has recently been challenged by demonstrating metastatic cancer growth along intact basement membranes within the mucosal layer, i.e. mucosal colonization. The histopathological, immunohistochemical and clinical features of secondary gastrointestinal tumors are discussed in detail, focusing on criteria for differential diagnosis. The prognosis of affected patients is generally poor.

OBSERVATIONS OF BINARY STARS WITH THE DIFFERENTIAL SPECKLE SURVEY INSTRUMENT. V. TOWARD AN EMPIRICAL METAL-POOR MASS–LUMINOSITY RELATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horch, Elliott P.; Van Altena, William F.; Demarque, Pierre

2015-05-15

In an effort to better understand the details of the stellar structure and evolution of metal-poor stars, the Gemini North telescope was used on two occasions to take speckle imaging data of a sample of known spectroscopic binary stars and other nearby stars in order to search for and resolve close companions. The observations were obtained using the Differential Speckle Survey Instrument, which takes data in two filters simultaneously. The results presented here are of 90 observations of 23 systems in which one or more companions was detected, and six stars where no companion was detected to the limit ofmore » the camera capabilities at Gemini. In the case of the binary and multiple stars, these results are then further analyzed to make first orbit determinations in five cases, and orbit refinements in four other cases. The mass information is derived, and since the systems span a range in metallicity, a study is presented that compares our results with the expected trend in total mass as derived from the most recent Yale isochrones as a function of metal abundance. These data suggest that metal-poor main-sequence stars are less massive at a given color than their solar-metallicity analogues in a manner consistent with that predicted from the theory.« less

Third-Line Chemotherapy for Metastatic Urothelial Cancer: A Retrospective Observational Study

PubMed Central

Di Lorenzo, Giuseppe; Buonerba, Carlo; Bellelli, Teresa; Romano, Concetta; Montanaro, Vittorino; Ferro, Matteo; Benincasa, Alfonso; Ribera, Dario; Lucarelli, Giuseppe; De Cobelli, Ottavio; Sonpavde, Guru; De Placido, Sabino

2015-01-01

Abstract The prognosis of locally advanced (T3/T4 or N1) and metastatic disease urothelial carcinoma is poor. In this retrospective study, we reviewed data about patients receiving third-line chemotherapy for metastatic disease, in view of the lack of data in this setting. We retrospectively analyzed medical records of patients with a pathologic diagnosis of urothelial carcinoma treated with systemic chemotherapy for metastatic disease at 4 participating Institutions between January, 2010, and January, 2015. Cox proportional hazards regression was used to evaluate the association of the chemotherapy agent used versus others with overall survival, adjusted for 5 externally validated prognostic factors in advanced urothelial carcinoma. Of 182 patients that received first-line chemotherapy/adjuvant chemotherapy as defined above, 116 patients (63.73%) received second-line salvage treatment. Fifty-two patients were finally included in this analysis, whereas 9 were excluded due to missing data. Third-line chemotherapy was based on cyclophosphamide, platinum, vinflunine, taxanes, and gemcitabine in 16, 12, 11, 10, and 3 patients, respectively. Median PFS (progression-free survival) and OS (overall survival) of the population were 13 (10–17) and 31 (28–36) weeks. Single-agent cyclophosphamide was associated with a PFS of 18 (13–22) and an OS of 38 (33–41) weeks, whereas platinum-based combinations were associated with a PFS of 5 weeks and an OS of 8 weeks. Multivariate analysis showed improved survival in patients treated with cyclophosphamide (hazard ratio (HR) = 0.42; 95% CI: 0.20–0.89; P = 0.025) and a worse survival in those treated with platinum-based regimens (HR: 4.37; 95% CI = 1.95–9.77; P < 0.01). We observed a significantly longer overall survival in patients receiving single-agent cyclophosphamide, with few grade 3 to 4 toxicities. Further studies should assess the efficacy of metronomic single-agent cyclophosphamide in advanced lines

Concomitant endometrial and gallbladder metastasis in advanced multiple metastatic invasive lobular carcinoma of the breast: A rare case report.

PubMed

Bezpalko, Kseniya; Mohamed, Mohamed A; Mercer, Leo; McCann, Michael; Elghawy, Karim; Wilson, Kenneth

2015-01-01

At time of presentation, fewer than 10% of patients have metastatic breast cancer. The most common sites of metastasis in order of frequency are bone, lung, pleura, soft tissue, and liver. Breast cancer metastasis to the uterus or gallbladder is rare and has infrequently been reported in the English literature. A 47 year old female with a recent history of thrombocytopenia presented with abnormal vaginal bleeding. Pelvic ultrasound revealed multiple uterine fibroids and endometrial curettings revealed cells consistent with lobular carcinoma of the breast. Breast examination revealed edema and induration of the lower half of the right breast. Biopsy of the right breast revealed invasive lobular carcinoma. Bone marrow aspiration obtained at a previous outpatient visit revealed extensive involvement by metastatic breast carcinoma. Shortly after discharge, the patient presented with acute cholecystitis and underwent cholecystectomy. Microscopic examination of the gallbladder revealed metastatic infiltrating lobular carcinoma. The final diagnosis was invasive lobular carcinoma of the right breast with metastasis to the bone marrow, endometrium, gallbladder, regional lymph nodes, and peritoneum. The growth pattern of invasive lobular carcinoma of the breast is unique and poses a challenge in diagnosing the cancer at an early stage. Unlike other types of breast cancer, it tends to metastasize more to the peritoneum, ovary, and gastrointestinal tract. Metastasis to the endometrium or gallbladder is rare. Metastatic spread should be considered in the differential diagnosis of patients with invasive lobular breast carcinoma presenting with abnormal vaginal bleeding or acute cholecystitis. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Extended Survival after Complete Pathological Response in Metastatic Pancreatic Ductal Adenocarcinoma Following Induction Chemotherapy, Chemoradiotherapy, and a Novel Immunotherapy Agent, IMM-101

PubMed Central

Giakoustidis, Alex; Stamp, Gordon; Gaya, Andy; Mudan, Satvinder

2015-01-01

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Median survival for metastatic patients is six to nine months and survivors beyond one year are exceptional. Pancreatic cancer is resistant to conventional chemotherapy and is often diagnosed at advanced stages. However, immunotherapy is a rapidly advancing new treatment modality, which shows promise in many solid tumor types.​ We present a patient with metastatic pancreatic cancer who underwent a synchronous resection of the primary tumour (pancreatoduodenectomy) and metastatic site (left hepatectomy) after multimodality neoadjuvant treatment with gemcitabine, nab-paclitaxel, and immunotherapy backbone with IMM-101 (an intradermally applied immunomodulator), as well as consolidation chemoradiation. Pathology of the specimens showed a complete response in both sites of the disease. The patient remains alive four years from the initial diagnosis and continues on maintenance immunotherapy. This exceptional response to initial chemo-immunotherapy was followed by a novel and off-protocol approach of low-dose capecitabine and IMM-101 as a maintenance strategy. The survival benefit and sustained performance status could set this as a new paradigm for the treatment of oligometastatic pancreatic cancer following response to systemic therapy and immunotherapy.​ PMID:26870619

Platelet-poor plasma stimulates the proliferation but inhibits the differentiation of rat osteoblastic cells in vitro.

PubMed

Hamdan, Ahmad Abdel-Salam; Loty, Sabine; Isaac, Juliane; Bouchard, Philippe; Berdal, Ariane; Sautier, Jean-Michel

2009-06-01

Recent studies have shown that the use of platelet preparations in bone and implant surgery might stimulate bone formation. However, the biological mechanisms are not well understood. Moreover, few studies have attempted to evaluate the effect of platelet-poor plasma (PPP), which is a product of the platelet-rich plasma preparation process. Thus, this study investigated the behavior of osteoblasts isolated from fetal rat calvaria cultivated in the presence of homologous PPP. PPP was obtained by centrifugation of the rat mother's blood and used in replacement of fetal calf serum, which is classically used in primary culture procedures. Proliferation was measured by an MTT assay at 24, 48, and 72 h. Real-time PCR was performed to study the expression of Runx2, Dlx5, and osteocalcin (OC) on days 0 (4 h), 1, 3, 7, and 12. Alkaline phosphatase (ALP) biochemical activity was evaluated on days 0 (4 h), 1, 3, 7, and 12. Observations by phase-contrast microscopy showed that osteoblasts were able to differentiate until the mineralization of the matrix in the presence of PPP. PPP enhanced the proliferation significantly compared with the control group (P< or =0.001). PCR results showed that Runx2, Dlx5, and OC were expressed by cells in the experimental group at lower levels compared with the control group. Biochemical assay of ALP showed a lower activity in the experimental group compared with the control group (P<0.001). These results suggest that, in the presence of homologous PPP, rat osteoblastic cells are able to maintain their phenotype, with a higher rate of proliferation. However, PPP seems to inhibit osteoblastic differentiation.

Silencing the hsp25 Gene Eliminates Migration Capability of the Highly Metastatic Murine 4T1 Breast Adenocarcinoma Cell

PubMed Central

Bausero, Maria A.; Bharti, Ajit; Page, Diana T.; Perez, Kristen D.; Eng, Jason W.-L.; Ordonez, Susana L.; Jantschitsch, Christian; Kindas-Muegge, Ingela; Ciocca, Daniel; Asea, Alexzander

2006-01-01

The 25-kDa heat shock protein (Hsp25) is associated with various malignancies and is expressed at high levels in biopsies as well as circulating in the serum of breast cancer patients. In this study, we used RNA interference technology to silence the hsp25 gene in 4T1 breast adenocarcinoma cells, known as a poorly immunogenic, highly metastatic cell line. We demonstrate that transfection of 4T1 cells with short interference RNA-Hsp25 dramatically inhibits proliferation as compared with control transfected cells. In addition, we show that 4T1 cells transfected with short interference RNA-Hsp25 abrogates tumor migration potential by a mechanism that is in part due to the repression of matrix metalloproteinase 9 expression and a concomitant upregulation of its antagonist, tissue inhibitor metalloproteinase 1. Taken together, these findings provide a model system for the study of metastatic potential of tumors and are suggestive of an earlier unrecognized role for Hsp25 in tumor migration. PMID:16340246

Metastatic breast cancer: The Odyssey of personalization.

PubMed

Sonnenblick, A; Pondé, N; Piccart, M

2016-10-01

Metastatic breast cancer is the most frequent cause of cancer death for women worldwide. In the last 15 years, a large number of new agents have entered clinical use, a result of the dramatic increase in our understanding of the molecular underpinnings of metastatic breast cancer. However, while these agents have led to better outcomes, they are also at the root cause of increasing financial pressure on healthcare systems. Moreover, decision making in an era where every year new agents are added to the therapeutic armamentarium has also become a significant challenge for medical oncologists. In the present article, we will provide an ample review on the most recent developments in the field of treatment of the different subtypes of metastatic breast cancer with a critical discussion on the slow progress made in identifying response biomarkers. New hopes in the form of ctDNA monitoring and functional imaging will be presented. Copyright © 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Incidental nodal metastasis of differentiated thyroid carcinoma in neck dissection specimens from head and neck cancer patients.

PubMed

Lenzi, R; Marchetti, M; Muscatello, L

2017-04-01

Occult differentiated thyroid carcinomas are not uncommon. The initial presentation of a thyroid carcinoma is often detection of a metastatic cervical lymph node. A retrospective review was performed of the medical records of 304 patients who underwent neck dissection between 1996 and 2008 for squamous cell carcinoma of the head and neck. Ten patients (3.3 per cent) had nodal metastasis originating from papillary thyroid cancer. All of these patients underwent thyroidectomy and post-operative 131iodine radiometabolic therapy. No patient developed a thyroid tumour after surgery. Despite its metastatic spread, thyroid cancer does not affect the overall prognosis of patients who are already being treated for a more aggressive malignancy. However, in otherwise healthy patients, it is worth treating this second malignancy to avoid potential complications related to local disease or metastatic thyroid cancer.

18F-FDG PET/CT in Detecting Metastatic Infection in Children.

PubMed

Kouijzer, Ilse J E; Blokhuis, Gijsbert J; Draaisma, Jos M T; Oyen, Wim J G; de Geus-Oei, Lioe-Fee; Bleeker-Rovers, Chantal P

2016-04-01

Metastatic infection is a severe complication of bacteremia with high morbidity and mortality. The aim of this study was to investigate the diagnostic value of 18F-FDG PET combined with CT (FDG PET/CT) in children suspected of having metastatic infection. The results of FDG PET/CT scans performed in children because of suspected metastatic infection from September 2003 to June 2013 were analyzed retrospectively. The results were compared with the final clinical diagnosis. FDG PET/CT was performed in 13 children with suspected metastatic infection. Of the total number of FDG PET/CT scans, 38% were clinically helpful. Positive predictive value of FDG PET/CT was 71%, and negative predictive value was 100%. FDG PET/CT appears to be a valuable diagnostic technique in children with suspected metastatic infection. Prospective studies of FDG PET/CT as part of a structured diagnostic protocol are needed to assess the exact additional diagnostic value.

Intensity ratio curve analysis of small renal masses on T2-weighted magnetic resonance imaging: Differentiation of fat-poor angiomyolipoma from renal cell carcinoma.

PubMed

Moriyama, Shingo; Yoshida, Soichiro; Tanaka, Hajime; Tanaka, Hiroshi; Yokoyama, Minato; Ishioka, Junichiro; Matsuoka, Yoh; Saito, Kazutaka; Kihara, Kazunori; Fujii, Yasuhisa

2018-03-25

To assess the diagnostic ability of a pixel intensity-based analysis in evaluating the magnetic resonance imaging characteristics of small renal masses, especially in differentiating fat-poor angiomyolipoma from renal cell carcinoma. T2-weighted images from 121 solid small renal masses (<4 cm) without visible fat (14 fat-poor angiomyolipomas, 92 clear cell renal cell carcinomas, six chromophobe renal cell carcinomas and nine papillary renal cell carcinomas) were retrospectively evaluated. An intensity ratio curve was plotted using intensity ratios, which were ratios of signal intensities of tumor pixels (each pixel along a linear region of interest drawn across the renal tumor on T2-weighted image) to the signal intensity of a normal renal cortex. The diagnostic ability of the intensity ratio curve analysis was evaluated. The tumors were classified into three types: intensity ratio fat-poor angiomyolipoma (n = 19) with no pseudocapsule, iso-low intensity and no heterogeneity; intensity ratio clear cell renal cell carcinoma (n = 76) with a pseudocapsule, iso-high intensity and heterogeneity; and other type of intensity ratio (n = 26), including tumors that did not fall into the above two categories. The sensitivity/specificity/accuracy of the intensity ratio curve analysis in diagnosing fat-poor angiomyolipoma was 93%/94%/94%, respectively. When the intensity ratio curve analysis was applied only to the tumor with undetermined radiological diagnosis, the sensitivity for diagnosing fat-poor angiomyolipoma compared with subjective reading alone significantly improved (93% vs 50%; P = 0.014). Our novel semiquantitative model for combined assessment of key features of fat-poor angiomyolipoma, including low intensity, homogeneity and absence of a pseudocapsule on T2-weighted image, might make diagnosis of fat-poor angiomyolipoma more accurate. © 2018 The Japanese Urological Association.

Novel Preclinical Testing Strategies for Treatment of Metastatic Pheochromocytoma

DTIC Science & Technology

2012-09-01

Treatment of Metastatic Pheochromocytoma PRINCIPAL INVESTIGATOR: Arthur S. Tischler...Treatment of Metastatic Pheochromocytoma 5a. CONTRACT NUMBER W81XWH-11-1-0670 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Pheochromocytomas (PCC) are catecholamine-producing neuroendocrine tumors. Up to 30% give

The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China.

PubMed

Ma, Xuhui; Wu, Yunteng; Zhang, Tian; Song, Hao; Jv, Houyu; Guo, Wei; Ren, Guoxin

2017-10-10

c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild-type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations.

An unusual case of gastric cancer presenting with breast metastasis with pleomorphic microcalcifications.

PubMed

Luk, Yiu Shiobhon; Ka, Solomon Yig Joon; Lo, Sherwin Shing Wai; Chu, Chi Yeung; Ma, Ming Wai

2012-09-01

Breast metastasis from gastric carcinoma is rare. We present a case of right breast mass with microcalcification in which the diagnosis of poorly differentiated adenocarcinoma from the stomach was made after a biopsy. Pleomorphic microcalcification was noted in the ill-defined breast mass, which is a rare feature in breast metastasis. Since breast metastasis usually signifies advanced metastatic disease, differentiating primary breast cancer from metastasis is important for appropriate treatment.

Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites

PubMed Central

Newton, Paul K; Mason, Jeremy; Venkatappa, Neethi; Jochelson, Maxine S; Hurt, Brian; Nieva, Jorge; Comen, Elizabeth; Norton, Larry; Kuhn, Peter

2015-01-01

Background: Cancer cell migration patterns are critical for understanding metastases and clinical evolution. Breast cancer spreads from one organ system to another via hematogenous and lymphatic routes. Although patterns of spread may superficially seem random and unpredictable, we explored the possibility that this is not the case. Aims: Develop a Markov based model of breast cancer progression that has predictive capability. Methods: On the basis of a longitudinal data set of 446 breast cancer patients, we created a Markov chain model of metastasis that describes the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Progression is modeled as a random walk on a directed graph, where nodes represent anatomical sites where tumors can develop. Results: We quantify how survival depends on the location of the first metastatic site for different patient subcategories. In addition, we classify metastatic sites as “sponges” or “spreaders” with implications regarding anatomical pathway prediction and long-term survival. As metastatic tumors to the bone (main spreader) are most prominent, we focus in more detail on differences between groups of patients who form subsequent metastases to the lung as compared with the liver. Conclusions: We have found that spatiotemporal patterns of metastatic spread in breast cancer are neither random nor unpredictable. Furthermore, the novel concept of classifying organ sites as sponges or spreaders may motivate experiments seeking a biological basis for these phenomena and allow us to quantify the potential consequences of therapeutic targeting of sites in the oligometastatic setting and shed light on organotropic aspects of the disease. PMID:28721371

Organtropic Metastatic Secretomes and Exosomes in Breast Cancer

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0427 TITLE: Organtropic Metastatic Secretomes and Exosomes in Breast Cancer PRINCIPAL INVESTIGATOR: Dr. David Lyden...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Organtropic Metastatic Secretomes and Exosomes in Breast Cancer 5b. GRANT NUMBER W81XWH-13-1-0427 5c...understanding of secreted metastasis regulators (extracellular proteins, cell-free nucleic acids and small vesicles – exosomes -) has tremendous

Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis

PubMed Central

Chatterjee, Aniruddha; Stockwell, Peter A; Ahn, Antonio; Rodger, Euan J; Leichter, Anna L; Eccles, Michael R

2017-01-01

Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, few studies have identified metastasis-related epigenetic drivers, in part because a framework for identifying driver epigenetic changes in metastasis has not been established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns in three cutaneous primary and metastatic melanoma cell line pairs to identify metastasis-related epigenetic drivers. Globally, metastatic melanoma cell lines were hypomethylated compared to the matched primary melanoma cell lines. Using whole genome RRBS we identified 75 shared (10 hyper- and 65 hypomethylated) differentially methylated fragments (DMFs), which were associated with 68 genes showing significant methylation differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation in metastatic cell lines, and was validated with bisulfite sequencing and in two publicly available independent melanoma cohorts (n = 40 and 458 melanomas, respectively). We found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression. RNAi-mediated knockdown of EBF3 mRNA levels decreased proliferation, migration and invasion in primary and metastatic melanoma cell lines. Overall, we have identified numerous epigenetic changes characterising metastatic melanoma cell lines, including EBF3-induced aggressive phenotypic behaviour with elevated EBF3 expression in metastatic melanoma, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis. PMID:28030832

Dedifferentiated liposarcoma with homologous lipoblastic differentiation: expanding the spectrum to include low-grade tumours.

PubMed

Liau, Jau-Yu; Lee, Jen-Chieh; Wu, Chen-Tu; Kuo, Kuan-Ting; Huang, Hsuan-Ying; Liang, Cher-Wei

2013-04-01

Dedifferentiated liposarcoma (DDLPS) is traditionally defined as a non-lipogenic high-grade sarcoma arising from a well-differentiated liposarcoma that confers metastatic potential. Recently, DDLPSs with lipoblastic differentiation, i.e. morphologically lipogenic DDLPSs, were reported. Because of the lipoblastic differentiation, these tumours caused confusion, and were reported under different names. However, cytogenetic and molecular studies have revealed their DDLPS nature. So far, the cases reported have been high-grade pleomorphic liposarcoma-like tumours. In this study we have collected another series that contains low-grade tumours, and expand the histological spectrum. Eighteen cases of DDLPS with lipoblastic differentiation from various anatomical locations were analysed by routine histology, immunohistochemistry, and MDM2 fluorescence in-situ hybridization. Two main histological patterns were seen: one featured a spindle cell sarcoma containing lipoblasts with variable nuclear pleomorphism, and the other a pleomorphic liposarcoma-like tumour including the epithelioid variant. Two cases showed low nuclear grade and lipogenic activity in the metastatic foci. CDK4, MDM2 and p16(INK) (4a) overexpression was seen in all except one case. MDM2 amplification was found in all 16 cases tested. We have expanded the spectrum of this variant of DDLPS to include low-grade tumours, in which a careful search for increased mitotic activity is essential. Like conventional DDLPS, these tumours are capable of metastasis. © 2012 Blackwell Publishing Ltd.

Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells

PubMed Central

Alonso-Lecue, Pilar; de Pedro, Isabel; Coulon, Vincent; Molinuevo, Rut; Lorz, Corina; Segrelles, Carmen; Ceballos, Laura; López-Aventín, Daniel; García-Valtuille, Ana; Bernal, José M; Mazorra, Francisco; Pujol, Ramón M; Paramio, Jesús; Ramón Sanz, J; Freije, Ana; Toll, Agustí; Gandarillas, Alberto

2017-01-01

Squamous cell carcinoma (SCC) or epidermoid cancer is a frequent and aggressive malignancy. However in apparent paradox it retains the squamous differentiation phenotype except for very dysplastic lesions. We have shown that cell cycle stress in normal epidermal keratinocytes triggers a squamous differentiation response involving irreversible mitosis block and polyploidisation. Here we show that cutaneous SCC cells conserve a partial squamous DNA damage-induced differentiation response that allows them to overcome the cell division block. The capacity to divide in spite of drug-induced mitotic stress and DNA damage made well-differentiated SCC cells more genomically instable and more malignant in vivo. Consistently, in a series of human biopsies, non-metastatic SCCs displayed a higher degree of chromosomal alterations and higher expression of the S phase regulator Cyclin E and the DNA damage signal γH2AX than the less aggressive, non-squamous, basal cell carcinomas. However, metastatic SCCs lost the γH2AX signal and Cyclin E, or accumulated cytoplasmic Cyclin E. Conversely, inhibition of endogenous Cyclin E in well-differentiated SCC cells interfered with the squamous phenotype. The results suggest a dual role of cell cycle stress-induced differentiation in squamous cancer: the resulting mitotic blocks would impose, when irreversible, a proliferative barrier, when reversible, a source of genomic instability, thus contributing to malignancy. PMID:28661481

Black-white disparity in physical performance among older women with newly diagnosed non-metastatic breast cancer: Exploring the role of inflammation and physical activity.

PubMed

Owusu, Cynthia; Schluchter, Mark; Koroukian, Siran M; Schmitz, Kathryn H; Berger, Nathan A

2018-04-23

To examine racial differences in physical performance among older women with newly diagnosed non-metastatic breast cancer and identify clinical, behavioral and biological factors that might contribute to such disparities. This is a cross-sectional study of women aged ≥65 years with newly diagnosed stage I-III breast cancer recruited from ambulatory oncology clinics at an academic center, between September 2010 and August 2015. Participants completed a Comprehensive Geriatric Assessment and laboratory testing for biomarkers of inflammation [interleukin-6 (IL6)] prior to receiving systemic treatment for cancer. The primary outcome was poor physical performance, defined as scoring ≤7 on the Short Physical Performance Battery, Yes or No. Logistic regression analyses were undertaken. Among 135 women with mean age of 74.8 years (SD = 6.9), 31% were African-American (AA), and 33% had poor physical performance. Controlling for age, education, comorbidities and geriatric syndromes, participants with poor physical performance were more likely to be AA [versus (vs.) Non-Hispanic Whites (NHW)], odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.18-8.15. Controlling further for physical activity (PA) attenuated the racial disparity in physical performance (OR = 2.50, CI = 0.91-6.84). Lastly, controlling for IL6 further diminished the racial disparity in physical performance (OR = 1.93, CI = 0.67-5.56). In adjusted models, PA and IL6 explained 29% and 38%, respectively, of the racial disparity in poor physical performance. Among older women with newly diagnosed non-metastatic breast cancer, poor physical performance was prevalent and AA were disproportionately affected. Less engagement in physical activity and subclinical inflammation partly contributed to this disparity. Copyright © 2018 Elsevier Inc. All rights reserved.

Metastatic infectious disease and clinical outcome in Staphylococcus aureus and Streptococcus species bacteremia.

PubMed

Vos, Fidel J; Kullberg, Bart Jan; Sturm, Patrick D; Krabbe, Paul F M; van Dijk, Arie P J; Wanten, Geert J A; Oyen, Wim J G; Bleeker-Rovers, Chantal P

2012-03-01

Early detection of metastatic infection in patients with Gram-positive bacteremia is important as morbidity and mortality are higher in the presence of these foci, probably due to incomplete eradication of clinically silent foci during initial treatment. We performed a prospective study in 115 patients with Staphylococcus aureus or Streptococcus species bacteremia with at least 1 risk factor for the development of metastatic foci, such as community acquisition, treatment delay, persistently positive blood cultures for >48 hours, and persistent fever >72 hours after initiation of treatment. An intensive search for metastatic infectious foci was performed including ¹⁸F-fluorodeoxyglucose-positron emission tomography in combination with low-dose computed tomography scanning for optimizing anatomical correlation (FDG-PET/CT) and echocardiography in the first 2 weeks of admission. Metastatic infectious foci were detected in 84 of 115 (73%) patients. Endocarditis (22 cases), endovascular infections (19 cases), pulmonary abscesses (16 cases), and spondylodiscitis (11 cases) were diagnosed most frequently. The incidence of metastatic infection was similar in patients with Streptococcus species and patients with S. aureus bacteremia. Signs and symptoms guiding the attending physician in the diagnostic workup were present in only a minority of cases (41%). An unknown portal of entry, treatment delay >48 hours, and the presence of foreign body material were significant risk factors for developing metastatic foci. Mean C-reactive protein levels on admission were significantly higher in patients with metastatic infectious foci (74 vs. 160 mg/L). FDG-PET/CT was the first technique to localize metastatic infectious foci in 35 of 115 (30%) patients. As only a minority of foci were accompanied by guiding signs or symptoms, the number of foci revealed by symptom-guided CT, ultrasound, and magnetic resonance imaging remained low. Mortality tended to be lower in patients without

Ribociclib and Doxorubicin in Treating Patients With Metastatic or Advanced Soft Tissue Sarcomas That Cannot Be Removed by Surgery

ClinicalTrials.gov

2018-05-09

Metastatic Angiosarcoma; Metastatic Epithelioid Sarcoma; Metastatic Fibrosarcoma; Metastatic Leiomyosarcoma; Metastatic Liposarcoma; Metastatic Malignant Peripheral Nerve Sheath Tumor; Metastatic Synovial Sarcoma; Metastatic Undifferentiated Pleomorphic Sarcoma; Myxofibrosarcoma; Pleomorphic Rhabdomyosarcoma; Stage III Soft Tissue Sarcoma; Stage IV Soft Tissue Sarcoma; Undifferentiated (Embryonal) Sarcoma

Real-world treatment patterns and costs in a US Medicare population with metastatic squamous non-small cell lung cancer.

PubMed

Davis, Keith L; Goyal, Ravi K; Able, Stephen L; Brown, Jacqueline; Li, Li; Kaye, James A

2015-02-01

Despite advances in the treatment of nonsquamous non-small cell lung cancer (NSCLC), therapeutic choices and overall disease course for squamous NSCLC have remained relatively unchanged over the past several years. We provide a detailed account of current treatment patterns, healthcare use, and survival in real-world clinical settings for metastatic squamous NSCLC. Patients aged ≥65 years with metastatic squamous NSCLC diagnosed 2001-2009 were identified and followed through 2010 using the Surveillance, Epidemiology and End Results-Medicare database. Treatment patterns were descriptively analyzed. Multivariate logistic regressions were estimated to identify predictors of treatment pattern events; generalized linear models were estimated for total all-cause and NSCLC-related costs to assess cost drivers. Of 17,133 patients, 72% received cancer-directed therapy (surgery, radiation, chemotherapy, or biologic therapy), whereas 28% received only supportive care. Median survival was significantly longer in patients receiving cancer-directed therapy (8 months) than in patients receiving supportive care only (2 months) (P<0.0001). An agent-specific first-line chemotherapy regimen was identified for 91% of the 7700 patients who received chemotherapy. Among these, the most common first-line regimen was carboplatin-paclitaxel combination therapy (46%). Common second-line regimens were gemcitabine monotherapy (16%) and pemetrexed monotherapy (11%). Factors associated with decreased odds of receiving cancer-directed treatment were black versus white race (OR, 0.72; 95% CI, 0.64-0.82), residence in the West versus South (OR, 0.73; 95% CI, 0.66-0.81), and metastatic disease at initial diagnosis versus progression to metastatic disease (OR, 0.77; 95% CI, 0.70-0.84). Our study shows that prognosis remains poor for patients with metastatic squamous NSCLC, even among those receiving treatment, but particularly for patients limited to supportive care only, highlighting the

Cancer stem cells with increased metastatic potential as a therapeutic target for esophageal cancer.

PubMed

Wang, D; Plukker, J Th M; Coppes, R P

2017-06-01

Esophageal cancers (EC) are highly aggressive tumors, commonly presented in a locally advanced stage with a poor prognosis and survival. Up to 50% of the patients are eligible for treatment with curative intent and receive the standard treatment with neoadjuvant chemoradiotherapy (nCRT) and surgery. Currently, pathologic complete response to nCRT is 20-30%, with a partial or no response in about 50% and 20%, respectively. EC recurrences occur frequently even after successful anti-cancer treatment, suggesting high aggressiveness with increased metastatic potential. A tumor sub-population of so-called cancer stem cells (CSCs), is known to display a high metastatic potential and resistance to conventional anti-cancer therapy, hereby being responsible for the unbeneficial clinical features. In this review, a concise overview will be given of the current literature on esophageal CSCs and related metastases. Esophageal CSC markers will be discussed followed by the pathways that initiate and sustain these cells. In addition, the cellular processes, epithelial-mesenchymal transition (EMT), hypoxia and autophagy, known to contribute to cancer stemness and metastasis will be explained. Finally, potential options for treatment also related to cancer genome atlas (TCGA) data on EC will be discussed. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Trespassing cancer cells: 'fingerprinting' invasive protrusions reveals metastatic culprits.

PubMed

Klemke, Richard L

2012-10-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial 'omics' approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. Copyright © 2012 Elsevier Ltd. All rights reserved.

Aspiration cytology of extramammary tumours metastatic to the breast.

PubMed

Handa, Uma; Chhabra, Seema; Mohan, Harsh

2007-10-01

This study was undertaken to highlight the use of fine needle aspiration cytology (FNAC) to distinguish tumours metastatic to the breast from primary breast malignancies. A total of 1866 fine needle aspirates of the breast were performed during a period of 7 years. Three hundred and fourteen cases of breast malignancies were diagnosed and 5 (1.5%) out of these cases were metastatic in origin. The metastatic tumors included, 2 cases of malignant melanoma (chest wall and left arm), 1 case each of haematolymphoid malignancy, adenocarcinoma of the ovary, and squamous cell carcinoma (left leg). FNA diagnosis of metastasis to the breast is essential in order to avoid unnecessary mastectomy and to ensure appropriate chemotherapy and/or irradiation treatment.

The Refusal of Palliative Radiation in Metastatic Non-Small Cell Lung Cancer and Its Prognostic Implications.

PubMed

Stavas, Mark J; Arneson, Kyle O; Ning, Matthew S; Attia, Albert A; Phillips, Sharon E; Perkins, Stephanie M; Shinohara, Eric T

2015-06-01

Patients with metastatic non-small cell lung cancer (NSCLC) have limited survival. Population studies have evaluated the impact of radiation refusal in the curative setting; however, no data exist concerning the prognostic impact of radiation refusal in the palliative care setting. To investigate the patterns of radiation refusal in newly diagnosed patients with metastatic NSCLC. Patients with Stage IV NSCLC diagnosed between 1988 and 2010 were identified in the Surveillance, Epidemiology, and End Results database. Univariate and multivariate analyses were used to identify predictors for refusal of radiation and the impact of radiation and refusal on survival in the palliative setting. A total of 285,641 patients were initially included in the analysis. Palliative radiation was recommended in 42% and refused by 3.1% of patients. Refusal rates remained consistent across included years of study. On multivariate analysis, older, nonblack/nonwhite, unmarried females were more likely to refuse radiation (P < 0.001 in all cases). Median survival for patients refusing radiation was three months vs. five months for those receiving radiation and two months for those whom radiation was not recommended. Patients with metastatic NSCLC who refuse recommended palliative radiation have a poor survival. Radiation refusal or the recommendation against treatment can serve as a trigger for integrating palliative care services sooner and contributes greatly to prognostic awareness. Further investigation into this survival difference and the factors behind refusal are warranted. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Outcomes of Metastatic Gestational Trophoblastic Neoplasia: Fourteen Year Experience from a Northern Thailand Tertiary Care Center.

PubMed

Suprasert, Prapaporn; Siriaree, Sitthicha; Manopunya, Manatsawee

2016-01-01

Metastatic gestational trophoblastic neoplasia (GTN) is an uncommon cancer. The principal treatment consists of chemotherapy with or without surgery or radiotherapy. We here retrospectively reviewed the outcomes of metastatic GTN treated at our institute between January, 1999 and December, 2013. Sixty-three patients met the criteria. The median age was 30.0 years and almost 90% were referral cases. Nearly 40% of the studied patients presented with vaginal bleeding while 22.2% were asymptomatic. The most common antecedent pregnancy was hydatidiform mole (57.1%) followed by term pregnancy (20.6%). The median interval time from antecedent pregnancy to the development of GTN was three months and the median pretreatment B-hCG was 58,274 mIU/ ml. Stage III (74.6%) was the most common staging followed by stage IV (20.6%) and stage II (4.8%). The most frequent surgery was hysterectomy (31.7%). Thoracotomy and craniotomy were performed in three and two patients, respectively. The most common first line chemotherapy regimen was methotrexate and folinic acid (36.5%) followed by EMA (etoposide, methotrexate, actinomycin D) (34.9%), EMACO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) (17.5%) with the remission rate of 66.7%. Nearly one-third of the patients were given a subsequent chemotherapy regimen after failure with the first line therapy and showed a final response rate of 73.0%. However, in stage IV, the response to first line treatment was only 38.5%. In conclusion, the outcomes of metastatic GTN were poor especially with the higher stages.

Histopathologically proven mucinous cystadenocarcinoma metastatic to the choroid.

PubMed

Henderson, Robert H; Cohen, Victoria M; Rath, Pamela P; Luthert, Philip; Hungerford, John L

2010-01-01

To report the first case of conventional transcleral choroidal biopsy in the diagnosis of ovarian carcinoma metastatic to the choroid and to summarize the published cases of ovarian carcinoma metastatic to the choroid. Case report and Medline literature review. This is the tenth case reported in the literature and the only case that underwent conventional transcleral choroidal biopsy. Transcleral choroidal biopsy allowed the diagnosis of metastatic mucinous cystadenocarcinoma of the ovary. Choroidal metastases are not associated with central nervous system involvement; however, investigations may reveal distal boney or pulmonary metastases. Ovarian carcinoma rarely metastases to the choroid and unlike breast carcinoma, concurrent central nervous system disease has not been reported. When systemic investigations fail to reveal active intraperitoneal disease or distal metastases, the clinician should consider referral to an ocular oncology center for a choroidal biopsy.

Risk Factors for Preoperative Seizures and Loss of Seizure Control in Patients Undergoing Surgery for Metastatic Brain Tumors.

PubMed

Wu, Adela; Weingart, Jon D; Gallia, Gary L; Lim, Michael; Brem, Henry; Bettegowda, Chetan; Chaichana, Kaisorn L

2017-08-01

Metastatic brain tumors are the most common brain tumors in adults. Patients with metastatic brain tumors have poor prognoses with median survival of 6-12 months. Seizures are a major presenting symptom and cause of morbidity and mortality. In this article, risk factors for the onset of preoperative seizures and postoperative seizure control are examined. Adult patients who underwent resection of one or more brain metastases at a single institution between 1998 and 2011 were reviewed retrospectively. Of 565 patients, 114 (20.2%) patients presented with seizures. Factors independently associated with preoperative seizures were preoperative headaches (P = 0.044), cognitive deficits (P = 0.031), more than 2 intracranial metastatic tumors (P = 0.013), temporal lobe location (P = 0.031), occipital lobe location (P = 0.010), and bone involvement by tumor (P = 0.029). Factors independently associated with loss of seizure control after surgical resection were preoperative seizures (P = 0.001), temporal lobe location (P = 0.037), lack of postoperative chemotherapy (P = 0.010), subtotal resection of tumor (P = 0.022), and local recurrence (P = 0.027). At last follow-up, the majority of patients (93.8%) were seizure-free. Thirty patients (5.30%) in total had loss of seizure control, and only 8 patients (1.41%) who did not have preoperative seizures presented with new-onset seizures after surgical resection of their metastases. The brain is a common site for metastases from numerous primary cancers, such as breast and lung. The identification of factors associated with onset of preoperative seizures as well as seizure control postoperatively could aid management strategies for patients with metastatic brain tumors. Patients with preoperative seizures who underwent resection tended to have good seizure control after surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

PubMed Central

Moreno-Bueno, Gema; Salvador, Fernando; Martín, Alberto; Floristán, Alfredo; Cuevas, Eva P; Santos, Vanesa; Montes, Amalia; Morales, Saleta; Castilla, Maria Angeles; Rojo-Sebastián, Alejandro; Martínez, Alejandra; Hardisson, David; Csiszar, Katalin; Portillo, Francisco; Peinado, Héctor; Palacios, José; Cano, Amparo

2011-01-01

Basal-like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and frequent triple negative status (ESR−, PR−, Her2neu−). We have previously shown that epithelial–mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl-oxidase-like 2 (LOXL2) as an EMT player and poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Breast carcinoma cell lines with basal-like phenotype show a specific cytoplasmic/perinuclear LOXL2 expression, and this subcellular distribution is significantly associated with distant metastatic incidence in basal-like breast carcinomas. LOXL2 silencing in basal-like carcinoma cells induces a mesenchymal-epithelial transition (MET) associated with a decrease of tumourigenicity and suppression of metastatic potential. Mechanistic studies indicate that LOXL2 maintains the mesenchymal phenotype of basal-like carcinoma cells by a novel mechanism involving transcriptional downregulation of Lgl2 and claudin1 and disorganization of cell polarity and tight junction complexes. Therefore, intracellular LOXL2 is a new candidate marker of basal-like carcinomas and a target to block metastatic dissemination of this aggressive breast tumour subtype. PMID:21732535

Treatment and care of patients with metastatic breast cancer.

PubMed

Beaumont, T; Leadbeater, M

This article provides an overview of the treatment options available for patients diagnosed with metastatic breast cancer. The article focuses on the four common organ sites affected by metastatic breast cancer, including the bone, lungs, liver and brain. The implications for nursing care are addressed, highlighting common side effects of treatment and frequent areas of concern for patients.

CD8+ T-cell immunosurveillance constrains lymphoid pre-metastatic myeloid cell accumulation

PubMed Central

Li, Wenzhao; Deng, Jiehui; Herrmann, Andreas; Priceman, Saul J.; Liang, Wei; Shen, Shudan; Pal, Sumanta K.; Hoon, Dave S.B.; Yu, Hua

2014-01-01

Increasing evidence suggests that pre-metastatic niches, consisting mainly of myeloid cells, provide microenvironment critical for cancer cell recruitment and survival to facilitate metastasis. While CD8+ T cells exert immunosurveillance in primary human tumors, whether they can exert similar effects on myeloid cells in the pre-metastatic environment is unknown. Here, we show that CD8+ T cells are capable of constraining pre-metastatic myeloid cell accumulation by inducing myeloid cell apoptosis in C57BL/6 mice. Antigen-specific CD8+ T-cell cytotoxicity against myeloid cells in pre-metastatic lymph nodes is compromised by Stat3. We demonstrate here that Stat3 ablation in myeloid cells leads to CD8+ T-cell activation and increased levels of IFN-γ and granzyme B in the pre-metastatic environment. Furthermore, Stat3 negatively regulates soluble antigen cross-presentation by myeloid cells to CD8+ T cells in the pre-metastatic niche. Importantly, in tumor-free lymph nodes of melanoma patients, infiltration of activated CD8+ T cells inversely correlates with STAT3 activity, which is associated with a decrease in number of myeloid cells. Our study suggested a novel role for CD8+ T cells in constraining myeloid cell activity through direct killing in the pre-metastatic environment, and the therapeutic potential by targeting Stat3 in myeloid cells to improve CD8+ T-cell immunosurveillance against metastasis. PMID:25310972

Low-molecular weight forms of cyclin E differentiate ovarian carcinoma from cells of mesothelial origin and are associated with poor survival in ovarian carcinoma.

PubMed

Davidson, Ben; Skrede, Martina; Silins, Ilvars; Shih, Ie-Ming; Trope, Claes G; Flørenes, Vivi Ann

2007-09-15

The authors recently reported on the role of cyclin E in differentiating ovarian/primary peritoneal carcinoma from malignant peritoneal mesothelioma using gene expression arrays. In the current study, they analyzed the expression of low-molecular weight (LMW) forms of cyclin E in ovarian carcinoma, malignant mesothelioma, and benign reactive effusions. Cyclin E protein expression was analyzed in 98 effusions (72 ovarian carcinomas, 14 malignant mesotheliomas, and 12 reactive specimens) using immunoblotting. Sixty-two ovarian carcinoma effusions were studied further for cyclin E expression using immunohistochemistry. The correlations between cyclin E expression in ovarian carcinoma and clinical parameters, including chemotherapy response, were analyzed. LMW forms of cyclin E were identified in 54 of 72 ovarian carcinoma effusions (75%) compared with 1 of 14 malignant mesothelioma effusions (7%) and 1 of 12 reactive effusions (8%) (P < .001). Their presence in ovarian carcinoma was associated with a higher percentage of cyclin E-positive cells (P = .001) and increased staining intensity (P < .001) using immunohistochemistry. The presence of LMW forms of cyclin E was correlated with shorter overall survival (P = .021) and progression-free survival (P = .020). The presence of a higher percentage of cyclin E-positive cells using immunohistochemistry was correlated with shorter progression-free survival (P = .026). No association with chemotherapy response was observed. LMW forms of cyclin E differentiated ovarian carcinoma from benign and malignant mesothelial cells and were associated with increased protein expression using immunohistochemistry. The expression of LMW cyclin E forms was not associated with chemotherapy response, although it may be a marker of aggressive disease in patients with metastatic ovarian carcinoma. (c) 2007 American Cancer Society.

Metastatic signet-ring cell cancer of the bladder responding to chemotherapy with capecitabine: case report and review of literature

PubMed Central

Michels, Jorg; Barbour, Sean; Cavers, Douglas; Chi, Kim N.

2010-01-01

Signet-ring cell cancers deriving from the bladder are rare entities and usually present with advanced incurable disease and associated poor outlook. No standard effective chemotherapeutic option has been described largely due to the rarity of this malignancy. We report a case of a patient with metastatic bladder cancer, signet-ring cell variant. The patient progressed rapidly on standard first-line bladder cancer chemotherapy with gemcitabine and carboplatin. He responded well to second-line capecitabine with a clinically meaningful progression-free survival. PMID:20368884

Merkel Cell Carcinoma Metastatic to Pleural Fluid: A Case Report.

PubMed

Rhee, Ye-Young; Kim, Soo Hee; Kim, Eun Kyung; Kim, Se Hoon

2018-05-01

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine carcinoma of the skin that shows locoregional or distant metastasis. Metastasis of MCC to body cavity effusion is extremely rare; only three cases have been reported so far. Metastatic MCC in effusion cytology shows small blue round cells with fine stippled chromatin like other small blue round cell tumors such as small cell lung carcinoma or lymphoma. The diagnosis of metastatic MCC can grant patients good chances at recently advanced therapeutic options. Here, we present a case of metastatic MCC to pleural effusion with characteristic single file-like pattern.

Differential presentation and survival of de novo and recurrent metastatic breast cancer over time: 1990-2010.

PubMed

Malmgren, Judith A; Mayer, Musa; Atwood, Mary K; Kaplan, Henry G

2018-01-01

Differences in de novo (dnMBC) and recurrent metastatic breast cancer (rMBC) presentation and survival over time have not been adequately described. A retrospective cohort study, 1990-2010, with follow up through 2015 of dnMBC patients (stage IV at diagnosis) and rMBC patients with subsequent distant metastatic recurrence (stage I-III initial diagnosis) [dnMBC = 247, rMBC = 911)]. Analysis included Chi squared tests of categorical variables, Kaplan-Meier survival estimates, and Cox proportional adjusted hazard ratios (HzR) and 95% confidence intervals (CI). Disease specific survival (DSS) was time from diagnosis or distant recurrence to BC death. Over time, 1990-1998, 1999-2004, and 2005-2010, dnMBC incidence was constant (3%) and rMBC incidence decreased [18% to 7% (p < 0.001)] with no change in dnMBC hormone receptor (HR) or her2-neu (HER2) status but a decrease in rMBC HER2-positive cases and increase in triple negative breast cancer (HR-negative/HER2-negative) (p = 0.049). Five-year dnMBC DSS was 44% vs. 21% for rMBC (p < 0.001). Five-year dnMBC DSS improved over time [28% to 55% (p = 0.008)] and rMBC worsened [23% to 13%, p = 0.065)]. Worse DSS was associated with HR-negative status (HzR = 1.63; 1.41, 1.89), rMBC (HzR = 1.88; 1.58, 2.23), older age (70 +) (HzR = 1.88; 1.58, 2.24), > 1 distant metastases (HzR 1.39; 1.20, 1.62), and visceral dominant disease (HzR 1.22; 1.05, 1.43). After 1998, HER2-positive disease was associated with better DSS (HzR = 0.72, 95% CI 0.56, 0.93). Factors associated with the widening survival gap and non-equivalence between dnMBC and rMBC and decreased rMBC incidence warrant further study.

EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas.

PubMed

Petrini, Iacopo; Lencioni, Monica; Vasile, Enrico; Fornaro, Lorenzo; Belluomini, Lorenzo; Pasquini, Giulia; Ginocchi, Laura; Caparello, Chiara; Musettini, Gianna; Vivaldi, Caterina; Caponi, Sara; Ricci, Sergio; Proietti, Agenese; Fontanini, Gabriella; Naccarato, Antonio Giuseppe; Nardini, Vincenzo; Santi, Stefano; Falcone, Alfredo

2018-02-14

The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.

Long-term survival in patients with metastatic melanoma treated with DTIC or temozolomide.

PubMed

Kim, Christina; Lee, Christopher W; Kovacic, Laurel; Shah, Amil; Klasa, Richard; Savage, Kerry J

2010-01-01

Patients with metastatic melanoma typically have a poor outcome; however, a small proportion of patients achieve long-term survival (LTS). It is unclear how often LTS is related to sensitivity to chemotherapy. All patients with metastatic melanoma treated with either dacarbazine (DTIC) or temozolomide (TMZ) at the British Columbia Cancer Agency (BCCA) from January 1, 1988 to February 1, 2006 were identified through the BCCA pharmacy electronic database, which was then linked to the surveillance and outcomes unit to identify patients with LTS, defined as survival > or =18 months following chemotherapy. In total, 397 patients were treated with either DTIC (n = 349) or TMZ (n = 48) and 43 patients (10.8%) were identified with LTS. Two additional patients with LTS were added prior to 1988 for a total of 45 patients. The 5-year overall and progression-free survival rates for patients with LTS were 33% and 16%, respectively. In total, 16% had a complete response (CR) to chemotherapy, which was the only factor identified that correlated with survival in the multivariate analysis. However, most patients with LTS had an incomplete response to chemotherapy. LTS occurs in select patients who achieve a CR to chemotherapy. However, this occurs in only a minority of patients and, in most cases, the longer survival is likely the result of indolent disease biology or host factors.

Long-Term Survival in Patients with Metastatic Melanoma Treated with DTIC or Temozolomide

PubMed Central

Kim, Christina; Lee, Christopher W.; Kovacic, Laurel; Shah, Amil; Klasa, Richard

2010-01-01

Background. Patients with metastatic melanoma typically have a poor outcome; however, a small proportion of patients achieve long-term survival (LTS). It is unclear how often LTS is related to sensitivity to chemotherapy. Methods. All patients with metastatic melanoma treated with either dacarbazine (DTIC) or temozolomide (TMZ) at the British Columbia Cancer Agency (BCCA) from January 1, 1988 to February 1, 2006 were identified through the BCCA pharmacy electronic database, which was then linked to the surveillance and outcomes unit to identify patients with LTS, defined as survival ≥18 months following chemotherapy. Results. In total, 397 patients were treated with either DTIC (n = 349) or TMZ (n = 48) and 43 patients (10.8%) were identified with LTS. Two additional patients with LTS were added prior to 1988 for a total of 45 patients. The 5-year overall and progression-free survival rates for patients with LTS were 33% and 16%, respectively. In total, 16% had a complete response (CR) to chemotherapy, which was the only factor identified that correlated with survival in the multivariate analysis. However, most patients with LTS had an incomplete response to chemotherapy. Conclusions. LTS occurs in select patients who achieve a CR to chemotherapy. However, this occurs in only a minority of patients and, in most cases, the longer survival is likely the result of indolent disease biology or host factors. PMID:20538743

Myogenic transcription factors regulate pro-metastatic miR-182.

PubMed

Dodd, R D; Sachdeva, M; Mito, J K; Eward, W C; Brigman, B E; Ma, Y; Dodd, L; Kim, Y; Lev, D; Kirsch, D G

2016-04-07

Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.

RT-06GAMMA KNIFE SURGERY AFTER NAVIGATION-GUIDED ASPIRATION FOR CYSTIC METASTATIC BRAIN TUMORS

PubMed Central

Chiba, Yasuyoshi; Mori, Kanji; Toyota, Shingo; Kumagai, Tetsuya; Yamamoto, Shota; Sugano, Hirofumi; Taki, Takuyu

2014-01-01

Metastatic brain tumors over 3 cm in diameter (volume of 14.1ml) are generally considered poor candidates for Gamma Knife surgery (GKS). We retrospectively assessed the method and efficacy of GKS for large cystic metastatic brain tumors after navigation-guided aspiration under local anesthesia. From September 2007 to April 2014, 38 cystic metastatic brain tumors in 32 patients (12 males, 20 females; mean age, 63.2 years) were treated at Kansai Rosai Hospital. The patients were performed navigation-guided cyst aspiration under local anesthesia, then at the day or the next day, were performed GKS and usually discharged on the day. The methods for preventing of leptomeningeal dissemination are following: 1) puncture from the place whose cerebral thickness is 1 cm or more; 2) avoidance of Ommaya reservoir implantation; and 3) placement of absorbable gelatin sponge to the tap tract. Tumor volume, including the cystic component, decreased from 25.4 ml (range 8.7-84.7 ml) to 11.4 ml (range 2.9-36.7 ml) following aspiration; the volume reduction was approximately 51.6%. Follow-up periods in the study population ranged from 0 to 24 months (median 3.5 months). The overall median survival was 6.7 months. There was no leptomeningeal dissemination related to the aspiration. One patient experienced radiation necrosis after GKS, one patient experienced re-aspiration by failure of aspiration, and two patients experienced surgical resections and one patient experienced re-aspiration by cyst regrowth after GKS. Long-term hospitalization is not desirable for the patients with brain metastases. In japan, Long-term hospitalization is required for surgical resection or whole brain radiation therapy, but only two days hospitalization is required for GKS after navigation-guided aspiration at our hospital. This GKS after navigation-guided aspiration is more effective and less invasive than surgical resection or whole brain radiation therapy.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

PubMed

Catino, Anna B; Hubbard, Rebecca A; Chirinos, Julio A; Townsend, Ray; Keefe, Stephen; Haas, Naomi B; Puzanov, Igor; Fang, James C; Agarwal, Neeraj; Hyman, David; Smith, Amanda M; Gordon, Mary; Plappert, Theodore; Englefield, Virginia; Narayan, Vivek; Ewer, Steven; ElAmm, Chantal; Lenihan, Daniel; Ky, Bonnie

2018-03-01

Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P =0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P <0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P <0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function. © 2018 American Heart

Gastrointestinal Stromal Tumors: Management of metastatic disease and emerging therapies

PubMed Central

Vadakara, Joseph

2013-01-01

Synopsis Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Prior to the advent of tyrosine kinase inhibitors like imatinib, there were few treatment options available to patients with metastatic GIST. Surgery was the mainstay of treatment and the prognosis for patients with metastatic GIST was dismal. With the advent of imatinib the prognosis of metastatic GIST has improved dramatically. Second line tyrosine kinase inhibitors (TKI) such as sunitinib and regorafenib have further bettered prognosis, however there is still a need for therapies for patients with disease refractory to TKI therapy. Newer agents such as the Hsp90 inhibitors, PI3K-AKT-mTOR inhibitors and IGF1-R inhibitors are currently under investigation and may have promise. This review discusses the current standard of care in terms of pharmacotherapy, both standard and investigational (summarized in Box 1), in the management of metastatic GIST. PMID:24093167

Olaparib In Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-27

Metastatic Breast Cancer; Invasive Breast Cancer; Somatic Mutation Breast Cancer (BRCA1); Somatic Mutation Breast Cancer (BRCA2); CHEK2 Gene Mutation; ATM Gene Mutation; PALB2 Gene Mutation; RAD51 Gene Mutation; BRIP1 Gene Mutation; NBN Gene Mutation

Treatment of metastatic uveal melanoma with intravenous fotemustine.

PubMed

Spagnolo, Francesco; Grosso, Marco; Picasso, Virginia; Tornari, Elena; Pesce, Marianna; Queirolo, Paola

2013-06-01

The purpose of the present study was to retrospectively evaluate the safety and activity of intravenous fotemustine in patients with metastatic uveal melanoma. We report on a series of 25 consecutive patients diagnosed with metastatic uveal melanoma. Fotemustine was administered intravenously as a first-line treatment to all patients. Thrombocytopenia and leukopenia (any grade) were observed in 60 and 52% of patients, respectively. Only two patients discontinued treatment because of toxicity (G3 thrombocytopenia), whereas all other patients were discontinued for progressive disease. Two partial responses were observed. Nine patients had stable disease (disease control rate=44%). The median survival duration was 13.9 months, and the 1-year survival rate was 60%. Intravenous fotemustine is well tolerated and could improve the outcome of metastatic uveal melanoma patients with or without liver involvement, although a randomized prospective trial is required to confirm these results.

Treatment of metastatic cutaneous Crohn disease with certolizumab.

PubMed

Kiuru, Maija; Camp, Brendan; Adhami, Katayun; Jacob, Vinita; Magro, Cynthia; Wildman, Horatio

2015-11-18

Metastatic Crohn disease is a rare cutaneous manifestation of Crohn disease characterized by granulomatous lesions discontinuous with the diseased areas of the gastrointestinal tract. We report a case of a 32-year-old woman with history of Crohn disease who was admitted for treatment of cellulitis after presenting with a tender erythematous plaque of the left calf. Microbiological tests including tissue cultures were negative. A skin biopsy revealed granulomatous dermatitis consistent with metastatic cutaneous Crohn disease. Owing to concomitant perianal fistulas and abscesses and prior infusion reaction to infliximab, the patient was treated with certolizumab, a pegylated tumor necrosis factor (TNF) inhibitor combined with methotrexate resulting in complete resolution of the skin lesion. This case emphasizes the importance of recognizing this rare skin manifestation of Crohn disease and adds certolizumab as one of TNF inhibitors useful in the treatment of metastatic cutaneous Crohn disease.

Metastatic Lymph Node Burden and Survival in Oral Cavity Cancer

PubMed Central

Kim, Sungjin; Tighiouart, Mourad; Gudino, Cynthia; Mita, Alain; Scher, Kevin S.; Laury, Anna; Prasad, Ravi; Shiao, Stephen L.; Van Eyk, Jennifer E.; Zumsteg, Zachary S.

2017-01-01

Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions. PMID

Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone

PubMed Central

2014-01-01

Background Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo. Methods The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer. Results A 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in 18F-FDG PET/CT and 18F-NaF bone PET/CT. The patient derived clinical benefit from therapy. Conclusion We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a

Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: the Spanish Oncologic Genitourinary Group (SOGUG) SPAZO study.

PubMed

Pérez-Valderrama, B; Arranz Arija, J A; Rodríguez Sánchez, A; Pinto Marín, A; Borrega García, P; Castellano Gaunas, D E; Rubio Romero, G; Maximiano Alonso, C; Villa Guzmán, J C; Puertas Álvarez, J L; Chirivella González, I; Méndez Vidal, M J; Juan Fita, M J; León-Mateos, L; Lázaro Quintela, M; García Domínguez, R; Jurado García, J M; Vélez de Mendizábal, E; Lambea Sorrosal, J J; García Carbonero, I; González del Alba, A; Suárez Rodríguez, C; Jiménez Gallego, P; Meana García, J A; García Marrero, R D; Gajate Borau, P; Santander Lobera, C; Molins Palau, C; López Brea, M; Fernández Parra, E M; Reig Torras, O; Basterretxea Badiola, L; Vázquez Estévez, S; González Larriba, J L

2016-04-01

Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice. Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died. According to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model. Our results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors.

PubMed

Singhi, Aatur D; Liu, Ta-Chiang; Roncaioli, Justin L; Cao, Dengfeng; Zeh, Herbert J; Zureikat, Amer H; Tsung, Allan; Marsh, J Wallis; Lee, Kenneth K; Hogg, Melissa E; Bahary, Nathan; Brand, Randall E; McGrath, Kevin M; Slivka, Adam; Cressman, Kristi L; Fuhrer, Kimberly; O'Sullivan, Roderick J

2017-01-15

Pancreatic neuroendocrine tumors (PanNET) are a heterogeneous group of neoplasms with increasing incidence and unpredictable behavior. Whole-exome sequencing has identified recurrent mutations in the genes DAXX and ATRX, which correlate with loss of protein expression and alternative lengthening of telomeres (ALT). Both ALT and DAXX/ATRX loss were initially reported to be associated with a favorable prognosis; however, recent studies suggest the contrary. Our aims were to assess the prevalence and prognostic significance of ALT and DAXX/ATRX in both primary and metastatic PanNETs. Telomere-specific FISH and DAXX/ATRX IHC was performed on a multi-institutional cohort of 321 patients with resected PanNET and 191 distant metastases from 52 patients. These results were correlated with clinicopathologic features, including disease-free survival (DFS) and disease-specific survival (DSS). The prevalence of ALT and DAXX/ATRX loss in resected PanNETs was 31% and 26%, respectively, and associated with larger tumor size, higher WHO grade, lymph node metastasis, and distant metastasis (P < 0.001). The 5-year DFS and 10-year DSS of patients with ALT-positive and DAXX/ATRX-negative PanNETs were 40% and 50%, respectively, as compared with 96% and 89%, respectively, for wild-type PanNETs. Among distant metastases, ALT and DAXX/ATRX loss was 67% and 52%, respectively, and only occurred in the setting of an ALT-positive and DAXX/ATRX-negative primary PanNET. By multivariate analysis, both ALT and DAXX/ATRX loss were negative, independent prognostic factors for DFS. ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer

PubMed Central

Johnstone, Cameron N.; Smith, Yvonne E.; Cao, Yuan; Burrows, Allan D.; Cross, Ryan S. N.; Ling, Xiawei; Redvers, Richard P.; Doherty, Judy P.; Eckhardt, Bedrich L.; Natoli, Anthony L.; Restall, Christina M.; Lucas, Erin; Pearson, Helen B.; Deb, Siddhartha; Britt, Kara L.; Rizzitelli, Alexandra; Li, Jason; Harmey, Judith H.; Pouliot, Normand; Anderson, Robin L.

2015-01-01

The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer. PMID:25633981

Leukemic blast cell colony formation in semisolid culture with erythropoietin: a case report of acute poorly differentiated erythroid leukemia.

PubMed

Tomonaga, M; Jinnai, I; Tagawa, M; Amenomori, T; Nishino, K; Yao, E; Nonaka, H; Kuriyama, K; Yoshida, Y; Matsuo, T

1987-02-01

The bone marrow of a patient with acute undifferentiated leukemia developed unique colonies after a 14-day culture in erythropoietin (EPO)-containing methylcellulose. The colonies consisted of 20 to 200 nonhemoglobinized large blast cells. Cytogenetic analysis of single colonies revealed hypotetraploid karyotypes with several marker chromosomes that were identical to those found in directly sampled bone marrow. The concurrently formed erythroid bursts showed only normal karyotypes. No leukemic colony formation was observed in other culture systems with either colony-stimulating activity (CSA) or phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). The leukemic colonies exhibited a complete EPO-dose dependency similar to that of the patient's normal BFU-E. Although cytochemical and immunologic marker studies of the bone marrow cells failed to clarify the cell lineage of the leukemic cells with extraordinarily large cell size, ultrastructural study revealed erythroid differentiation such as siderosome formation in the cytoplasm and ferritin particles in the rhophecytosis invaginations. These findings indicate that the patient had poorly differentiated erythroid leukemia and that some of the clonogenic cells might respond to EPO in vitro. Corresponding to this biological feature, the leukemic cells were markedly decreased in number in response to repeated RBC transfusions, and partial remission was obtained. These observations suggest that erythroid leukemia distinct from erythroleukemia (M6) with a myeloblastic component, can develop as a minor entity of human acute leukemia.

Optical detection of metastatic cancer cells using a scanned laser pico-projection system

NASA Astrophysics Data System (ADS)

Huang, Chih-Ling; Chiu, Wen-Tai; Lo, Yu-Lung; Chuang, Chin-Ho; Chen, Yu-Bin; Chang, Shu-Jing; Ke, Tung-Ting; Cheng, Hung-Chi; Wu, Hua-Lin

2015-03-01

Metastasis is responsible for 90% of all cancer-related deaths in humans. As a result, reliable techniques for detecting metastatic cells are urgently required. Although various techniques have been proposed for metastasis detection, they are generally capable of detecting metastatic cells only once migration has already occurred. Accordingly, the present study proposes an optical method for physical characterization of metastatic cancer cells using a scanned laser pico-projection system (SLPP). The validity of the proposed method is demonstrated using five pairs of cancer cell lines and two pairs of non-cancer cell lines treated by IPTG induction in order to mimic normal cells with an overexpression of oncogene. The results show that for all of the considered cell lines, the SLPP speckle contrast of the high-metastatic cells is significantly higher than that of the low-metastatic cells. As a result, the speckle contrast measurement provides a reliable means of distinguishing quantitatively between low- and high-metastatic cells of the same origin. Compared to existing metastasis detection methods, the proposed SLPP approach has many advantages, including a higher throughput, a lower cost, a larger sample size and a more reliable diagnostic performance. As a result, it provides a highly promising solution for physical characterization of metastatic cancer cells in vitro.

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence.

PubMed

O'Regan, Kevin; Breen, Micheál; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J; Hodi, F Stephen; Van den Abbeele, Annick D

2013-12-30

Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38-76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin.

Metastatic ovarian tumors: a clinicopathologic study of 150 cases.

PubMed

Alvarado-Cabrero, Isabel; Rodríguez-Gómez, Adriana; Castelan-Pedraza, Jorge; Valencia-Cedillo, Raquel

2013-10-01

To determine the frequency of metastatic ovarian tumors and to identify their clinicopathologic features. A total of 150 patients with pathologically confirmed metastatic ovarian carcinoma who were treated between 1995 and 2011 at the Mexican Oncology Hospital were identified by retrospective review. Clinicopathologic data were analyzed. Metastatic ovarian carcinoma accounted for 15.7% of all ovarian malignancies. The primary sites of nongynecologic tumors were the colon (30%), stomach (16%), appendix (13%), breast (13%), pancreas (12%), biliary tract (15%), and liver (4%). Gynecologic primary sites were the uterine cervix (4%) and the uterine body (23%). Primary malignancies were detected first in 66 patients (44%) and simultaneously with ovarian metastasis in 53 patients (35.3%). An ovarian mass was the first manifestation of disease in 20.6% of the cases. The patients ranged in age from 26 to 72 years (mean, 51). Krukenberg tumors were found in 35 patients (23%). The cut surfaces of the ovaries were solid in 68 patients, solid-cystic in 38, and multicystic in 44. Metastatic ovarian carcinomas are an important group of ovarian neoplasms, constituting 15.7% of all ovarian malignancies. Most of them arise from the gastrointestinal tract.

Development and External Validation of a Prognostic Nomogram for Metastatic Uveal Melanoma

PubMed Central

Valpione, Sara; Moser, Justin C.; Parrozzani, Raffaele; Bazzi, Marco; Mansfield, Aaron S.; Mocellin, Simone; Pigozzo, Jacopo; Midena, Edoardo; Markovic, Svetomir N.; Aliberti, Camillo; Campana, Luca G.; Chiarion-Sileni, Vanna

2015-01-01

Background Approximately 50% of patients with uveal melanoma (UM) will develop metastatic disease, usually involving the liver. The outcome of metastatic UM (mUM) is generally poor and no standard therapy has been established. Additionally, clinicians lack a validated prognostic tool to evaluate these patients. The aim of this work was to develop a reliable prognostic nomogram for clinicians. Patients and Methods Two cohorts of mUM patients, from Veneto Oncology Institute (IOV) (N=152) and Mayo Clinic (MC) (N=102), were analyzed to develop and externally validate, a prognostic nomogram. Results The median survival of mUM was 17.2 months in the IOV cohort and 19.7 in the MC cohort. Percentage of liver involvement (HR 1.6), elevated levels of serum LDH (HR 1.6), and a WHO performance status=1 (HR 1.5) or 2–3 (HR 4.6) were associated with worse prognosis. Longer disease-free interval from diagnosis of UM to that of mUM conferred a survival advantage (HR 0.9). The nomogram had a concordance probability of 0.75 (SE .006) in the development dataset (IOV), and 0.80 (SE .009) in the external validation (MC). Nomogram predictions were well calibrated. Conclusions The nomogram, which includes percentage of liver involvement, LDH levels, WHO performance status and disease free-interval accurately predicts the prognosis of mUM and could be useful for decision-making and risk stratification for clinical trials. PMID:25780931

Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

NASA Astrophysics Data System (ADS)

Coughlin, Mark F.; Fredberg, Jeffrey J.

2013-12-01

Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion.

A novel synthetic oleanane triterpenoid suppresses adhesion, migration and invasion of highly metastatic melanoma cells by modulating gelatinase signaling axis

PubMed Central

Sinha, Dona; Dutta, Kaustav; Ganguly, Kirat K.; Biswas, Jaydip; Bishayee, Anupam

2014-01-01

Background A methyl derivative natural triterpenoid amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) has been found to possess antiproliferative, proapoptotic and anti-inflammatory effects against established tumor cells. Large-scale synthesis of pure AMR-Me has eliminated the need of the natural phytochemical for further development of AMR-Me as an anticancer drug. Metastatic melanoma is a fatal form of cutaneous malignancy with poor prognosis and limited therapeutic options. It was hypothesized that antitumor pharmacological effect of AMR-Me could be linked to AMR-Me-mediated suppression of the metastatic potential of B16F10 murine melanoma. Methods AMR-Me was assessed for its antimetastatic efficacy by cell adhesion, migration and invasion assays in B16F10 cells. The signaling crosstalk was explored by gelatin zymography, Western blot, ELISA and immunocytochemistry. Results The results elicited that AMR-Me was successful in restricting the adhesion, migration and invasion of highly metastatic cells. The antimetastatic potential of this compound may be attributed to the reduced expression of membrane type 1 metalloproteinase (MT1-MMP) and matrix metalloproteinases (MMP-2 and MMP-9). AMR-Me was found to downregulate vascular endothelial growth factor (VEGF)/prosphorylated forms of focal adhesion kinase (pFAK397)/Jun N-terminus kinase (pJNK)/extracellular signal-regulated kinase (pERK). This, in turn, inhibited transcription factor nuclear factor-κB (NF-κB) and transactivation of MMPs. Moreover the activation of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) might have influenced the downmodulation of MT1-MMP, MMP-2 and MMP-9. Conclusion AMR-Me suppresses the activity of MT1-MMP, MMP-2 and MMP-9 by downregulation of VEGF/pFAK397/pJNK/pERK/NF-κB and activation of TIMP-1 and TIMP-2 in metastatic melanoma cell line, B16F10. General significance AMR-Me has the potential as an effective anticancer drug for metastatic melanoma which is a

The Use of Microgravity To Emulate Three-Dimensional Tissue Interactions in Colorectal Cancer Metastasis

NASA Technical Reports Server (NTRS)

Jessup, J. Milburn

1997-01-01

The hypothesis of this ground-based project was that simulated microgravity may be used to recreate with high fidelity the in vivo environment in tissue culture. The objectives were to determine whether: (1) simulated microgravity induces differentiation within poorly differentiated human colon carcinoma cells that are similar to that observed in experimental metastases in vivo in nude mice; and (2) the use of simulated microgravity helps define the experimental metastatic potential of human colorectal carcinoma.

Calvarial sarcoid mimicking metastatic disease.

PubMed

Bodie, B F; Kheir, S M; Omura, E F

1980-10-01

A 61-year-old white woman presented with localized cutaneous Boeck's sarcoid and multiple lytic skull lesions mimicking metastatic carcinoma. Complete workup revealed no neoplastic process; biopsy of the skull lesions showed noncaseating granulomas consistent with sarcoid. Although rare, calvarial sarcoid can occur.

Trespassing cancer cells: ‘fingerprinting’ invasive protrusions reveals metastatic culprits

PubMed Central

Klemke, Richard L.

2012-01-01

Metastatic cancer cells produce invasive membrane protrusions called invadopodia and pseudopodia, which play a central role in driving cancer cell dissemination in the body. Malignant cells use these structures to attach to and degrade extracellular matrix proteins, generate force for cell locomotion, and to penetrate the vasculature. Recent work using unique subcellular fractionation methodologies combined with spatial genomic, proteomic, and phosphoproteomic profiling has provided insight into the invadopodiome and pseudopodiome signaling networks that control the protrusion of invasive membranes. Here I highlight how these powerful spatial “omics” approaches reveal important signatures of metastatic cancer cells and possible new therapeutic targets aimed at treating metastatic disease. PMID:22980730

Metastatic breast cancer presenting as linitis plastica of the stomach.

PubMed

Whitty, Lisa A; Crawford, David L; Woodland, Jay H; Patel, Jitendra C; Nattier, Bryce; Thomas, Charles R

2005-01-01

Early detection and treatment of breast cancer, leading to longer survival, has revealed the natural history of this disease process. Linitis plastica of the stomach is a potential long-term sequela of metastatic breast cancer. Here we present a case of metastatic breast cancer presenting as linitis plastica, as well as the treatment algorithm for this rare clinical entity. The world literature describes a clear pattern of linitis plastica for metastatic infiltrating lobular breast cancer and a discrete nodular pattern for infiltrating ductal cancer, in regard to metastasis to the stomach. To our knowledge, this is the first case of infiltrating ductal cancer presenting as linitis plastica of the stomach.

Carboplatin AUC 10 for IGCCCG good prognosis metastatic seminoma.

PubMed

Tookman, Laura; Rashid, Sukaina; Matakidou, Athena; Phillips, Melissa; Wilson, Peter; Ansell, Wendy; Jamal-Hanjani, Mariam; Chowdhury, Simon; Harland, Stephen; Sarwar, Naveed; Oliver, Timothy; Powles, Thomas; Shamash, Jonathan

2013-06-01

Metastatic seminoma is a highly curable disease. Standard treatment comprises of combination chemotherapy. The short- and long-term toxicities of this treatment are increasingly recognised and the possibility of over treatment in such a curable disease should be considered. We have therefore assessed the use of single agent carboplatin at a dose of AUC 10 in patients with good prognosis metastatic seminoma. Patients with good prognosis metastatic seminoma treated with carboplatin (AUC 10) were identified at our institution and affiliated institutions. Treatment was three weekly for a total of three or four cycles. Outcome and toxicities were analysed. With a median follow-up of 36 months, 61 patients in total were treated with carboplatin AUC 10, all good prognosis by the IGCCCG criteria. Forty-eight percent had stage IIA/IIB disease and 52% had greater than stage IIB disease. Thirty-one patients (51%) had a complete response following treatment. Three-year survival was 96.3% with a three-year progression free survival of 93.2%. The main treatment toxicity was haematological with 46% having grade 3, 24% having grade 4 neutropenia and 54% experiencing grade 3/4 thrombocytopenia. There were no treatment related deaths. Single agent carboplatin at a dose of AUC 10 is an effective treatment for good prognosis metastatic seminoma. The outcome compares favourably to previously published outcomes of combination chemotherapy. Although haematological toxicity is a concern, single agent carboplatin treatment for good prognosis metastatic seminoma could be considered a treatment option and is associated with less toxicity than combination regimens currently used.

Nonpigmented Metastatic Melanoma in a Two-Year-Old Girl: A Serious Diagnostic Dilemma

PubMed Central

Diniz, Gulden; Tosun Yildirim, Hulya; Yamaci, Selcen

2015-01-01

Although rare, malignant melanoma may occur in children. Childhood melanomas account for only 0.3–3% of all melanomas. In particular the presence of congenital melanocytic nevi is associated with an increased risk of development of melanoma. We herein report a case of malignant melanoma that developed on a giant congenital melanocytic nevus and made a metastasis to the subcutaneous tissue of neck in a two-year-old girl. The patient was hospitalized for differential diagnosis and treatment of cervical mass with a suspicion of hematological malignancy, because the malignant transformation of congenital nevus was not noticed before. In this case, we found out a nonpigmented malignant tumor of pleomorphic cells after the microscopic examination of subcutaneous lesion. Nonpigmented metastatic melanoma was diagnosed by several immunohistochemical and flow cytometric studies. She was offered palliative chemotherapy; however, her parents did not accept treatment. The patient died within 9 months of diagnosis. We emphasized here that the possibility of malignant melanoma in the differential diagnosis of childhood tumors should be kept in mind. PMID:25763285

Biomechanics of metastatic disease in the vertebral column.

PubMed

Whyne, Cari M

2014-06-01

Metastatic disease in the vertebral column compromises the structural stability of the spine leading to increased risk of fracture. The complex patterns of osteolytic and osteoblastic disease within the bony spine have motivated a multimodal approach to better characterize the biomechanics of tumor-involved bone. This review presents our current understanding of the biomechanical behavior of metastatically involved vertebrae, and experimental and computational image-based approaches that have been employed to quantify structural integrity in preclinical models with translation to clinical data sets.

Anti-epidermal or anti-vascular endothelial growth factor as first-line metastatic colorectal cancer in modified Glasgow prognostic score 2' patients

PubMed Central

Dréanic, Johann; Dhooge, Marion; Barret, Maximilien; Brezault, Catherine; Mir, Olivier; Chaussade, Stanislas; Coriat, Romain

2015-01-01

Background In metastatic colorectal cancer, the modified Glasgow prognostic score (mGPS) has been approved as an independent prognostic indicator of survival. No data existed on poor prognosis patients treated with molecular-targeted agents. Methods From January 2007 to February 2012, patients with metastatic colorectal cancer and poor predictive survival score (mGPS = 2), treated with 5-fluorouracil-based chemotherapy in addition to an anti-epidermal growth factor receptor (EGFR) or anti-vascular epidermal growth factor (VEGF) therapy, were included to assess the interest of targeted therapy within mGPS = 2' patients. Results A total of 27 mGPS = 2' patients were included and received a 5-fluorouracil-based systemic chemotherapy in addition to an anti-EGFR treatment (cetuximab; n = 18) or an anti-VEGF treatment (bevacizumab; n = 9). Median follow-up was 12.1 months (interquartile range 4.9–22). Patients were Eastern Cooperative Oncology Group (ECOG) Performance Status 1, 2, and 3 in 66% (n = 18), 26% (n = 7), and 8% (n = 2), respectively. Comparing anti-EGFR and anti-VEGF groups, median progression-free survival was 3.9 and 15.4 months, respectively, and was significantly different (P = 0.046). Conversely, the median overall survival was not significantly different between the two groups (P = 0.15). Conclusion Our study confirmed the poor survival of patients with mGPS = 2 despite the use of targeted therapy and identified the superiority of an anti-VEGF treatment in progression-free survival, without a significant benefit in the overall survival compared with the anti-EGFR therapy. Our results deserved confirmation by a prospective clinical trial. PMID:26401469

Metastatic synovial sarcoma of the scalp: Case report.

PubMed

Lippert, Dylan C; Britt, Christopher J; Pflum, Zachary E; Rush, Patrick S; Hartig, Gregory K

2016-02-01

Synovial sarcoma is a malignant tumor of soft tissue that is rarely found in the head and neck. Even less common are metastasis within the head and neck. We describe a case of a delayed metastatic synovial sarcoma to the scalp. A man who had been diagnosed and treated 16 years previously for monophasic synovial sarcoma of the groin, presented with a new scalp lesion confirmed to be metastatic monophasic synovial sarcoma. Wide local excision and sentinel lymph node biopsy (SLNB) were performed and adjuvant radiation therapy was deferred. A positron emission tomography (PET)/CT was obtained 3 months after surgery and showed no evidence of local recurrence or metastatic disease. This case report describes a rare case of synovial sarcoma metastasizing to the scalp. The genetic, histopathologic, and clinical features of synovial sarcoma are reviewed with a focus on their manifestation and management within the head and neck. © 2015 Wiley Periodicals, Inc.

Network-based co-expression analysis for exploring the potential diagnostic biomarkers of metastatic melanoma.

PubMed

Wang, Li-Xin; Li, Yang; Chen, Guan-Zhi

2018-01-01

Metastatic melanoma is an aggressive skin cancer and is one of the global malignancies with high mortality and morbidity. It is essential to identify and verify diagnostic biomarkers of early metastatic melanoma. Previous studies have systematically assessed protein biomarkers and mRNA-based expression characteristics. However, molecular markers for the early diagnosis of metastatic melanoma have not been identified. To explore potential regulatory targets, we have analyzed the gene microarray expression profiles of malignant melanoma samples by co-expression analysis based on the network approach. The differentially expressed genes (DEGs) were screened by the EdgeR package of R software. A weighted gene co-expression network analysis (WGCNA) was used for the identification of DEGs in the special gene modules and hub genes. Subsequently, a protein-protein interaction network was constructed to extract hub genes associated with gene modules. Finally, twenty-four important hub genes (RASGRP2, IKZF1, CXCR5, LTB, BLK, LINGO3, CCR6, P2RY10, RHOH, JUP, KRT14, PLA2G3, SPRR1A, KRT78, SFN, CLDN4, IL1RN, PKP3, CBLC, KRT16, TMEM79, KLK8, LYPD3 and LYPD5) were treated as valuable factors involved in the immune response and tumor cell development in tumorigenesis. In addition, a transcriptional regulatory network was constructed for these specific modules or hub genes, and a few core transcriptional regulators were found to be mostly associated with our hub genes, including GATA1, STAT1, SP1, and PSG1. In summary, our findings enhance our understanding of the biological process of malignant melanoma metastasis, enabling us to identify specific genes to use for diagnostic and prognostic markers and possibly for targeted therapy.

High-dose interleukin 2 in patients with metastatic renal cell carcinoma with sarcomatoid features.

PubMed

Achkar, Tala; Arjunan, Ananth; Wang, Hong; Saul, Melissa; Davar, Diwakar; Appleman, Leonard J; Friedland, David; Parikh, Rahul A

2017-01-01

High-dose interleukin-2 (HD IL-2) is used in the treatment of metastatic renal cell carcinoma (mRCC) and has an overall response rate (ORR) of 12-20% and a complete response rate (CR) of 8% in unselected populations with predominantly clear cell type renal cell carcinoma. Nearly 10-15% of patients with renal cell carcinoma exhibit sarcomatoid differentiation, a feature which correlates with a median overall survival (OS) of 9 months and overall poor prognosis. We report a single institution experience with 21 patients with mRCC with sarcomatoid features post-nephrectomy who were treated with HD IL-2. Twenty one patients with mRCC with sarcomatoid features post-nephrectomy who underwent therapy with HD IL-2 were identified at the University of Pittsburgh Medical Center from 2004 to 2016. Baseline patient characteristics, HD IL-2 cycles, time to progression, and subsequent therapies were evaluated. OS and progression-free survival (PFS) in the cohort were calculated using the Kaplan-Meier method. Disease characteristics were evaluated for significance using the Fischer's exact test and Wilcoxon rank sum test. Patients were predominantly Caucasian males with a median age of 54 years. A majority, 86% of these patients, had metastatic disease at time of initial presentation, primarily with lung and lymph node involvement. The ORR and CR with HD IL-2 was 10% and 5%, respectively. Initial localized disease presentation is the only variable that was significantly associated with response to HD IL-2 (p = 0.0158). Number of HD IL-2 doses did not correlate with response with a mean of 16.5 and 15.0 total doses in responders and non-responders, respectively (p = 0.53). Median PFS with HD IL-2 was 7.9 months (95% CI, 5.0-21.3). Median OS was 30.5 months (95% CI 13.3-57.66). Within the subset of patients who had progression on IL-2, median OS was 19.4 months (95% CI, 13.3-35.3). In patients who received second-line therapy, median PFS was 7.9 months (95% CI 2.4-10.2). In

Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial.

PubMed

Balar, Arjun V; Galsky, Matthew D; Rosenberg, Jonathan E; Powles, Thomas; Petrylak, Daniel P; Bellmunt, Joaquim; Loriot, Yohann; Necchi, Andrea; Hoffman-Censits, Jean; Perez-Gracia, Jose Luis; Dawson, Nancy A; van der Heijden, Michiel S; Dreicer, Robert; Srinivas, Sandy; Retz, Margitta M; Joseph, Richard W; Drakaki, Alexandra; Vaishampayan, Ulka N; Sridhar, Srikala S; Quinn, David I; Durán, Ignacio; Shaffer, David R; Eigl, Bernhard J; Grivas, Petros D; Yu, Evan Y; Li, Shi; Kadel, Edward E; Boyd, Zachary; Bourgon, Richard; Hegde, Priti S; Mariathasan, Sanjeev; Thåström, AnnChristine; Abidoye, Oyewale O; Fine, Gregg D; Bajorin, Dean F

2017-01-07

First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event

Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell.

PubMed

Bausero, Maria A; Bharti, Ajit; Page, Diana T; Perez, Kristen D; Eng, Jason W-L; Ordonez, Susana L; Asea, Edwina E; Jantschitsch, Christian; Kindas-Muegge, Ingela; Ciocca, Daniel; Asea, Alexzander

2006-01-01

The 25-kDa heat shock protein (Hsp25) is associated with various malignancies and is expressed at high levels in biopsies as well as circulating in the serum of breast cancer patients. In this study, we used RNA interference technology to silence the hsp25 gene in 4T1 breast adenocarcinoma cells, known as a poorly immunogenic, highly metastatic cell line. We demonstrate that transfection of 4T1 cells with short interference RNA-Hsp25 dramatically inhibits proliferation as compared with control transfected cells. In addition, we show that 4T1 cells transfected with short interference RNA-Hsp25 abrogates tumor migration potential by a mechanism that is in part due to the repression of matrix metalloproteinase 9 expression and a concomitant upregulation of its antagonist, tissue inhibitor metalloproteinase 1. Taken together, these findings provide a model system for the study of metastatic potential of tumors and are suggestive of an earlier unrecognized role for Hsp25 in tumor migration. Copyright 2006 S. Karger AG, Basel.

Measuring the metastatic potential of cancer cells

NASA Technical Reports Server (NTRS)

Morrison, Dennis R.; Gratzner, Howard; Atassi, M. Z.

1993-01-01

Cancer cells must secrete proteolytic enzymes to invade adjacent tissues and migrate to a new metastatic site. Urokinase (uPA) is a key enzyme related to metastasis in cancers of the lung, colon, gastric, uterine, breast, brain, and malignant melanoma. A NASA technology utilization project has combined fluorescence microscopy, image analysis, and flow cytometry, using fluorescent dyes, and urokinase-specific antibodies to measure uPA and abnormal DNA levels (related to cancer cell proliferation) inside the cancer cells. The project is focused on developing quantitative measurements to determine if a patient's tumor cells are actively metastasizing. If a significant number of tumor cells contain large amounts of uPA (esp. membrane-bound) then the post-surgical chemotherapy or radiotherapy can be targeted for metastatic cells that have already left the primary tumor. These analytical methods have been applied to a retrospective study of biopsy tissues from 150 node negative, stage 1 breast cancer patients. Cytopathology and image analysis has shown that uPA is present in high levels in many breast cancer cells, but not found in normal breast. Significant amounts of uPA also have been measured in glioma cell lines cultured from brain tumors. Commercial applications include new diagnostic tests for metastatic cells, in different cancers, which are being developed with a company that provides a medical testing service using flow cytometry for DNA analysis and hormone receptors on tumor cells from patient biopsies. This research also may provide the basis for developing a new 'magic bullet' treatment against metastasis using chemotherapeutic drugs or radioisotopes attached to urokinase-specific monoclonal antibodies that will only bind to metastatic cells.

Clinical significance of peripheral circulating tumor cell counts in colorectal polyps and non-metastatic colorectal cancer.

PubMed

Yang, Chengguang; Zhuang, Wenfang; Hu, Yuemei; Zhu, Leiming

2018-01-22

The presence of peripheral circulating tumor cells indicates the possible existence of a tumor in vivo; however, low numbers of circulating tumor cells (CTCs) can be detected in peripheral blood of healthy individuals as well as patients with benign tumors. It is not known whether peripheral CTC counts differ between patients with benign colorectal disease and those with colorectal cancer. Comparative analysis of preoperative peripheral circulating tumor cells counts was completed in patients with benign colorectal disease (colorectal polyps) and non-metastatic cancer of the colon and rectum. The results of this analysis showed that patients with colorectal cancer had higher CTC counts than patients with colorectal polyps (3.47 ± 0.32/3.2 ml vs 1.49 ± 0.2/3.2 ml, P < 0.001). Colorectal cancer patients with tumors of the sigmoid colon displayed the highest CTC counts (4.87 ± 0.95/3.2 ml), followed by those with tumors of the rectum (3.73 ± 0.54/3.2 ml), ascending colon (3.5 ± 0.63/3.2 ml), transverse colon (2.4 ± 0.68/3.2 ml), and descending colon (2.08 ± 0.46/3.2 ml). Colorectal polyp patients with polyps in the rectum showed the highest CTC counts (2.2 ± 0.77/3.2 ml), followed by those with polyps in the ascending colon (1.82 ± 0.54/3.2 ml), sigmoid colon (1.38 ± 0.25/3.2 ml), transverse colon (0.75 ± 0.25/3.2 ml), and descending colon (0.33 ± 0.21/3.2 ml). The differences in CTC counts suggest that anatomical location of colorectal tumors may affect blood vessel metastasis. Meanwhile, patients with moderately differentiated and poorly differentiated tumors displayed higher peripheral blood CTC counts compared to those with well-differentiated tumors (P < 0.001). This result suggests that the type of tissue differentiation of colorectal tumors may act as another factor that affects blood vessel metastasis. Circulating tumor cells can be detected in the peripheral blood of colorectal

Altered Redox Status Accompanies Progression to Metastatic Human Bladder Cancer

PubMed Central

Hempel, Nadine; Ye, Hanqing; Abessia, Bryan; Mian, Badar; Melendez, J. Andres

2009-01-01

The role of reactive oxygen species (ROS) in bladder cancer progression remains an unexplored field. Expression levels of enzymes regulating ROS levels are often altered in cancer. Search of publicly available micro-array data reveals that expression of mitochondrial manganese superoxide dismutase (Sod2), responsible for the conversion of superoxide (O2-.) to hydrogen peroxide (H2O2), is consistently increased in high grade and advanced stage bladder tumors. Here we aim to identify the role of Sod2 expression and ROS in bladder cancer. Using an in vitro human bladder tumor model we monitored the redox state of both non-metastatic (253J) and highly metastatic (253J B-V) bladder tumor cell lines. 253J B-V cells displayed significantly higher Sod2 protein and activity levels compared to their parental 253J cell line. The increase in Sod2 expression was accompanied by a significant decrease in catalase activity, resulting in a net increase in H2O2 production in the 253J B-V line. Expression of pro-metastatic and –angiogenic factors, matrix metalloproteinase 9 (MMP-9) and vascular endothelial derived growth factor (VEGF), respectively, were similarly upregulated in the metastatic line. Expression of both MMP-9 and VEGF were shown to be H2O2-dependent, as removal of H2O2 by overexpression of catalase attenuated their expression. Similarly, expression of catalase effectively reduced the clonogenic activity of 253J B-V cells. These findings indicate that metastatic bladder cancer cells display an altered antioxidant expression profile, resulting in a net increase in ROS production, which leads to the induction of redox-sensitive pro-tumorigenic and pro-metastatic genes such as VEGF and MMP-9. PMID:18930813

Metastatic pancreatic cancer: Is there a light at the end of the tunnel?

PubMed Central

Vaccaro, Vanja; Sperduti, Isabella; Vari, Sabrina; Bria, Emilio; Melisi, Davide; Garufi, Carlo; Nuzzo, Carmen; Scarpa, Aldo; Tortora, Giampaolo; Cognetti, Francesco; Reni, Michele; Milella, Michele

2015-01-01

Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate

Metastatic pancreatic cancer: Is there a light at the end of the tunnel?

PubMed

Vaccaro, Vanja; Sperduti, Isabella; Vari, Sabrina; Bria, Emilio; Melisi, Davide; Garufi, Carlo; Nuzzo, Carmen; Scarpa, Aldo; Tortora, Giampaolo; Cognetti, Francesco; Reni, Michele; Milella, Michele

2015-04-28

Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate

An unusual case of metastatic intracardiac plasmacytoma.

PubMed

Tak, T; Rashtian, M; De Tar, M; Chandraratna, P A; Gill, P

1994-10-01

The authors report the case of a 36-year-old male who, following investigations for dyspnea, othopnea and peripheral cyanosis, was found to have metastatic intracardiac plasmacytoma. Diagnosis was made initially with transesophageal echocardiography and emergent cardiac surgery was performed. Postoperative transthoracic and transesophageal echocardiograms revealed residual masses in the right and left atrium. The patient was subsequently treated with systemic chemotherapy and was symptom-free within three months of treatment, with rapid decline of paraproteins in the serum and urine. This case of intracardiac metastatic plasmacytoma is deemed unique because cardiac involvement with multiple myeloma has not been studied in detail, largely due to the rarity of such a presentation.

Dabrafenib in metastatic melanoma: a monocentric ‘real life’ experience

PubMed Central

Cocorocchio, E; Gandini, S; Alfieri, S; Battaglia, A; Pennacchioli, E; Tosti, G; Spadola, G; Barberis, M; Leo, M Di; Riviello, C; Pala, L; Intelisano, A; Martinoli, C; Ferrucci, PF

2016-01-01

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3–4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts. PMID:26981153

Cost-Effectiveness Analysis of Regorafenib for Metastatic Colorectal Cancer

PubMed Central

Goldstein, Daniel A.; Ahmad, Bilal B.; Chen, Qiushi; Ayer, Turgay; Howard, David H.; Lipscomb, Joseph; El-Rayes, Bassel F.; Flowers, Christopher R.

2015-01-01

Purpose Regorafenib is a standard-care option for treatment-refractory metastatic colorectal cancer that increases median overall survival by 6 weeks compared with placebo. Given this small incremental clinical benefit, we evaluated the cost-effectiveness of regorafenib in the third-line setting for patients with metastatic colorectal cancer from the US payer perspective. Methods We developed a Markov model to compare the cost and effectiveness of regorafenib with those of placebo in the third-line treatment of metastatic colorectal cancer. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2014. Model robustness was addressed in univariable and probabilistic sensitivity analyses. Results Regorafenib provided an additional 0.04 QALYs (0.13 life-years) at a cost of $40,000, resulting in an incremental cost-effectiveness ratio of $900,000 per QALY. The incremental cost-effectiveness ratio for regorafenib was > $550,000 per QALY in all of our univariable and probabilistic sensitivity analyses. Conclusion Regorafenib provides minimal incremental benefit at high incremental cost per QALY in the third-line management of metastatic colorectal cancer. The cost-effectiveness of regorafenib could be improved by the use of value-based pricing. PMID:26304904

Metastatic mucosal melanoma: imaging patterns of metastasis and recurrence

PubMed Central

O’Regan, Kevin; Ramaiya, Nikhil; Jagannathan, Jyothi; DiPiro, Pamela J.; Stephen Hodi, F.; Van den Abbeele, Annick D.

2013-01-01

Abstract Purpose: Mucosal melanoma is a rare but aggressive subtype of melanoma with unique clinicopathologic features. We hypothesize that mucosal melanoma shows predilection for separate and unique metastatic pathways. Materials and methods: This was a retrospective analysis of 19 patients (5 men and 14 women; median age 60 years, range 38–76 years) with metastatic mucosal melanoma presenting to a tertiary oncology center between 2005 and 2010. We performed a review of medical records and histologic and imaging studies to evaluate the natural history, metastatic patterns and the role of imaging in the management of patients with advanced mucosal melanoma. Results: At presentation, disease was confined to the primary site (58%, n = 11) or to the regional lymph nodes (32%, n = 6) in most patients. The most common site of metastasis was the lungs (89%, n = 16), followed by the liver (67%, n = 12) and peritoneum (44%, n = 8). Sinonasal melanoma preferentially spread to the liver (100%, n = 4), vaginal melanoma to the lungs (100%, n = 7) and anal melanoma to the inguinal lymph nodes (100%, n = 4). Conclusion: Pathways of metastatic spread in mucosal melanoma may differ from other forms of melanoma and between different primary sites of mucosal origin. PMID:24434078

m-RNA mammaglobin expression in metastatic breast cancer patient at Medan city, Indonesia

NASA Astrophysics Data System (ADS)

Rimbun, S.; Siregar, Y.

2018-03-01

Breast cancer is the most common causes of women’s death in the world. Metastatic spread presents a major clinical problem in about 30% of the patients. The study aims to investigate the clinical reliability of mammaglobin mRNA as a marker of circulating cancer cells in breast cancer patients. The positivity of blood was analyzed in relation to clinical and pathological characteristics. This study was on 29 breast cancer patients (13 metastatic, 16 non- metastatic patients), where28 were invasive intraductal carcinoma type and 1 was invasive lobular carcinoma type. Breast cancer patients were according to the histologic grade into grade I (7 patients),grade II (6 patients) and grade III (15 patients). All individuals included in this study were subjected to detection of mammaglobin m-RNA of circulating tumor cells in peripheral blood using RT-PCR technique. Positivity for mammaglobin in blood samples was in 38% of patients with metastatic but not in the non-metastatic patients. The presence of mammaglobin correlated with metastatic tumor (P = 0.011). Mammaglobin overexpression in breast tissue was significantly positive in low-grade tumors (I and II).

Imaging of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-HBED-CC-PSMA PET/CT.

PubMed

Lütje, Susanne; Gomez, Benedikt; Cohnen, Joseph; Umutlu, Lale; Gotthardt, Martin; Poeppel, Thorsten D; Bockisch, Andreas; Rosenbaum-Krumme, Sandra

2017-01-01

The prostate-specific membrane antigen (PSMA) was shown to be overexpressed on the neovasculature of several malignancies. Here, the role of Ga-HBED-CC-PSMA PET/CT for the detection of PSMA expression in patients with metastasized differentiated thyroid cancer (DTC) was evaluated. Six patients with iodine-negative and F-FDG-positive metastasized DTC (mean TG, 1616 ng/mL) received 71-93 MBq of the Ga-labeled PSMA ligand and underwent PET/CT at 62 ± 7 minutes p.i.. Tumor accumulation capacity of the tracer and the detection rate of local recurrences and metastases were compared with F-FDG. Tracer uptake was quantified in terms of the SUVmax. In 5 of 6 patients, sites of putative metastatic disease could be identified using Ga-HBED-CC-PSMA PET/CT. All lesions detected with Ga-HBED-CC-PSMA PET/CT (n = 42) were confirmed by F-FDG PET/CT or conventional CT imaging. Using Ga-HBED-CC-PSMA PET/CT, all tumor lesions identified with F-FDG PET/CT imaging could be visualized in 3 of 5 patients. In 2 patients, only the most prominent lesions detected with F-FDG PET/CT imaging were visualized by Ga-HBED-CC-PSMA PET/CT. Ga-HBED-CC-PSMA uptake ranged from low in 1 patient (mean SUVmax 3.3) to intermediate (1 patient; mean SUVmax, 6.1) to intense (3 patients; mean SUVmax, 12.8, 16.2, and 18.3). The highest SUVmax values were observed for a bone lesion, reaching 39.7. These preliminary results indicate that Ga-HBED-CC-PSMA PET/CT might be suitable for staging of patients with metastasized DTC. Ga-HBED-CC-PSMA PET/CT could be useful for the identification of patients who might qualify for PSMA-targeted radionuclide therapy because of high PSMA uptake.

Modeling pre-metastatic lymphvascular niche in the mouse ear sponge assay

NASA Astrophysics Data System (ADS)

García-Caballero, Melissa; van de Velde, Maureen; Blacher, Silvia; Lambert, Vincent; Balsat, Cédric; Erpicum, Charlotte; Durré, Tania; Kridelka, Frédéric; Noel, Agnès

2017-01-01

Lymphangiogenesis, the formation of new lymphatic vessels, occurs in primary tumors and in draining lymph nodes leading to pre-metastatic niche formation. Reliable in vivo models are becoming instrumental for investigating alterations occurring in lymph nodes before tumor cell arrival. In this study, we demonstrate that B16F10 melanoma cell encapsulation in a biomaterial, and implantation in the mouse ear, prevents their rapid lymphatic spread observed when cells are directly injected in the ear. Vascular remodeling in lymph nodes was detected two weeks after sponge implantation, while their colonization by tumor cells occurred two weeks later. In this model, a huge lymphangiogenic response was induced in primary tumors and in pre-metastatic and metastatic lymph nodes. In control lymph nodes, lymphatic vessels were confined to the cortex. In contrast, an enlargement and expansion of lymphatic vessels towards paracortical and medullar areas occurred in pre-metastatic lymph nodes. We designed an original computerized-assisted quantification method to examine the lymphatic vessel structure and the spatial distribution. This new reliable and accurate model is suitable for in vivo studies of lymphangiogenesis, holds promise for unraveling the mechanisms underlying lymphatic metastases and pre-metastatic niche formation in lymph nodes, and will provide new tools for drug testing.

The Calcium-Sensing Receptor and Integrins in Cellular Differentiation and Migration

PubMed Central

Tharmalingam, Sujeenthar; Hampson, David R.

2016-01-01

The calcium-sensing receptor (CaSR) is a widely expressed homodimeric G-protein coupled receptor structurally related to the metabotropic glutamate receptors and GPRC6A. In addition to its well characterized role in maintaining calcium homeostasis and regulating parathyroid hormone release, evidence has accumulated linking the CaSR with cellular differentiation and migration, brain development, stem cell engraftment, wound healing, and tumor growth and metastasis. Elevated expression of the CaSR in aggressive metastatic tumors has been suggested as a potential novel prognostic marker for predicting metastasis, especially to bone tissue where extracellular calcium concentrations may be sufficiently high to activate the receptor. Recent evidence supports a model whereby CaSR-mediated activation of integrins promotes cellular migration. Integrins are single transmembrane spanning heterodimeric adhesion receptors that mediate cell migration by binding to extracellular matrix proteins. The CaSR has been shown to form signaling complexes with the integrins to facilitate both the movement and differentiation of cells, such as neurons during normal brain development and tumor cells under pathological circumstances. Thus, CaSR/integrin complexes may function as a universal cell migration or homing complex. Manipulation of this complex may be of potential interest for treating metastatic cancers, and for developmental disorders pertaining to aberrant neuronal migration. PMID:27303307

Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma.

PubMed

Chuang, Ai-Ying; DeMarzo, Angelo M; Veltri, Robert W; Sharma, Rajni B; Bieberich, Charles J; Epstein, Jonathan I

2007-08-01

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial

TNFRSF10C copy number variation is associated with metastatic colorectal cancer

PubMed Central

Tanenbaum, Daniel G.; Hall, William A.; Colbert, Lauren E.; Bastien, Amanda J.; Brat, Daniel J.; Kong, Jun; Kim, Sungjin; Dwivedi, Bhakti; Kowalski, Jeanne; Landry, Jerome C.

2016-01-01

Background Genetic markers for distant metastatic disease in patients with colorectal cancer (CRC) are not well defined. Identification of genetic alterations associated with metastatic CRC could help to guide systemic and local treatment strategies. We evaluated the association of tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) copy number variation (CNV) with distant metastatic disease in patients with CRC using The Cancer Genome Atlas (TCGA). Methods Genetic sequencing data and clinical characteristics were obtained from TCGA for all available patients with CRC. There were 515 CRC patient samples with CNV and clinical outcome data, including a subset of 144 rectal adenocarcinoma patient samples. Using the TCGA CRC dataset, CNV of TNFRSF10C was evaluated for association with distant metastatic disease (M1 vs. M0). Multivariate logistic regression analysis with odds ratio (OR) using a 95% confidence interval (CI) was performed adjusting for age, T stage, N stage, adjuvant chemotherapy, gender, microsatellite instability (MSI), location, and surgical margin status. Results TNFRSF10C CNV in patients with CRC was associated with distant metastatic disease [OR 4.81 (95% CI, 2.13–10.85) P<0.001] and positive lymph nodes [OR 18.83 (95% CI, 8.42–42.09)]; P<0.001) but not MSI (OR P=0.799). On multivariate analysis, after adjusting for pathologic T stage, N stage, adjuvant chemotherapy, gender, and MSI, TNFRSF10C CNV remained significantly associated with distant metastatic disease (OR P=0.018). Subset analysis revealed that TNFRSF10C CNV was also significantly associated with distant metastatic disease in patients with rectal adenocarcinoma (OR P=0.016). Conclusions TNFRSF10C CNV in patients with CRC is associated with distant metastatic disease. With further validation, such genetic profiles could be used clinically to support optimal systemic treatment strategies versus more aggressive local therapies in patients with CRC, including radiation

Comprehensive Genomic Profiling Aids in Distinguishing Metastatic Recurrence from Second Primary Cancers

PubMed Central

Weinberg, Benjamin A.; Gowen, Kyle; Lee, Thomas K.; Ou, Sai‐Hong Ignatius; Bristow, Robert; Krill, Lauren; Almira‐Suarez, M. Isabel; Ali, Siraj M.; Miller, Vincent A.; Liu, Stephen V.

2017-01-01

Abstract Background. Metastatic recurrence after treatment for locoregional cancer is a major cause of morbidity and cancer‐specific mortality. Distinguishing metastatic recurrence from the development of a second primary cancer has important prognostic and therapeutic value and represents a difficult clinical scenario. Advances beyond histopathological comparison are needed. We sought to interrogate the ability of comprehensive genomic profiling (CGP) to aid in distinguishing between these clinical scenarios. Materials and Methods. We identified three prospective cases of recurrent tumors in patients previously treated for localized cancers in which histologic analyses suggested subsequent development of a distinct second primary. Paired samples from the original primary and recurrent tumor were subjected to hybrid capture next‐generation sequencing‐based CGP to identify base pair substitutions, insertions, deletions, copy number alterations (CNA), and chromosomal rearrangements. Genomic profiles between paired samples were compared using previously established statistical clonality assessment software to gauge relatedness beyond global CGP similarities. Results. A high degree of similarity was observed among genomic profiles from morphologically distinct primary and recurrent tumors. Genomic information suggested reclassification as recurrent metastatic disease, and patients received therapy for metastatic disease based on the molecular determination. Conclusions. Our cases demonstrate an important adjunct role for CGP technologies in separating metastatic recurrence from development of a second primary cancer. Larger series are needed to confirm our observations, but comparative CGP may be considered in patients for whom distinguishing metastatic recurrence from a second primary would alter the therapeutic approach. Implications for Practice. Distinguishing a metastatic recurrence from a second primary cancer can represent a difficult clinicopathologic

Atezolizumab and CYT107 in Treating Participants With Locally Advanced, Inoperable, or Metastatic Urothelial Carcinoma

ClinicalTrials.gov

2018-05-18

Metastatic Bladder Urothelial Carcinoma; Metastatic Renal Pelvis Urothelial Carcinoma; Metastatic Ureter Urothelial Carcinoma; Metastatic Urethral Urothelial Carcinoma; Metastatic Urothelial Carcinoma; Recurrent Bladder Urothelial Carcinoma; Recurrent Renal Pelvis Urothelial Carcinoma; Recurrent Ureter Urothelial Carcinoma; Recurrent Urethral Urothelial Carcinoma; Stage III Bladder Cancer AJCC v8; Stage III Renal Pelvis Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage III Urethral Cancer AJCC v8; Stage IV Bladder Cancer AJCC v8; Stage IV Renal Pelvis Cancer AJCC v8; Stage IV Ureter Cancer AJCC v8; Stage IV Urethral Cancer AJCC v8; Stage IVA Bladder Cancer AJCC v8; Stage IVB Bladder Cancer AJCC v8

Ocular melanoma metastatic to skin: the value of HMB-45 staining.

PubMed

Schwartz, Robert A; Kist, Joseph M; Thomas, Isabelle; Fernández, Geover; Cruz, Manuel A; Koziorynska, Ewa I; Lambert, W Clark

2004-06-01

Cutaneous metastatic disease is an important finding that may represent the first sign of systemic cancer, or, if already known, that may change tumor staging and thus dramatically altered therapeutic plans. Although cutaneous metastases are relatively frequent in patients with cutaneous melanoma, they are less so from ocular melanoma. To demonstrate the value of HMB-45, staining in the detection of ocular melanoma metastatic to skin. The immunohistochemical stain HMB-45 a monoclonal antibody directed against intact human melanoma cells, was employed on a skin biopsy specimen from a cutaneous tumor. HMB-45 staining was positive in the atypical hyperchromatic cells of the deep dermis. HMB-45 may be of value in the detection of ocular melanoma metastatic to skin. Cutaneous metastatic disease is a somewhat common and extremely important diagnosis. Although cutaneous metastases from cutaneous melanoma are relatively frequent, those from ocular melanomas are less so. Use of histochemical staining, especially the HMB-45 stain, allows confirmation of the diagnosis.

Effect of cordycepin (3'-deoxyadenosine) on hematogenic lung metastatic model mice.

PubMed

Nakamura, Kazuki; Konoha, Keiko; Yoshikawa, Noriko; Yamaguchi, Yu; Kagota, Satomi; Shinozuka, Kazumasa; Kunitomo, Masaru

2005-01-01

We investigated the anti-metastatic effect of cordycepin (3'-deoxyadenosine) on a hematogenic metastatic mouse model which was intravenously injected with B16-BL6 melanoma cells. A 3-hour exposure to various concentrations of cordycepin (0.3, 1 and 3 microg/ml) dose-dependently reduced the number of nodules formed in lung at 15 days after the tumor injection. To elucidate the mechanism of this anti-metastatic effect, we examined the effect of cordycepin on the invasiveness of B16-BL6 cells using a chemo-invasion chamber in vitro. The B16-BL6 cells pretreated with cordycepin (3 microg/ml) for 3 hours showed a significant decrease in invasiveness. Under the same conditions, however, cordycepin did not influence the growth curve of B16-BL6 cells at concentrations up to 3 microg/ml. These results suggest that cordycepin exerts an anti-metastatic action, in part, by inhibiting the invasiveness of mouse melanoma cells.

Metastatic breast carcinoma presenting as unilateral pulsatile tinnitus: a case report.

PubMed

Moore, Andrew; Cunnane, Max; Fleming, Jason C

2015-02-01

Pulsatile tinnitus is a rare symptom, yet it may herald life-threatening pathology in the absence of other symptoms or signs. Pulsatile tinnitus tends to imply a vascular cause, but metastatic disease also can present in this way. Clinicians should therefore adopt a specific diagnostic algorithm for pulsatile tinnitus and always consider the possibility of metastatic disease. A history of malignant disease and new cranial nerve palsies should raise clinical suspicion for skull base metastases. We describe the case of a 63-year-old woman presenting with unilateral subjective pulsatile tinnitus and a middle ear mass visible on otoscopy. Her background included the diagnosis of idiopathic unilateral vagal and hypoglossal nerve palsies 4 years previously, with normal magnetic resonance imaging (MRI). Repeat MRI and computed tomography imaging were consistent with metastatic breast carcinoma. This case raises important questions about imaging protocols and the role of serial scanning in patients at high risk of metastatic disease.

Living Well? Strategies Used by Women Living With Metastatic Breast Cancer.

PubMed

Lewis, Sophie; Willis, Karen; Yee, Jasmine; Kilbreath, Sharon

2016-07-01

Metastatic breast cancer is a disease of changing status-once an imminent death sentence, now a chronic (albeit incurable) disease. Medical intervention advances mean women with metastatic breast cancer now have symptoms alleviated and, potentially, life extended. Living with this disease, however, requires more than a medical approach to symptoms. We were interested to know whether women manage, and if so, how, to "live well" with metastatic cancer. We conducted interviews with 18 women. Women differed in the approaches they used. Most common was the attempt to reestablish a sense of normality in their lives. However, a second group reevaluated and reprioritized their lives; and a third group was restricted in their capacity to live well because of symptoms. The findings provide the foundation for future research exploring normalization of experiences of metastatic cancer, and other chronic illnesses, where people are living with knowledge that they have contracted time. © The Author(s) 2015.

Epigenetic dysregulation of KCa 3.1 channels induces poor prognosis in lung cancer.

PubMed

Bulk, Etmar; Ay, Anne-Sophie; Hammadi, Mehdi; Ouadid-Ahidouch, Halima; Schelhaas, Sonja; Hascher, Antje; Rohde, Christian; Thoennissen, Nils H; Wiewrodt, Rainer; Schmidt, Eva; Marra, Alessandro; Hillejan, Ludger; Jacobs, Andreas H; Klein, Hans-Ulrich; Dugas, Martin; Berdel, Wolfgang E; Müller-Tidow, Carsten; Schwab, Albrecht

2015-09-15

Epigenomic changes are an important feature of malignant tumors. How tumor aggressiveness is affected by DNA methylation of specific loci is largely unexplored. In genome-wide DNA methylation analyses, we identified the KCa 3.1 channel gene (KCNN4) promoter to be hypomethylated in an aggressive non-small-cell lung carcinoma (NSCLC) cell line and in patient samples. Accordingly, KCa 3.1 expression was increased in more aggressive NSCLC cells. Both findings were strong predictors for poor prognosis in lung adenocarcinoma. Increased KCa 3.1 expression was associated with aggressive features of NSCLC cells. Proliferation and migration of pro-metastatic NSCLC cells depended on KCa 3.1 activity. Mechanistically, elevated KCa 3.1 expression hyperpolarized the membrane potential, thereby augmenting the driving force for Ca(2+) influx. KCa 3.1 blockade strongly reduced the growth of xenografted NSCLC cells in mice as measured by positron emission tomography-computed tomography. Thus, loss of DNA methylation of the KCNN4 promoter and increased KCa 3.1 channel expression and function are mechanistically linked to poor survival of NSCLC patients. © 2015 UICC.

High Expression of KCa3.1 in Patients with Clear Cell Renal Carcinoma Predicts High Metastatic Risk and Poor Survival

PubMed Central

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L.; Marcussen, Niels; Köhler, Ralf

2015-01-01

Background Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. Methodology/Principal Findings We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Conclusions/Significance Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative

High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival.

PubMed

Rabjerg, Maj; Oliván-Viguera, Aida; Hansen, Lars Koch; Jensen, Line; Sevelsted-Møller, Linda; Walter, Steen; Jensen, Boye L; Marcussen, Niels; Köhler, Ralf

2015-01-01

Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival. We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro. Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short

Simultaneous peritoneal and retroperitoneal splenosis mimics metastatic right adrenal mass.

PubMed

Hashem, Abdelwahab; Elbaset, M A; Zahran, Mohamed H; Osman, Yasser

2018-06-05

Right retroperitoneal splenosis is rare with few reported cases. We report, here, the case of simultaneous peritoneal and retroperitoneal splenosis mimics metastatic right adrenal mass. A 28-year-old man who had previously undergone post traumatic splenectomy at childhood and subsequently presented with an large incidental non-functioning right adrenal mass with presence of extra-hepatic peritoneal focal lesion diagnosed as metastasis by magnetic resonance imaging (MRI). Adrenalectomy with metatstectomy was performed, and both masses were identified to be splenosis. Adrenal incidentalomas (AIs) is defined as asymptomatic masses >1 cm. on cross-sectional imaging studies. AIs have significant malignant potential for masses > 6 cm. Splenosis are found most frequently in the left retroperitoneum in cases involving retroperitoneal splenosis. However, right retroperitoneal splenosis have been reported. Traditional imaging techniques cannot differentiate splenosis from malignancy. Large right adrenal incidentalomas present with other abdominal, peritoneal masses could be splenosis in patient following post-traumatic splenectomy. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

DTIC Science & Technology

2011-05-01

8 4 INTRODUCTION The focus of this project is to evaluate the anti-tumor effects of benzimidazoles as a...potential anti-metastatic prostate cancer therapy. We identified benzimidazoles , a class of anti-parasitic drug, in a drug screening process for...preferential anti-tumor activity on metastatic prostate cancer cells. We have data indicate that benzimidazoles have potent anti-tumor activities

N-Myc Differentially Regulates Expression of MXI1 Isoforms in Neuroblastoma1

PubMed Central

Armstrong, Michael B; Mody, Rajen J; Ellis, D Christian; Hill, Adam B; Erichsen, David A; Wechsler, Daniel S

2013-01-01

Amplification of the MYCN proto-oncogene is associated with a poor prognosis in patients with metastatic neuroblastoma (NB). MYCN encodes the N-Myc protein, a transcriptional regulator that dimerizes with the Max transcription factor, binds to E-box DNA sequences, and regulates genes involved in cell growth and apoptosis. Overexpression of N-Myc leads to transcriptional activation and an increase in NB cell proliferation. Mxi1, a member of the Myc family of transcriptional regulators, also binds to Max. However, Mxi1 is a transcriptional repressor and inhibits proliferation of NB cells, suggesting that Mxi1 functions as an N-Myc antagonist. Our laboratory previously identified Mxi1-0, an alternatively transcribed Mxi1 isoform. Mxi1-0 has properties distinct from those of Mxi1; in contrast to Mxi1, Mxi1-0 is unable to suppress c-Myc-dependent transcription. We now show that Mxi1-0 expression increases in response to MYCN overexpression in NB cells, with a positive correlation between MYCN and MXI1-0 RNA levels. We also show that N-Myc expression differentially regulates the MXI1 and MXI1-0 promoters: Increased MYCN expression suppresses MXI1 promoter activity while enhancing transcription through the MXI1-0 promoter. Finally, induction of Mxi1-0 leads to increased proliferation, whereas expression of Mxi1 inhibits cell growth, indicating differential roles for these two proteins. These data suggest that N-Myc differentially regulates the expression of MXI1 and MXI1-0 and can alter the balance between the two transcription factors. Furthermore, MXI1-0 appears to be a downstream target of MYCN-dependent signaling pathways and may contribute to N-Myc-dependent cell growth and proliferation. PMID:24403858

Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes

PubMed Central

Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

2016-01-01

Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis. PMID:27589561

Periostin is identified as a putative metastatic marker in breast cancer-derived exosomes.

PubMed

Vardaki, Ioulia; Ceder, Sophia; Rutishauser, Dorothea; Baltatzis, George; Foukakis, Theodoros; Panaretakis, Theocharis

2016-11-15

Breast cancer (BrCa) is the most frequent cancer type in women and a leading cause of cancer related deaths in the world. Despite the decrease in mortality due to better diagnostics and palliative care, there is a lack of prognostic markers of metastasis. Recently, the exploitation of liquid biopsies and in particular of the extracellular vesicles has shown promise in the identification of such prognostic markers. In this study we compared the proteomic content of exosomes derived from metastatic and non-metastatic human (MCF7 and MDA-MB-231) and mouse (67NR and 4T1) cell lines. We found significant differences not only in the amount of secreted exosomes but most importantly in the protein content of exosomes secreted from metastatic versus non-metastatic ones. We identified periostin as a protein that is enriched in exosomes secreted by metastatic cells and validated its presence in a pilot cohort of breast cancer patient samples with localized disease or lymph node (LN) metastasis.

A primary tumor of mixed histological type is a novel poor prognostic factor for patients undergoing resection of liver metastasis from gastric cancer.

PubMed

Ikari, Naoki; Taniguchi, Kiyoaki; Serizawa, Akiko; Yamada, Takuji; Yamamoto, Masakazu; Furukawa, Toru

2017-05-01

Surgical resection can be an option for the treatment of metastatic liver tumors originating from gastric cancer; however, its prognostic impact is controversial. The aim of this study was to identify prognostic factors in patients with surgical resection of liver metastasis from gastric cancer. We retrospectively analyzed the clinicopathological features of 38 consecutive patients undergoing hepatectomy for metastatic tumors from gastric cancer in our institution between 1990 and 2014. The median overall survival of the patients was 28 months. The 5-year survival rate was 33.9%. Primary tumors of a mixed histological type, and residual tumors during the course of treatment were identified as significant independent poor prognostic factors. Histological evaluation of primary tumors may aid to identify patients suitable for undergoing surgical resection of liver metastasis from gastric cancer. © 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

Metastatic spinal cord compression from basal cell carcinoma of the skin treated with surgical decompression and vismodegib: case report and review of Hedgehog signalling pathway inhibition in advanced basal cell carcinoma.

PubMed

McGrane, J; Carswell, S; Talbot, T

2017-01-01

We report a case of a 66-year-old man with locally advanced and metastatic basal cell carcinoma (BCC) causing spinal cord compression, which was treated with spinal surgery and subsequent vismodegib. The patient presented with a large fungating chest wall lesion and a metastasis in T8 that was causing cord compression. He had neurosurgical decompression of the T8 lesion and fixation of the spine. Punch biopsy from the fungating chest wall lesion showed a BCC with some malignant squamous differentiation (basosquamous). Histopathological examination of the metastatic lesion in T8 at the time of surgical decompression identified features identical to the punch biopsy. The patient was referred to the oncology clinic for adjuvant treatment. In light of his metastatic disease and the large area over his chest wall that could not fully be covered by radiotherapy, he was treated with the novel oral Hedgehog signalling pathway (HHSP) inhibitor vismodegib, which led to marked improvement. © 2016 British Association of Dermatologists.

The key role of extracellular vesicles in the metastatic process.

PubMed

Zhao, Hongyun; Achreja, Abhinav; Iessi, Elisabetta; Logozzi, Mariantonia; Mizzoni, Davide; Di Raimo, Rossella; Nagrath, Deepak; Fais, Stefano

2018-01-01

Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

ERBB2 Increases Metastatic Potentials Specifically in Androgen-Insensitive Prostate Cancer Cells

PubMed Central

Tome-Garcia, Jessica; Li, Dan; Ghazaryan, Seda; Shu, Limin; Wu, Lizhao

2014-01-01

Despite all the blood-based biomarkers used to monitor prostate cancer patients, prostate cancer remains as the second common cause of cancer mortality in men in the United States. This is largely due to a lack of understanding of the molecular pathways that are responsible for the aggressive forms of prostate cancers, the castrate-resistant prostate cancer and the metastatic prostate cancer. Cell signaling pathways activated by the ERBB2 oncogene or the RAS oncogene are frequently found to be altered in metastatic prostate cancers. To evaluate and define the role of the ERBB2/RAS pathway in prostate cancer metastasis, we have evaluated the impact of ERBB2- or RAS-overexpression on the metastatic potentials for four prostate cancer cell lines derived from tumors with different androgen sensitivities. To do so, we transfected the human DU145, LnCaP, and PC3 prostate cancer cells and the murine Myc-CaP prostate cancer cells with the activated form of ERBB2 or H-RAS and assessed their metastatic potentials by three complementary assays, a wound healing assay, a transwell motility assay, and a transwell invasion assay. We showed that while overexpression of ERBB2 increased the metastatic potential of the androgen-insensitive prostate cancer cells (i.e. PC3 and DU145), it did not affect metastatic potentials of the androgen-sensitive prostate cancer cells (i.e. LnCaP and Myc-CaP). In contrast, overexpression of H-RAS only increased the cell motility of Myc-CaP cells, which overexpress the human c-MYC oncogene. Our data suggest that ERBB2 collaborates with androgen signaling to promote prostate cancer metastasis, and that although RAS is one of the critical downstream effectors of ERBB2, it does not phenocopy ERBB2 for its impact on the metastatic potentials of prostate cancer cell lines. PMID:24937171

Should Aggressive Surgical Local Control Be Attempted in All Patients with Metastatic or Pelvic Ewing's Sarcoma?

PubMed Central

Thorpe, Steven W.; Weiss, Kurt R.; Goodman, Mark A.; Heyl, Alma E.; McGough, Richard L.

2012-01-01

In previous reports, patients with Ewing's sarcoma received radiation therapy (XRT) for definitive local control because metastatic disease and pelvic location were thought to preclude aggressive local treatment. We sought to determine if single-site metastatic disease should be treated differently from multicentric-metastatic disease. We also wanted to reinvestigate the impact of XRT, pelvic location, and local recurrence on outcomes. Our results demonstrated a significant difference in overall survival (OS) between patients with either localized disease or a single-metastatic site and patients with multicentric-metastatic disease (P = 0.004). Local control was also found to be an independent predictor of outcomes as demonstrated by a significant difference in OS between those with and without local recurrence (P = 0.001). Axial and pelvic location did not predict a decreased OS. Based on these results, we concluded that pelvic location and the diagnosis of metastatic disease at diagnosis should not preclude aggressive local control, except in cases of multicentric-metastatic disease. PMID:22550427

Atezolizumab in invasive and metastatic urothelial carcinoma.

PubMed

Crist, Michael; Balar, Arjun

2017-12-01

Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses. Atezolizumab is an engineered humanized anti-PD-L1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and B7.1, enhancing immune-mediated tumor killing and is currently approved as second-line treatment after failure of platinum-based chemotherapy as well as first-line in cisplatin-ineligible patients. Areas covered: This article summarizes all reported phase I, II and III clinical trials that assessed the safety and efficacy of atezolizumab in the treatment of locally advanced and metastatic urothelial carcinoma. Expert commentary: Treatment with atezolizumab showed durable response and a toxicity profile that appears favorable to cytotoxic chemotherapy historically in the treatment of metastatic urothelial cancer among individuals who had progressed after prior platinum-based therapy and among those ineligible for treatment with first-line cisplatin. PD-L1 expression and tumor mutation load associate with response, however further research is needed to identify additional markers to improve prediction of response to atezolizumab.

Transarterial embolization of metastatic mediastinal hepatocellular carcinoma

PubMed Central

Chen, Chia-Chang; Yeh, Hong-Zen; Chang, Chi-Sen; Ko, Chung-Wang; Lien, Han-Chung; Wu, Chun-Ying; Hung, Siu-Wan

2013-01-01

This paper introduces an innovative treatment for extra-hepatic metastasis of hepatocellular carcinoma. A 71-year-old patient had a stable liver condition following treatment for hepatocellular carcinoma, but later developed symptomatic mediastinal metastasis. This rapidly growing mediastinal mass induced symptoms including cough and hoarseness. Serial sessions of transarterial embolization (TAE) successfully controlled this mediastinal mass with limited side effects. The patient’s survival time since the initial diagnosis of the mediastinal hepatocellular carcinoma was 32 mo, significantly longer than the 12 mo mean survival period of patients with similar diagnoses: metastatic hepatocellular carcinoma and a liver condition with a Child-Pugh class A score. Currently, oral sorafenib is the treatment of choice for metastatic hepatocellular carcinoma. Recent studies indicate that locoregional treatment of extra-hepatic metastasis of hepatocellular carcinomas might also significantly improve the prognosis in patients with their primary hepatic lesions under control. Many effective locoregional therapies for extrahepatic metastasis, including radiation and surgical resection, may provide palliative effects for hepatocellular carcinoma-associated mediastinal metastasis. This case report demonstrates that TAE of metastatic mediastinal hepatocellular carcinoma provided this patient with tumor control and increased survival time. This finding is important as it can potentially provide an alternative treatment option for patients with similar symptoms and diagnoses. PMID:23801848

Risk of metastatic ovarian involvement in nongynecologic malignancies.

PubMed

Kim, Kidong; Cho, Soo Youn; Park, Sang-Il; Kang, Hye Jin; Kim, Beob-Jong; Kim, Moon-Hong; Choi, Seok-Cheol; Ryu, Sang-Young; Lee, Eui-Don

2012-01-01

The objectives were to evaluate the risk of malignant adnexal tumors in women with nongynecologic malignancies and to identify variables associated with the risk of malignant adnexal tumors. The eligibility criteria included the diagnosis of a nongynecologic malignancy and adnexal tumors, which were resected or subjected to biopsy at our institute between 1999 and 2010. The risk of malignant adnexal tumors was assessed by dividing the number of patients with metastatic tumors to the adnexa or primary adnexal cancers by the total number of patients. The association of clinicopathologic variables with the risk of malignant adnexal tumors was evaluated using the Fisher exact test and binary logistic regression analysis. In patients with metastatic tumors to the adnexa, the association of clinicopathologic variables with overall survival after adnexal surgery was examined using the log-rank test. In 166 patients with adnexal tumors, 41 benign tumors, 113 metastatic tumors to the adnexa, and 12 primary adnexal cancers were diagnosed. Age older than 46 years, a tumor type associated with a high risk for malignant adnexal tumors, and bilateral tumors significantly increased the risk of malignant adnexal tumors. The overall survival of the patients with stomach cancer was significantly worse than the patients with colorectal or breast cancers. One hundred twenty-five of the 166 patients with nongynecologic malignancies who had adnexal tumors managed surgically were shown to have malignant tumors, and most of the tumors were metastatic from primary sites. The risk of malignant adnexal tumors was associated with age, nongynecologic malignancy, and bilaterality.

Metastatic intraocular hemangiopericytoma in a dog.

PubMed

Pucket, Jonathan D; Allbaugh, Rachel A; Higginbotham, Mary L; Rankin, Amy J; Teixeira, Leandro

2017-01-01

A 10-year-old Labrador Retriever who had been undergoing therapy for a recurrent hemangiopericytoma of the right flank presented to the Kansas State University Ophthalmology service for evaluation of a painful left eye. Examination revealed secondary glaucoma and irreversible blindness of the affected eye and multifocal chorioretinal lesions in the fellow eye. Therapeutic and diagnostic enucleation of the left eye was performed and histopathologic examination demonstrated the presence of a presumed metastatic spindle cell sarcoma. Further immunohistochemical staining confirmed the intraocular neoplasia to be metastatic spread from the previously removed flank mass. Rapid progression in size and number of chorioretinal lesions in the right eye was noted in the post-operative period until the patient was euthanized one month after surgery. This case report is the first to document intraocular metastasis of hemangiopericytoma in a veterinary patient.

Metastatic intraocular hemangiopericytoma in a dog

PubMed Central

Pucket, Jonathan D.; Allbaugh, Rachel A.; Higginbotham, Mary L.; Rankin, Amy J.; Teixeira, Leandro

2017-01-01

A 10-year-old Labrador Retriever who had been undergoing therapy for a recurrent hemangiopericytoma of the right flank presented to the Kansas State University Ophthalmology service for evaluation of a painful left eye. Examination revealed secondary glaucoma and irreversible blindness of the affected eye and multifocal chorioretinal lesions in the fellow eye. Therapeutic and diagnostic enucleation of the left eye was performed and histopathologic examination demonstrated the presence of a presumed metastatic spindle cell sarcoma. Further immunohistochemical staining confirmed the intraocular neoplasia to be metastatic spread from the previously removed flank mass. Rapid progression in size and number of chorioretinal lesions in the right eye was noted in the post-operative period until the patient was euthanized one month after surgery. This case report is the first to document intraocular metastasis of hemangiopericytoma in a veterinary patient. PMID:28652979

Chemotherapeutic agents for the treatment of metastatic breast cancer: An update.

PubMed

Abotaleb, Mariam; Kubatka, Peter; Caprnda, Martin; Varghese, Elizabeth; Zolakova, Barbora; Zubor, Pavol; Opatrilova, Radka; Kruzliak, Peter; Stefanicka, Patrik; Büsselberg, Dietrich

2018-05-01

Breast cancer is the second greatest cause of death among women worldwide; it comprises a group of heterogeneous diseases that evolves due to uncontrolled cellular growth and differentiation and the loss of normal programmed cell death. There are different molecular sub-types of breast cancer; therefore, various options are selected for treatment of different forms of metastatic breast cancer. However, the use of chemotherapeutic drugs is usually accompanied by deleterious side effects and the development of drug resistance when applied for a longer period. This review offers a classification of these chemotherapeutic agents according to their modes of action and therefore improves the understanding of molecular targets that are affected during treatment. Overall, it will allow the clinician to identify more specific targets to increase the effectiveness of a drug and to reduce general toxicity, resistance and other side effects. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

THE IMMIGRANT POOR AND THE RESIDUAL POOR.

ERIC Educational Resources Information Center

SEGALMAN, RALPH

AN ANALYSIS OF THE LIVES OF THE POOR IN AMERICA WILL SHOW DIFFERENCES BETWEEN THE IMMIGRANT (AND REFUGEE) POOR AND THE RESIDUAL POOR (NEGROES, PUERTO RICANS, LATIN AMERICANS, INDIANS, AND OTHERS). THE IMMIGRANT POOR WERE ACCULTURATED AND ABSORBED INTO THE MAINSTREAM OF AMERICAN LIFE WITHIN THREE GENERATIONS, WHEREAS THE RESIDUAL POOR HAVE BEEN…

Transforming growth factor-β signaling: emerging stem cell target in metastatic breast cancer?

PubMed Central

Tan, Antoinette R.; Alexe, Gabriela; Reiss, Michael

2009-01-01

In most human breast cancers, lowering of TGFβ receptor- or Smad gene expression combined with increased levels of TGFβs in the tumor microenvironment is sufficient to abrogate TGFβs tumor suppressive effects and to induce a mesenchymal, motile and invasive phenotype. In genetic mouse models, TGFβ signaling suppresses de novo mammary cancer formation but promotes metastasis of tumors that have broken through TGFβ tumor suppression. In mouse models of “triple-negative” or basal-like breast cancer, treatment with TGFβ neutralizing anti-bodies or receptor kinase inhibitors strongly inhibits development of lung- and bone metastases. These TGFβ antagonists do not significantly affect tumor cell proliferation or apoptosis. Rather, they de-repress anti-tumor immunity, inhibit angiogenesis and reverse the mesenchymal, motile, invasive phenotype characteristic of basal-like and HER2-positive breast cancer cells. Patterns of TGFβ target genes upregulation in human breast cancers suggest that TGFβ may drive tumor progression in estrogen-independent cancer, while it mediates a suppressive host cell response in estrogen-dependent luminal cancers. In addition, TGFβ appears to play a key role in maintaining the mammary epithelial (cancer) stem cell pool, in part by inducing a mesenchymal phenotype, while differentiated, estrogen receptor-positive, luminal cells are unresponsive to TGFβ because the TGFBR2 receptor gene is transcriptionally silent. These same cells respond to estrogen by downregulating TGFβ, while antiestrogens act by upregulating TGFβ. This model predicts that inhibiting TGFβ signaling should drive the differentiation of mammary stem cells into ductal cells. Consequently, TGFβ antagonists may convert basal-like or HER2-positive cancers to a more epithelioid, non-proliferating (and, perhaps, non-metastatic) phenotype. Conversely, these agents might antagonize the therapeutic effects of anti-estrogens in estrogen-dependent luminal cancers. These

Ductal Breast Carcinoma Metastatic to the Stomach Resembling Primary Linitis Plastica in a Male Patient.

PubMed

Ricciuti, Biagio; Leonardi, Giulia Costanza; Ravaioli, Noemi; De Giglio, Andrea; Brambilla, Marta; Prosperi, Enrico; Ribacchi, Franca; Meacci, Marialuisa; Crinò, Lucio; Maiettini, Daniele; Chiari, Rita; Metro, Giulio

2016-09-01

Breast cancer metastases to the gastrointestinal tract are very rare occurrences. Among the histological subtypes of breast cancer, invasive lobular carcinomas have a high capacity of metastasis to uncommon sites including the stomach. Conversely, there has not been sufficient evidence supporting the gastric metastasis of invasive ductal carcinoma. Herein, we report a unique case of metastatic ductal breast carcinoma mimicking primary linitis plastica in a male patient, particularly focusing on the clinical and pathological features of presentation. Moreover, we propose a immunohistochemical panel of selected antibodies including those for cytokeratin 20, cytokeratin 7, estrogen receptor, progesterone receptor, E-cadherin, gross cystic disease fluid protein 15, and GATA binding protein 3 for an accurate differential diagnosis.

Personalized oncogenomic analysis of metastatic adenoid cystic carcinoma: using whole-genome sequencing to inform clinical decision-making

PubMed Central

Chahal, Manik; Pleasance, Erin; Grewal, Jasleen; Zhao, Eric; Ng, Tony; Chapman, Erin; Jones, Martin R.; Shen, Yaoqing; Mungall, Karen L.; Bonakdar, Melika; Taylor, Gregory A.; Ma, Yussanne; Mungall, Andrew J.; Moore, Richard A.; Lim, Howard; Renouf, Daniel; Yip, Stephen; Jones, Steven J.M.; Marra, Marco A.; Laskin, Janessa

2018-01-01

Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets. We report five cases of metastatic ACC, not originating in the salivary glands, in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Genomic workup included whole-genome and transcriptome sequencing, detailed analysis of tumor alterations, and integration with existing knowledge of drug–target combinations to identify potential therapeutic targets. Analysis reveals low mutational burden in these five ACC cases, and mutation signatures that are commonly observed in multiple cancer types. Notably, the only recurrent structural aberration identified was the well-described MYB-NFIB fusion that was present in four of five cases, and one case exhibited a closely related MYBL1-NFIB fusion. Recurrent mutations were also identified in BAP1 and BCOR, with additional mutations in individual samples affecting NOTCH1 and the epigenetic regulators ARID2, SMARCA2, and SMARCB1. Copy changes were rare, and they included amplification of MYC and homozygous loss of CDKN2A in individual samples. Genomic analysis revealed therapeutic targets in all five cases and served to inform a therapeutic choice in three of the cases to date. PMID:29610392

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes.

PubMed

Ho, T H; Serie, D J; Parasramka, M; Cheville, J C; Bot, B M; Tan, W; Wang, L; Joseph, R W; Hilton, T; Leibovich, B C; Parker, A S; Eckel-Passow, J E

2017-03-01

The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email

Retrospective evaluation of toceranib (Palladia) treatment for canine metastatic appendicular osteosarcoma.

PubMed

Kim, Changseok; Matsuyama, Arata; Mutsaers, Anthony J; Woods, J Paul

2017-10-01

This retrospective study evaluated the outcomes of dogs with macroscopic pulmonary metastasis of appendicular osteosarcoma (OSA) treated with toceranib. Medical records of 20 dogs with macroscopic pulmonary metastasis of OSA that received toceranib were reviewed. The median dose and duration of toceranib administration were 2.52 mg/kg (range: 2.12 to 2.72 mg/kg) and 60 days (range: 17 to 231 days). The median progression free survival (PFS) and overall survival (OS) were 36 days (range: 17 to 231 days) and 90 days (range: 17 to 433 days), respectively. The clinical benefit rate was 10% (2/20; 1 partial response and 1 stable disease). The longest length of initial pulmonary nodules had significant impact on both PFS ( P = 0.01) and OS ( P = 0.02). The prognosis for dogs with metastatic OSA was poor with only 10% of dogs showing clinical benefit from toceranib. These results suggest that toceranib may not improve outcome in dogs with macroscopic pulmonary metastasis of OSA.

Addison's disease as a presentation of metastatic malignant melanoma.

PubMed

Srinivasan, B; Patel, M; Ethunandan, M; Ilankovan, V

2016-01-01

Melanoma accounts for 5% of all skin cancers. The risk of metastasis is related to the thickness of the tumour, and can affect local, regional and distant sites. Adrenal metastasis from melanoma of the head and neck is uncommon and often asymptomatic. Addison's disease as a presentation of metastatic melanoma is extremely rare and we are unaware of previous reports in the world literature. We report a case of a patient with metastatic melanoma presenting with signs and symptoms of Addison's disease.

Experimental Drug Metarrestin Targets Metastatic Tumors

Cancer.gov

An experimental drug called metarrestin appears to selectively target tumors that have spread to other parts of the body. As this Cancer Currents blog post reports, the drug shrank metastatic tumors and extended survival in in mouse models of pancreatic cancer.

[A case of fat embolism syndrome associated with pathological femoral fracture caused by metastatic adenocarcinoma of the lung].

PubMed

Sato, Takashi; Soejima, Kenzo; Nakayama, Sohei; Satomi, Ryosuke; Sayama, Koichi; Asano, Koichiro

2010-10-01

A 76-year-old woman with multiple bone metastases from lung adenocarcinoma was admitted due to a pathological femoral fracture. On the night after admission, her consciousness deteriorated rapidly and she developed progressive respiratory failure. Computed tomography of the chest revealed diffuse ground glass opacities in both lungs, and magnetic resonance imaging of the brain showed multiple acute infarctions. Her condition improved after several days of supportive treatment with oxygen, corticosteroids and diuretics. Fat embolism syndrome should be considered as a differential diagnosis if consciousness disturbance and respiratory failure occur in patients with metastatic bone carcinoma and pathological long bone fractures.

Role of the neural niche in brain metastatic cancer

PubMed Central

Termini, John; Neman, Josh; Jandial, Rahul

2014-01-01

Metastasis is the relenteless pursuit of cancer to escape its primary site and colonize distant organs. This malignant evolutionary process is biologically heterogeneous, yet one unifying element is the critical role of the microenvironment for arriving metastatic cells. Historically brain metastases were rarely investigated since patients with advanced cancer were considered terminal. Fortunately, advances in molecular therapies have led to patients living longer with metastatic cancer. However, one site remains recalcitrant to our treatment efforts – the brain. The central nervous system is the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We suggest that the interrelated cellular responses in traumatic brain injury may guide us towards new perspectives in understanding brain metastases. In this view, brain metastases may be conceptualized as progressive oncologic injury to the nervous system. This review discusses our evolving understanding of the bidirectional interactions between the brain milieu and metastatic cancer. PMID:25035392

5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells

PubMed Central

Malashchuk, Igor; Lajoie, Brian R.; Mardaryev, Andrei N.; Gdula, Michal R.; Sharov, Andrey A.; Kohwi-Shigematsu, Terumi; Fessing, Michael Y.

2017-01-01

Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and

Axitinib for preoperative downstaging of renal cell carcinoma with sarcomatoid differentiation and direct invasion of the duodenum and inferior vena cava: a case report

PubMed Central

Yuki, Hideo; Kamai, Takao; Kubota, Keiichi; Abe, Hideyuki; Nishihara, Daisaku; Mizuno, Tomoya; Masuda, Akinori; Betsunoh, Hironori; Yashi, Masahiro; Fukabori, Yoshitatsu; Yoshida, Ken-Ichiro

2014-01-01

Background Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen. Methods We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy. Results Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not. Conclusion

Combined miRNA profiling and proteomics demonstrates that different miRNAs target a common set of proteins to promote colorectal cancer metastasis.

PubMed

Torres, Sofía; Garcia-Palmero, Irene; Bartolomé, Rubén A; Fernandez-Aceñero, María Jesús; Molina, Elena; Calviño, Eva; Segura, Miguel F; Casal, J Ignacio

2017-05-01

The process of liver colonization in colorectal cancer remains poorly characterized. Here, we addressed the role of microRNA (miRNA) dysregulation in metastasis. We first compared miRNA expression profiles between colorectal cancer cell lines with different metastatic properties and then identified target proteins of the dysregulated miRNAs to establish their functions and prognostic value. We found that 38 miRNAs were differentially expressed between highly metastatic (KM12SM/SW620) and poorly metastatic (KM12C/SW480) cancer cell lines. After initial validation, we determined that three miRNAs (miR-424-3p, -503, and -1292) were overexpressed in metastatic colorectal cancer cell lines and human samples. Stable transduction of non-metastatic cells with each of the three miRNAs promoted metastatic properties in culture and increased liver colonization in vivo. Moreover, miR-424-3p and miR-1292 were associated with poor prognosis in human patients. A quantitative proteomic analysis of colorectal cancer cells transfected with miR-424-3p, miR-503, or miR-1292 identified alterations in 149, 129, or 121 proteins, respectively, with an extensive overlap of the target proteins of the three miRNAs. Importantly, down-regulation of two of these shared target proteins, CKB and UBA2, increased cell adhesion and proliferation in colorectal cancer cells. The capacity of distinct miRNAs to regulate the same mRNAs boosts the capacity of miRNAs to regulate cancer metastasis and underscores the necessity of targeting multiple miRNAs for effective cancer therapy. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The clinical significance of occult gynecologic primary tumours in metastatic cancer.

PubMed

Hannouf, M B; Winquist, E; Mahmud, S M; Brackstone, M; Sarma, S; Rodrigues, G; Rogan, P K; Hoch, J S; Zaric, G S

2017-10-01

We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002-2011. We defined patients as having an "occult" primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have "obvious" primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women ( n = 285 of 2552, 11.2%) than in men ( n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours ( n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts ( n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes.

The clinical significance of occult gynecologic primary tumours in metastatic cancer

PubMed Central

Hannouf, M.B.; Winquist, E.; Mahmud, S.M.; Brackstone, M.; Sarma, S.; Rodrigues, G.; Rogan, P.K.; Hoch, J.S.; Zaric, G.S.

2017-01-01

Objective We estimated the frequency of occult gynecologic primary tumours (gpts) in patients with metastatic cancer from an uncertain primary and evaluated the effect on disease management and overall survival (os). Methods We used Manitoba administrative health databases to identify all patients initially diagnosed with metastatic cancer during 2002–2011. We defined patients as having an “occult” primary tumour if the primary was classified at least 6 months after the initial diagnosis. Otherwise, we considered patients to have “obvious” primaries. We then compared clinicopathologic and treatment characteristics and 2-year os for women with occult and with obvious gpts. We used Cox regression adjustment and propensity score methods to assess the effect on os of having an occult gpt. Results Among the 5953 patients diagnosed with metastatic cancer, occult primary tumours were more common in women (n = 285 of 2552, 11.2%) than in men (n = 244 of 3401, 7.2%). In women, gpts were the most frequent occult primary tumours (n = 55 of 285, 19.3%). Compared with their counterparts having obvious gpts, women with occult gpts (n = 55) presented with similar histologic and metastatic patterns but received fewer gynecologic diagnostic examinations during diagnostic work-up. Women with occult gpts were less likely to undergo surgery, waited longer for radiotherapy, and received a lesser variety of chemotherapeutic agents. Having an occult compared with an obvious gpt was associated with decreased os (hazard ratio: 1.62; 95% confidence interval: 1.2 to 2.35). Similar results were observed in adjusted analyses. Conclusions In women with metastatic cancer from an uncertain primary, gpts constitute the largest clinical entity. Accurate diagnosis of occult gpts early in the course of metastatic cancer might lead to more effective treatment decisions and improved survival outcomes. PMID:29089807

Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives

PubMed Central

2014-01-01

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome, and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations, the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future, advances in targeted therapy will depend on the availability of metastatic tissue. PMID:25032257

Management of recurrent and persistent metastatic lymph nodes in well-differentiated thyroid cancer: a multifactorial decision-making guide for the Thyroid Cancer Care Collaborative.

PubMed

Urken, Mark L; Milas, Mira; Randolph, Gregory W; Tufano, Ralph; Bergman, Donald; Bernet, Victor; Brett, Elise M; Brierley, James D; Cobin, Rhoda; Doherty, Gerard; Klopper, Joshua; Lee, Stephanie; Machac, Josef; Mechanick, Jeffrey I; Orloff, Lisa A; Ross, Douglas; Smallridge, Robert C; Terris, David J; Clain, Jason B; Tuttle, Michael

2015-04-01

Well-differentiated thyroid cancer (WDTC) recurs in up to 30% of patients. Guidelines from the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) provide valuable parameters for the management of recurrent disease, but fail to guide the clinician as to the multitude of factors that should be taken into account. The Thyroid Cancer Care Collaborative (TCCC) is a web-based repository of a patient's clinical information. Ten clinical decision-making modules (CDMMs) process this information and display individualized treatment recommendations. We conducted a review of the literature and analysis of the management of patients with recurrent/persistent WDTC. Surgery remains the most common treatment in recurrent/persistent WDTC and can be performed with limited morbidity in experienced hands. However, careful observation may be the recommended course in select patients. Reoperation yields biochemical remission rates between 21% and 66%. There is a reported 1.2% incidence of permanent unexpected nerve paralysis and a 3.5% incidence of permanent hypoparathyroidism. External beam radiotherapy and percutaneous ethanol ablation have been reported as therapeutic alternatives. Radioactive iodine as a primary therapy has been reported previously for metastatic lymph nodes, but is currently advocated by the ATA as an adjuvant to surgery. The management of recurrent lymph nodes is a multifactorial decision and is best determined by a multidisciplinary team. The CDMMs allow for easy adoption of contemporary knowledge, making this information accessible to both patient and clinician. © 2014 Wiley Periodicals, Inc.

Nivolumab-induced vitiligo in a metastatic melanoma patient: A case report.

PubMed

Edmondson, Lindsay A; Smith, Leticia V; Mallik, Alka

2017-12-01

The programmed-death-1 inhibitors selectively block programmed-death-1 interaction with its receptor, which restores active T-cell response directed at tumor cells, inducing an anti-tumor effect. This nonspecific activation of the immune system can also lead to a wide spectrum of side effects. Nivolumab has been used effectively to prolong survival in patients with metastatic melanoma and is recommended as a category 1 agent for systemic therapy in metastatic or unresectable melanoma per the National Comprehensive Cancer Network guidelines. We present a case of a 64-year-old woman who began nivolumab therapy for metastatic melanoma. After six doses of nivolumab therapy, the patient experienced generalized hypopigmentation on her face, chest, back, arms, and lower extremities. Although vitiligo has been reported in as many as 10.7% of patients undergoing nivolumab therapy in some clinical trials, we believe this is the first case to describe the progression of nivolumab-induced vitiligo in a metastatic melanoma patient. This case provides significant insight into the onset, symptoms, development, and treatment options for patients experiencing vitiligo as a result of nivolumab therapy.

Metastatic squamous cell carcinoma thyroid from functionally cured cancer cervix

PubMed Central

Vamsy, Mohana; Dattatreya, Palanki Satya; Sarma, Lella Yugandhar; Dayal, Monal; Janardhan, Nandigam; Rao, Vatturi Venkata Satya Prabhakar

2013-01-01

The authors report a very unusual occurrence of a metastatic squamous carcinoma to thyroid gland from a treated squamous cell carcinoma cervix 12 years before with no recurrence at the primary site. The case also has an additional complexity of rapid progression of the metastatic thyroid carcinoma to wide spread dissemination to lungs and bones while on concurrent chemo radio therapy confirming the aggressiveness of the entity. PMID:24163519

Evaluate Risk/Benefit of Nab Paclitaxel in Combination With Gemcitabine and Carboplatin Compared to Gemcitabine and Carboplatin in Triple Negative Metastatic Breast Cancer (or Metastatic Triple Negative Breast Cancer)

ClinicalTrials.gov

2018-03-07

Breast Tumor; Breast Cancer; Cancer of the Breast; Estrogen Receptor- Negative Breast Cancer; HER2- Negative Breast Cancer; Progesterone Receptor- Negative Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Triple-negative Breast Cancer; Triple-negative Metastatic Breast Cancer; Metastatic Breast Cancer

Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis.

PubMed

Afriansyah, Andika; Hamid, Agus Rizal Ardy Hariandy; Mochtar, Chaidir Arif; Umbas, Rainy

2018-01-01

Aim: Metastatic prostate cancer (mPCa) has a poor outcome with median survival of two to five years. The use of androgen deprivation therapy (ADT) is a gold standard in management of this stage.  Aim of this study is to analyze the prognostic value of PSA kinetics of patient treated with hormonal therapy related to survival from several published studies Method: Systematic review and meta-analysis was performed using literature searching in the electronic databases of MEDLINE, Science Direct, and Cochrane Library. Inclusion criteria were mPCa receiving ADT, a study analyzing Progression Free Survival (PFS), Overall Survival (OS), or Cancer Specific Survival (CSS) and prognostic factor of survival related to PSA kinetics (initial PSA, PSA nadir, and time to achieve nadir (TTN)). The exclusion criteria were metastatic castration resistant of prostate cancer (mCRPC) and non-metastatic disease. Generic inverse variance method was used to combine hazard ratio (HR) within the studies. Meta-analysis was performed using Review Manager 5.2 and a p-value <0.05 was considered statistically significant. Results: We found 873 citations throughout database searching with 17 studies were consistent with inclusion criteria. However, just 10 studies were analyzed in the quantitative analysis. Most of the studies had a good methodological quality based on Ottawa Scale. No significant association between initial PSA and PFS. In addition, there was no association between initial PSA and CSS/ OS. We found association of reduced PFS (HR 2.22; 95% CI 1.82 to 2.70) and OS/ CSS (HR 3.31; 95% CI 2.01-5.43) of patient with high PSA nadir. Shorter TTN was correlated with poor result of survival either PFS (HR 2.41; 95% CI 1.19 - 4.86) or CSS/ OS (HR 1.80; 95%CI  1.42 - 2.30) Conclusion: Initial PSA before starting ADT do not associated with survival in mPCa.  There is association of PSA nadir and TTN with survival.

Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis

PubMed Central

Afriansyah, Andika; Hamid, Agus Rizal Ardy Hariandy; Mochtar, Chaidir Arif; Umbas, Rainy

2018-01-01

Aim: Metastatic prostate cancer (mPCa) has a poor outcome with median survival of two to five years. The use of androgen deprivation therapy (ADT) is a gold standard in management of this stage.  Aim of this study is to analyze the prognostic value of PSA kinetics of patient treated with hormonal therapy related to survival from several published studies Method: Systematic review and meta-analysis was performed using literature searching in the electronic databases of MEDLINE, Science Direct, and Cochrane Library. Inclusion criteria were mPCa receiving ADT, a study analyzing Progression Free Survival (PFS), Overall Survival (OS), or Cancer Specific Survival (CSS) and prognostic factor of survival related to PSA kinetics (initial PSA, PSA nadir, and time to achieve nadir (TTN)). The exclusion criteria were metastatic castration resistant of prostate cancer (mCRPC) and non-metastatic disease. Generic inverse variance method was used to combine hazard ratio (HR) within the studies. Meta-analysis was performed using Review Manager 5.2 and a p-value <0.05 was considered statistically significant. Results: We found 873 citations throughout database searching with 17 studies were consistent with inclusion criteria. However, just 10 studies were analyzed in the quantitative analysis. Most of the studies had a good methodological quality based on Ottawa Scale. No significant association between initial PSA and PFS. In addition, there was no association between initial PSA and CSS/ OS. We found association of reduced PFS (HR 2.22; 95% CI 1.82 to 2.70) and OS/ CSS (HR 3.31; 95% CI 2.01-5.43) of patient with high PSA nadir. Shorter TTN was correlated with poor result of survival either PFS (HR 2.41; 95% CI 1.19 – 4.86) or CSS/ OS (HR 1.80; 95%CI  1.42 – 2.30) Conclusion: Initial PSA before starting ADT do not associated with survival in mPCa.  There is association of PSA nadir and TTN with survival PMID:29904592

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer

PubMed Central

Simone, Brittany A.; Dan, Tu; Palagani, Ajay; Jin, Lianjin; Han, Sunny Y.; Wright, Christopher; Savage, Jason E.; Gitman, Robert; Lim, Meng Kieng; Palazzo, Juan; Mehta, Minesh P.; Simone, Nicole L.

2016-01-01

ABSTRACT Purpose: Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease. Methods: An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model. Results: CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR. Conclusions: CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer. PMID:27027731

Caloric restriction coupled with radiation decreases metastatic burden in triple negative breast cancer.