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1.
Urol Case Rep ; 27: 101009, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31516836

RESUMO

Penile cancer is normally discovered in an early stage due to its visibility to the patient. This case report demonstrates a morbidly obese patient with a locally advanced penile cancer hidden by fatty tissue. Biopsy showed P16-positive tumor cells, which responded to concurrent chemo-radiotherapy with no evidence of disease at 24 months of follow-up. We also review the significance of p16-positive cell biology.

2.
Sci Rep ; 9(1): 11117, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366895

RESUMO

The gastrin-releasing peptide receptor (BB2r) is overexpressed in a variety of cancers including prostate cancer. As a consequence, the development of BB2r-targeted diagnostic/therapeutic radiopharmaceuticals has been widely explored. Both subcutaneous and orthotopic mouse models have been extensively used in BB2r-targeted agent development, but side-by-side studies examining how biological parameters (tumor perfusion efficacy, hypoxic burden and microvasculature density) impact BB2r-targeted agent delivery has not been reported. Herein, we examine these biological parameters using subcutaneous and orthotopic PC-3 xenografts. Using a dual isotope biodistribution study, tumor perfusion was accessed using [99mTc]NaTcO4 and BB2r-targeted uptake evaluated by utilization of a novel 177Lu-labeled conjugate ([177Lu]Lu-DOTA-SP714). Immunofluorescence, immunohistochemistry and autoradiography were utilized to examine the tumor vascular density, hypoxic burden and microdistribution of the BB2r-targeted agent. Our studies demonstrated that compared to the subcutaneous model the PC-3 orthotopic tumors had significantly higher levels of perfusion that led to higher BB2r-targeted uptake and lower levels of hypoxia burden. It is anticipated that our results will allow researchers to better understand the biological variables affecting drug delivery and assist them in more clearly interpreting their results in this common prostate cancer mouse model.

4.
Pharm Res ; 36(4): 64, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30859327

RESUMO

BACKGROUND: Tofacitinib (Tofa) has been approved for moderately to severely active ulcerative colitis (UC). To improve its therapeutic efficacy and limit dose-dependent toxicity, we developed a macromolecular prodrug of Tofa (P-Tofa). If the prodrug design improves the potency and duration of Tofa therapy, it would widen its therapeutic window, potentially leading to improved safety and better clinical management of UC. METHODS: P-Tofa was synthesized by conjugating Tofa to N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer via a cleavable carbamate linker. DSS-induced UC mouse model were treated with Tofa (daily oral gavage, from day 8), P-Tofa (single intravenous administration on day 8, dose equivalent to Tofa treatment) and saline. Healthy mice were used as a positive control. The therapeutic efficacy was evaluated using disease activity index (DAI), endoscopic score and end-point histology. The optical imaging, immunohistochemistry and flow cytometry were used to understand P-Tofa's working mechanism. RESULTS: DAI results suggested that a single dose P-Tofa treatment was more efficacious than dose equivalent daily Tofa treatment. Endoscopic evaluation and histology analyses confirmed that while both P-Tofa and Tofa protected the colon, P-Tofa treated group was observed with better colon integrity with less tissue damage. Optical imaging, flow cytometry and immunohistochemistry results showed that P-Tofa passively targeted the inflamed colon and being retained via cellular sequestration. CONCLUSIONS: Single intravenous administration of P-Tofa was more effective than dose equivalent daily oral Tofa gavage in ameliorating DSS-induced colitis. This observed superior therapeutic efficacy may be attributed to P-Tofa's passive targeting to and retention by the inflamed colon.


Assuntos
Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/efeitos dos fármacos , Sulfato de Dextrana/farmacologia , Janus Quinases/antagonistas & inibidores , Pró-Fármacos/farmacologia , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Metacrilatos/química , Camundongos , Piperidinas/farmacologia , Polímeros/química , Pirimidinas/farmacologia , Pirróis/farmacologia
5.
Oncogene ; 38(26): 5265-5280, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30914801

RESUMO

Farnesyl diphosphate synthase (FDPS), a mevalonate pathway enzyme, is highly expressed in several cancers, including prostate cancer (PCa). To date, the mechanistic, functional, and clinical significance of FDPS in cancer remains unexplored. We evaluated the FDPS expression and its cancer-associated phenotypes using in vitro and in vivo methods in PTEN-deficient and sufficient human and mouse PCa cells and tumors. Interestingly, FDPS overexpression synergizes with PTEN deficiency in PTEN conditionally knockout mice (P < 0.05) and expressed significantly higher in human (P < 0.001) PCa tissues, cell lines, and murine tumoroids compared to respective controls. In silico analysis revealed that FDPS is associated with increasing Gleason score, PTEN functionally deficient status, and poor survival of PCa. Ectopic overexpression of FDPS promotes oncogenic phenotypes such as colony formation (P < 0.01) and proliferation (P < 0.01) through activation of AKT and ERK signaling by prenylating Rho A, Rho G, and CDC42 small GTPases. Of interest, knockdown of FDPS in PCa cells exhibits decreased colony growth and proliferation (P < 0.001) by modulating AKT and ERK pathways. Further, genetic and pharmacological inhibition of PI3K but not AKT reduced FDPS expression. Pharmacological targeting of FDPS by zoledronic acid (ZOL), which is already in clinics, exhibit reduced growth and clonogenicity of human and murine PCa cells (P < 0.01) and 3D tumoroids (P < 0.02) by disrupting AKT and ERK signaling through direct interference of small GTPases protein prenylation. Thus, FDPS plays an oncogenic role in PTEN-deficient PCa through GTPase/AKT axis. Identifying mevalonate pathway proteins could serve as a therapeutic target in PTEN dysregulated tumors.

6.
J Pharmacol Exp Ther ; 370(3): 894-901, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30683666

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1ß3-Gal-T-specific molecular chaperone, a specific chaperone for the activity of core 1 ß3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen-specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.

7.
J Natl Compr Canc Netw ; 16(9): 1041-1053, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30181416

RESUMO

The NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with bladder cancer. These NCCN Guidelines Insights discuss important updates to the 2018 version of the guidelines, including implications of the 8th edition of the AJCC Cancer Staging Manual on treatment of muscle-invasive bladder cancer and incorporating newly approved immune checkpoint inhibitor therapies into treatment options for patients with locally advanced or metastatic disease.


Assuntos
Oncologia/normas , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Assistência ao Convalescente/métodos , Assistência ao Convalescente/normas , Vacina BCG/uso terapêutico , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Quimioterapia Adjuvante/normas , Cistectomia/efeitos adversos , Cistectomia/métodos , Cistectomia/normas , Humanos , Metástase Linfática/diagnóstico , Metástase Linfática/patologia , Oncologia/métodos , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/normas , Estadiamento de Neoplasias , Tratamentos com Preservação do Órgão/efeitos adversos , Tratamentos com Preservação do Órgão/métodos , Tratamentos com Preservação do Órgão/normas , Seleção de Pacientes , Qualidade de Vida , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/métodos , Radioterapia Adjuvante/normas , Ensaios Clínicos Controlados Aleatórios como Assunto , Sociedades Médicas/normas , Resultado do Tratamento , Estados Unidos , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
8.
Proc Natl Acad Sci U S A ; 115(29): E6760-E6769, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29967145

RESUMO

Zyxin is a member of the focal adhesion complex and plays a critical role in actin filament polymerization and cell motility. Several recent studies showed that Zyxin is a positive regulator of Yki/YAP (Yes-associated protein) signaling. However, little is known about the mechanisms by which Zyxin itself is regulated and how Zyxin affects Hippo-YAP activity. We first showed that Zyxin is phosphorylated by CDK1 during mitosis. Depletion of Zyxin resulted in significantly impaired colon cancer cell proliferation, migration, anchorage-independent growth, and tumor formation in xenograft animal models. Mitotic phosphorylation is required for Zyxin activity in promoting growth. Zyxin regulates YAP activity through the colon cancer oncogene CDK8. CDK8 knockout phenocopied Zyxin knockdown in colon cancer cells, while ectopic expression of CDK8 substantially restored the tumorigenic defects of Zyxin-depletion cells. Mechanistically, we showed that CDK8 directly phosphorylated YAP and promoted its activation. Fully activated YAP is required to support the growth in CDK8-knockout colon cancer cells in vitro and in vivo. Together, these observations suggest that Zyxin promotes colon cancer tumorigenesis in a mitotic-phosphorylation-dependent manner and through CDK8-mediated YAP activation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias do Colo/metabolismo , Quinase 8 Dependente de Ciclina/metabolismo , Mitose , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Zixina/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Quinase 8 Dependente de Ciclina/genética , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Fosforilação/genética , Fatores de Transcrição , Zixina/genética
9.
Mol Pharm ; 15(8): 3456-3467, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-29966420

RESUMO

While highly efficacious in treating rheumatoid arthritis (RA), the approved Janus kinase (JAK) inhibitor, Tofacitinib (Tofa, CP-690 550), has dose-dependent toxicities that limit its clinical application. In this study, we have examined whether a prodrug design that targets arthritic joints would enhance Tofa's therapeutic efficacy, which may provide an opportunity for future development of safer Tofa dosing regimens. A prodrug of Tofa (P-Tofa) was synthesized by conjugating the drug to the N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer via an acid cleavable carbamate linker. The therapeutic efficacy of a single dose of P-Tofa was compared to the dose-equivalent daily oral administration of Tofa in an adjuvant-induced arthritis (AA) rat model. Saline treated AA rats and age-matched healthy rats were used as controls. Observational analyses support the superior and sustained efficacy of a single dose P-Tofa treatment compared to the dose-equivalent daily Tofa administration in ameliorating joint inflammation. Micro-CT and histological analyses demonstrated that the P-Tofa treatment provided a structural preservation of the joints better than that of the dose-equivalent Tofa. Optical imaging, immunohistochemistry, and fluorescence-activated cell sorting analyses attribute P-Tofa's superior therapeutic efficacy to its passive targeting to arthritic joints and inflammatory cell-mediated sequestration. In vitro cell culture studies reveal that the P-Tofa treatment produced sustained the inhibition of JAK/STAT6 signaling in IL-4-treated murine bone marrow macrophages, consistent with a gradual subcellular release of Tofa. Collectively, a HPMA-based nanoscale prodrug of P-Tofa has the potential to enhance the therapeutic efficacy and widen the therapeutic window of Tofa therapy in RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pró-Fármacos/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Acrilamidas/química , Administração Oral , Animais , Articulação do Tornozelo/diagnóstico por imagem , Articulação do Tornozelo/efeitos dos fármacos , Articulação do Tornozelo/patologia , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/etiologia , Artrite Experimental/patologia , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/etiologia , Artrite Reumatoide/patologia , Células Cultivadas , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Macrófagos , Masculino , Camundongos Endogâmicos C57BL , Piperidinas/química , Piperidinas/farmacologia , Cultura Primária de Células , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ratos , Ratos Endogâmicos Lew , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais/efeitos dos fármacos , Distribuição Tecidual , Resultado do Tratamento , Microtomografia por Raio-X
10.
Cell Rep ; 24(3): 655-669, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30021163

RESUMO

Protein kinase C (PKC) isozymes are commonly recognized as oncoproteins based on their activation by tumor-promoting phorbol esters. However, accumulating evidence indicates that PKCs can be inhibitory in some cancers, with recent findings propelling a shift in focus to understanding tumor suppressive functions of these enzymes. Here, we report that PKCα acts as a tumor suppressor in PI3K/AKT-driven endometrial cancer. Transcriptional suppression of PKCα is observed in human endometrial tumors in association with aggressive disease and poor prognosis. In murine models, loss of PKCα is rate limiting for endometrial tumor initiation. PKCα tumor suppression involves PP2A-family-dependent inactivation of AKT, which can occur even in the context of genetic hyperactivation of PI3K/AKT signaling by coincident mutations in PTEN, PIK3CA, and/or PIK3R1. Together, our data point to PKCα as a crucial tumor suppressor in the endometrium, with deregulation of a PKCα→PP2A/PP2A-like phosphatase signaling axis contributing to robust AKT activation and enhanced endometrial tumorigenesis.


Assuntos
Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Endométrio/enzimologia , Endométrio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C-alfa/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ativação Enzimática , Feminino , Células HEK293 , Humanos , Camundongos , Gradação de Tumores , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosforilação , Proteína Quinase C-alfa/deficiência , Proteína Fosfatase 2/metabolismo
11.
Pharm Res ; 35(8): 164, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29943090

RESUMO

PURPOSE: Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity. METHOD: The prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model. RESULTS: In vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1ß, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data. CONCLUSION: SIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Periodontite/prevenção & controle , Pró-Fármacos/uso terapêutico , Sinvastatina/uso terapêutico , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/patologia , Animais , Linhagem Celular , Citocinas/análise , Citocinas/antagonistas & inibidores , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Maxila/efeitos dos fármacos , Maxila/patologia , Camundongos , Periodontite/patologia , Fosforilação , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Células RAW 264.7 , Ratos Sprague-Dawley , Sinvastatina/administração & dosagem , Sinvastatina/análogos & derivados , Solubilidade
12.
Gastroenterology ; 155(3): 892-908.e6, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29864419

RESUMO

BACKGROUND & AIMS: Cigarette smoking is a major risk factor for pancreatic cancer. Aggressive pancreatic tumors contain cancer cells with stem cell features. We investigated whether cigarette smoke induces stem cell features in pancreatic cancer cells. METHODS: KrasG12D; Pdx1-Cre mice were exposed to cigarette smoke or clean air (controls) for up to 20 weeks; pancreata were collected and analyzed by histology, quantitative reverse transcription polymerase chain reaction, and confocal immunofluorescence microscopy. HPNE and Capan1 cells were exposed to cigarette smoke extract (CSE), nicotine and nicotine-derived carcinogens (NNN or NNK), or clean air (controls) for 80 days and evaluated for stem cell markers and features using flow cytometry-based autofluorescence, sphere formation, and immunoblot assays. Proteins were knocked down in cells with small interfering RNAs. We performed RNA sequencing analyses of CSE-exposed cells. We used chromatin immunoprecipitation assays to confirm the binding of FOS-like 1, AP-1 transcription factor subunit (FOSL1) to RNA polymerase II-associated factor (PAF1) promoter. We obtained pancreatic ductal adenocarcinoma (PDAC) and matched nontumor tissues (n = 15) and performed immunohistochemical analyses. RESULTS: Chronic exposure of HPNE and Capan1 cells to CSE caused them to increase markers of stem cells, including autofluorescence and sphere formation, compared with control cells. These cells increased expression of ABCG2, SOX9, and PAF1, via cholinergic receptor nicotinic alpha 7 subunit (CHRNA7) signaling to mitogen-activated protein kinase 1 and FOSL1. CSE-exposed pancreatic cells with knockdown of PAF1 did not show stem cell features. Exposure of cells to NNN and NNK led to increased expression of CHRNA7, FOSL1, and PAF1 along with stem cell features. Pancreata from KrasG12D; Pdx1-Cre mice exposed to cigarette smoke had increased levels of PAF1 mRNA and protein, compared with control mice, as well as increased expression of SOX9. Levels of PAF1 and FOSL1 were increased in PDAC tissues, especially those from smokers, compared with nontumor pancreatic tissue. CSE exposure increased expression of PHD-finger protein 5A, a pluripotent transcription factor and its interaction with PAF1. CONCLUSIONS: Exposure to cigarette smoke activates stem cell features of pancreatic cells, via CHRNA7 signaling and FOSL1 activation of PAF1 expression. Levels of PAF1 are increased in pancreatic tumors of humans and mice with chronic cigarette smoke exposure.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Proteínas de Transporte/metabolismo , Fumar Cigarros/efeitos adversos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/etiologia , Linhagem Celular Tumoral , Humanos , Camundongos , Pâncreas/citologia , Neoplasias Pancreáticas/etiologia , Proteínas Proto-Oncogênicas c-fos/fisiologia , Transdução de Sinais/fisiologia , Receptor Nicotínico de Acetilcolina alfa7/fisiologia
13.
Hum Pathol ; 73: 122-127, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29307622

RESUMO

Morphologically, distinguishing between leiomyoma (LM) and leiomyosarcoma (LMS) is not always straightforward, especially with benign variants such as bizarre leiomyoma (BLM). To identify potential markers of malignancy in uterine smooth muscle tumors, proteomic studies were performed followed by assessment of protein expression by immunohistochemistry. Archival formalin-fixed, paraffin-embedded tissues from tumors (n = 23) diagnosed as LM, BLM, and LMS (using published criteria) were selected for the study. Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry was applied to pooled samples of formalin-fixed, paraffin-embedded LM and LMS tumor tissue to assay the relative protein quantities and look for expression patterns differentiating the 2 tumor types. A total of 592 proteins were quantified, and 10 proteins were differentially expressed between LM and LMS. Select proteins were chosen for evaluation by immunohistochemistry (IHC) based on antibody availability and biologic relevance in the literature. IHC was performed on a tissue microarray, and intensity was evaluated using imaging software. Major vault protein (MVP) and catechol O-methyltransferase had 3.05 and 13.94 times higher expression in LMS relative to LM by sequential window acquisition of all theoretical fragment ion spectra mass spectrometry, respectively. By IHC, MVP (clone 1014; Santa Cruz Biotechnology, Dallas, TX) was found to be 50% sensitive and 100% specific when comparing LMS to LM. Catechol O-methyltransferase (clone FL-271; Santa Cruz Biotechnology) had a sensitivity of 38% and a specificity of 88%. Six of 7 BLM had expression of MVP similar to LM. Immunohistochemical staining for MVP is a useful adjunct in distinguishing LMS from LM and BLM in difficult cases.


Assuntos
Biomarcadores Tumorais/análise , Leiomioma/diagnóstico , Leiomioma/patologia , Leiomiossarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Partículas de Ribonucleoproteínas em Forma de Abóbada/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Leiomiossarcoma/patologia , Pessoa de Meia-Idade , Neoplasias Uterinas/patologia , Partículas de Ribonucleoproteínas em Forma de Abóbada/análise
14.
J Natl Compr Canc Netw ; 15(10): 1240-1267, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28982750

RESUMO

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.


Assuntos
Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/terapia , Terapia Combinada/métodos , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade
15.
Urol Case Rep ; 13: 140-142, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28567329

RESUMO

Spermatic cord tumors (SCTs) are rare neoplasms with 80% exhibiting benign pathology. Of the malignant SCTs, 90% are sarcomas. To date there has only been one documented case of primary CS of the spermatic cord which occurred in a 40 year old with no reported medical history. A 76-year-old male with a history of biopsy proven Gleason score 7 (3 + 4) prostatic adenocarcinoma underwent external beam radiation therapy (7920 cGy) in 44 fractions in 2004. He presented with a 3 year history of an asymptomatic right hydrocele. Several scrotal ultrasounds had been performed confirming a hydrocele, with the most recent revealing a hydrocele measuring 10 × 14 cm and several epididymal cysts. During the hydrocelectomy a firm suspicious mass was noted inside the tunica vaginalis and involving the spermatic cord. Given the intraoperative findings, decision was made to proceed with radical orchiectomy. Final pathologic examination revealed the tumor to have a biphasic pattern composed of spindled cells and also cells with an epithelioid morphology. Five months following orchiectomy he patient presented with a painful, enlarging right upper scrotal mass. A CT scan revealed new soft tissue lesions suspicious for necrotic lymph nodes within the right inguinal canal. Additional metastatic evaluation revealed multiple new pleural and parenchymal lung nodules. CT guided needle biopsy of a left lung nodule demonstrated spindle cells with high cellularity and areas of necrosis which were histomorphologically similar to the previous scrotal CS. Gemcitabine therapy was subsequently started. Four months following the diagnosis of metastatic CS, the patient expired. Dedifferentiation of prostatic adenocarcinoma to prostatic CS should be considered as a treatment outcome after localized radiation therapy to the prostate due to the highly aggressive nature of metastatic CS.

16.
BMC Urol ; 17(1): 34, 2017 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-28449665

RESUMO

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is a rare high-grade carcinoma that resembles nasopharyngeal lymphoepithelioma and can occur throughout the body. First reported in 1991, bladder LELC has an incidence of about 1% of all bladder carcinomas. Due to its rare occurrence, prognoses and ideal treatment guidelines have not been clearly defined. METHODS: A PubMed search was performed using two terms, "lymphoepithelioma-like carcinoma" and "bladder." Review articles, articles in foreign languages, expression studies, and studies not performed in the bladder were excluded. We report a case of LELC of the bladder including treatment and outcome and performed a systematic review of all 36 available English literatures from 1991 to 2016 including the present case to identify factors affecting disease-free survival. RESULTS: One hundred forty cases of bladder LELC were analyzed. The mean age of the patients was 70.1 years ranging from 43 to 90 years with 72% males and 28% females. Pure LELC occurs most often at 46% followed by mixed LELC 28% and predominant LELC 26%. EBV testing was negative in all cases tested. Mean follow-up length for all cases was 33.8 months with no evidence of disease in 62.2%, while 11.1% died of disease, 10.4% alive with metastasis, and 8.2% died without disease. 5.0% of cases had recurrence at an average of 31.3 months. Prognosis is significantly favorable for patients presenting with pure or predominant forms of LELC compared to mixed type (p < 0.0001). The treatment significantly associated with the highest disease mortality and lowest disease-free survival was TURBT alone when compared to any multi-modality treatment (p < 0.01). CONCLUSION: We conclude that the best treatment modality associated with the highest disease-free survival is multi-modal treatment including radical cystectomy.


Assuntos
Carcinoma de Células de Transição/terapia , Neoplasias da Bexiga Urinária/terapia , Idoso , Carcinoma de Células de Transição/classificação , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias da Bexiga Urinária/classificação
17.
Clin Cancer Res ; 23(14): 3906-3917, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28196872

RESUMO

Purpose: MUC16, a tumor biomarker and cell surface-associated mucin, is overexpressed in various cancers; however, its role in lung cancer pathogenesis is unknown. Here, we have explored the mechanistic role of MUC16 in lung cancer.Experimental Design: To identify the functional role of MUC16, stable knockdown was carried in lung cancer cells with two different shRNAs. Clinical significance of MUC16 was evaluated in lung cancer patient tissues using IHC. We have generated genetically engineered mouse model (KrasG12D; AdCre) to evaluate the preclinical significance of MUC16.Results: MUC16 was overexpressed (P = 0.03) in lung cancer as compared with normal tissues. MUC16 knockdown (KD) in lung cancer cell lines decreased the in vitro growth rate (P < 0.05), migration (P < 0.001), and in vivo tumor growth (P = 0.007), whereas overexpression of MUC16-carboxyl terminal (MUC16-Cter) resulted in increased growth rate (P < 0.001). Transcriptome analysis of MUC16 KD showed a downregulation (P = 0.005) of TSPYL5 gene, which encodes for a testis-specific Y-like protein. Rescue studies via overexpression of MUC16-Cter in MUC16 KD cells showed activation of signaling proteins, such as JAK2 (Y1007/1008), STAT3 (Y705), and glucocorticoid receptor (GR), which constitutes an important axis for the regulation of TSPYL5 for oncogenic process. Further, inhibition of STAT3 (Y705) led to decreased GR and TSPYL5, suggesting that MUC16 regulates TSPYL5 through the JAK2/STAT3/GR axis. Also, MUC16 overexpression induced cisplatin and gemcitabine resistance by downregulation of p53.Conclusions: Our findings indicate a significant role of MUC16 in tumorigenesis and metastasis of lung cancer cells possibly via regulation of TSPYL5 through the JAK2/STAT3/GR axis. Clin Cancer Res; 23(14); 3906-17. ©2017 AACR.


Assuntos
Antígeno Ca-125/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Proteína Supressora de Tumor p53/genética , Células A549 , Animais , Movimento Celular , Proliferação de Células/genética , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 2/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Fator de Transcrição STAT3/genética
18.
J Natl Compr Canc Netw ; 14(10): 1213-1224, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27697976

RESUMO

These NCCN Guidelines Insights discuss the major recent updates to the NCCN Guidelines for Bladder Cancer based on the review of the evidence in conjunction with the expert opinion of the panel. Recent updates include (1) refining the recommendation of intravesical bacillus Calmette-Guérin, (2) strengthening the recommendations for perioperative systemic chemotherapy, and (3) incorporating immunotherapy into second-line therapy for locally advanced or metastatic disease. These NCCN Guidelines Insights further discuss factors that affect integration of these recommendations into clinical practice.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia
19.
Clin Case Rep ; 4(3): 303-4, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-27014458

RESUMO

A rare cause for rapid adrenal enlargement is adrenal oncocytoma of uncertain malignant potential. A full biochemical evaluation is warranted to screen secreting adrenal adenomas as well as to evaluate adrenal cortical carcinoma. Careful pathologic evaluation is required as the diagnosis of AOC cannot be made by imaging.

20.
Hum Pathol ; 46(12): 1945-50, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26482606

RESUMO

Digital whole slide imaging (WSI) is a diagnostic modality that has gained acceptance as a tool for use in some areas of surgical pathology such as remote consultations. Accurate control of color representation of digitally rendered images of histologic sections is considered an important parameter of WSI. Currently, professional societies, physicians, and other stakeholders are in the process of establishing clinical guidelines outlining the use of these devices, which include color integrity and color calibration of scanners and viewing devices. Although color is a component of surgical pathology diagnoses, it was posited that pathologists could accurately diagnose surgical specimens without color. To test this hypothesis, 5 pathologists were presented breast biopsy specimens from 20 patients consisting of 22 separate tissue specimens and WSI of 158 hematoxylin and eosin-stained slides imaged at ×20. No special stains were included. The pathologists reviewed each case using a 16-bit grayscale monitor and rendered a diagnosis for each case. Diagnoses were compared to the original light microscopy diagnoses and scored for concordance. A 92.7% concordance was observed. Discordant diagnoses represented well-known areas of diagnostic disagreement in breast pathology as well as known limitations of WSI. The research demonstrated that surgical pathologists did not rely primarily on color to render accurate diagnoses of breast biopsy cases but rather used architectural features of tissue and cellular morphology to reach a diagnostic conclusion. This research did not suggest that color is an unimportant factor in pathology diagnosis, but its importance may be overstated.


Assuntos
Neoplasias da Mama/patologia , Patologia Cirúrgica/métodos , Coloração e Rotulagem , Telepatologia/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Variações Dependentes do Observador
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