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1.
J Surg Res ; 224: 215-221, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29506843

RESUMO

BACKGROUND: Despite advances in the treatment of rectal adenocarcinoma, the management of locally advanced disease remains a challenge. The standard of care for patients with stages II and III rectal cancer includes neoadjuvant chemoradiation followed by total mesorectal excision and postoperative chemotherapy. Much effort has been dedicated to the identification of predictive factors associated with pathologic complete response (pCR). The aim of our study was to examine our institutional experience and determine whether any association exists between anatomic tumor location and the rate of pCR. We hypothesized that lesions more than 6 cm from the anal verge are more likely to achieve a pCR. METHODS: Using data from our prospectively maintained tumor registry, a query was completed to identify all patients with locally advanced rectal adenocarcinoma who underwent treatment at Fox Chase Cancer Center from 2002 to 2015. Demographics, pretreatment, posttreatment, and final pathologic TNM staging data were collected as well as treatment intervals in days, recurrence status, overall survival, and disease-free survival. Patients with incomplete endoscopic data, staging information, survival, or recurrence status were excluded. The primary outcome measured was the degree of pathologic response. Logistic regression was used to adjust for covariates. RESULTS: Of the 135 patients eligible in the study cohort, 39% were female and 61% were male. Regarding initial clinical stage, 43% were stage II and 57% were stage III. A total of 29% had a pCR, 43% had partial pathologic response, and 28% had no response to neoadjuvant treatment. Tumor location ranged from 0 to 13 cm from the anal verge. Longitudinal tumor length was recorded in 111 patients, facilitating the calculation of mean tumor distance from the anal verge. This ranged from 0 to 15.5 cm. Univariate and multivariable analyses were completed using pCR as a primary outcome. No statistically significant difference was noted based on tumor location, regardless of measurement approach. CONCLUSIONS: Anatomic location of cancer of the rectum does not affect pCR after neoadjuvant therapy and subsequent surgical resection.


Assuntos
Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia
2.
J Hepatol ; 57(4): 766-73, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22641092

RESUMO

BACKGROUND & AIMS: The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury. METHODS: The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested. RESULTS: Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1ß, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs. CONCLUSIONS: Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Benzamidas , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hepatócitos , Mesilato de Imatinib , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Fosforilação/efeitos dos fármacos , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Traumatismo por Reperfusão/patologia
3.
PLoS One ; 12(5): e0176562, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28486549

RESUMO

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, our understanding of FL-HCC is limited. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC. We analyzed 38 specimens from 26 patients by array comparative genomic hybridiziation (aCGH) and 35 specimens from 15 patients by transcriptome sequencing (RNA-seq). All tumor specimens exhibited genomic instability, with a higher frequency of genomic amplifications or deletions in metastatic tumors. The regions encoding 71 microRNAs (miRs) were deleted in at least 25% of tumor specimens. Five of these recurrently deleted miRs targeted the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) gene product, and a correlating 100-fold upregulation of IGF2BP1 mRNA was seen in tumor specimens. Transcriptome analysis demonstrated intrapatient tumor similarity, independent of recurrence site or time. The p53 tumor suppressor pathway was downregulated as demonstrated by both aCGH and RNA-seq analysis. Notch, EGFR, NRAS, and RB1 pathways were also significantly dysregulated in tumors compared with normal liver tissue. The findings illuminate the genomic and transcriptomic landscape of this rare disease and provide insight into dysregulated oncogenic pathways and potential therapeutic targets in FL-HCC.


Assuntos
Carcinoma Hepatocelular/genética , Perfilação da Expressão Gênica , Genes p53 , Genoma Humano , Proteínas de Ligação a RNA/genética , Transcriptoma , Adolescente , Adulto , Feminino , Humanos , Adulto Jovem
4.
Cancer Res ; 75(10): 2061-70, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25836719

RESUMO

Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Pirimidinas/farmacologia , Anilidas/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Indóis/farmacologia , Concentração Inibidora 50 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Proto-Oncogênicas c-kit/genética , Piridinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Sunitinibe , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Clin Cancer Res ; 20(9): 2350-62, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24583793

RESUMO

PURPOSE: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. EXPERIMENTAL DESIGN: We treated Kit(V558del/+) mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. RESULTS: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit(V558del)(/+) murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. CONCLUSIONS: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.


Assuntos
Antineoplásicos/farmacologia , Tumores do Estroma Gastrointestinal/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacologia , Animais , Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Biópsia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Concentração Inibidora 50 , Camundongos Knockout , Terapia de Alvo Molecular , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Pirróis/administração & dosagem , Pirróis/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Carga Tumoral/efeitos dos fármacos
6.
J Exp Med ; 210(13): 2873-86, 2013 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-24323358

RESUMO

Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.


Assuntos
Tumores do Estroma Gastrointestinal/metabolismo , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Sarcoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Benzamidas/química , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proliferação de Células , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib , Inflamação , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Fenótipo , Piperazinas/química , Pirimidinas/química , Sarcoma/tratamento farmacológico , Sarcoma/genética
7.
Nat Med ; 17(9): 1094-100, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21873989

RESUMO

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Benzamidas , Western Blotting , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunoprecipitação da Cromatina , Citometria de Fluxo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/terapia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Mesilato de Imatinib , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos
8.
Transplantation ; 90(5): 465-74, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20555306

RESUMO

The thymus serves as the central organ of immunologic self-nonself discrimination. Thymocytes undergo both positive and negative selection, resulting in T cells with a broad range of reactivity to foreign antigens but with a lack of reactivity to self-antigens. The thymus is also the source of a subset of regulatory T cells that inhibit autoreactivity of T-cell clones that may escape negative selection. As a result of these functions, the thymus has been shown to be essential for the induction of tolerance in many rodent and large animal models. Proper donor antigen presentation in the thymus after bone marrow, dendritic cell, or solid organ transplantation has been shown to induce tolerance to allografts. The molecular mechanisms of positive and negative selection and regulatory T-cell development must be understood if a tolerance-inducing therapeutic intervention is to be designed effectively. In this brief and selective review, we present some of the known information on T-cell development and on the role of the thymus in experimental models of transplant tolerance. We also cite some clinical attempts to induce tolerance to allografts using pharmacologic or biologic interventions.


Assuntos
Tolerância Imunológica , Linfócitos T/imunologia , Timo/imunologia , Animais , Antígenos CD/imunologia , Autoantígenos/imunologia , Autoimunidade , Células Dendríticas/imunologia , Humanos , Síndromes de Imunodeficiência/imunologia , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Roedores , Tolerância a Antígenos Próprios/imunologia , Imunologia de Transplantes
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