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1.
Cancers (Basel) ; 14(6)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35326655

RESUMO

Invasive melanoma is the deadliest type of skin cancer, with 101,110 expected cases to be diagnosed in 2021. Recurrent BRAF and NRAS mutations are well documented in melanoma. Biologic implications of gene fusions and the efficacy of therapeutically targeting them remains unknown. Retrospective review of patient samples that underwent next-generation sequencing of the exons of 592 cancer-relevant genes and whole transcriptome sequencing for the detection of gene fusion events and gene expression profiling. Expression of PDL1 and ERK1/2 was assessed by immunohistochemistry (IHC). There were 33 (2.6%) cases with oncogenic fusions (14 novel), involving BRAF, RAF1, PRKCA, TERT, AXL, and FGFR3. MAPK pathway-associated genes were over-expressed in BRAF and RAF1 fusion-positive tumors in absence of other driver alterations. Increased expression in tumors with PRKCA and TERT fusions was concurrent with MAPK pathway alterations. For a subset of samples with available tissue, increased phosphorylation of ERK1/2 was observed in BRAF, RAF1, and PRKCA fusion-positive tumors. Oncogenic gene fusions are associated with transcriptional activation of the MAPK pathway, suggesting they could be therapeutic targets with available inhibitors. Additional analyses to fully characterize the oncogenic effects of these fusions may support biomarker driven clinical trials.

2.
Surgery ; 169(1): 138-144, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32709489

RESUMO

BACKGROUND: At presentation, 21% to 49% of patients with adrenocortical cancer have metastases. Standard chemotherapy has a 23% response rate. We assessed whether next generation sequencing could elucidate additional treatment options in refractory adrenocortical cancer. METHODS: Retrospective analysis using a commercial, 592-gene DNA-based panel was performed of next generation sequencing data from 94 adrenocortical cancer tumors profiled for clinical care. We compared our data to the adrenocortical cancer database of The Cancer Genome Atlas containing survival data. We evaluated mutations, indels, amplifications, tumor mutation burden, microsatellite instability, and programmed death-ligand 1 protein expression. RESULTS: Our cohort included 54 primary neoplasms and 40 metastatic lesions. The most frequently mutated genes were TP53 (36%) and CTNNB1 (19%). Low prevalence mutations were noted in 37 genes including DNA damage repair genes in 15 samples. High tumor mutation burden was seen in 3 patients, and programmed death-ligand 1 was positive in 12. Potential targets to Food and Drug Administration-approved drugs were seen in 16% of cases. CONCLUSION: DNA sequencing panel tests may identify therapeutic options for some patients with adrenocortical cancer. TP53 and mutations were associated with an adverse outcome. An expanded repertoire of drugs and, perhaps, more expansive multi-omic sequencing are needed to advance the treatment of adrenocortical cancer.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Adolescente , Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/patologia , Adulto , Idoso , Antineoplásicos/farmacologia , Biomarcadores Tumorais/antagonistas & inibidores , Criança , Reparo do DNA/genética , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Amplificação de Genes , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Medicina de Precisão/métodos , Estudos Retrospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genética , Adulto Jovem , beta Catenina/genética
3.
Oncology (Williston Park) ; 34(8): 321-327, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785929

RESUMO

Advances in immuno-oncology over the last several years have led to FDA approvals of novel agents. As our understanding of immune response and its checkpoints has evolved, further advances have been made in treatment for several cancer types. To predict a response to immunotherapy, the initial biomarkers used were expression of the PD-1 receptor and PD-L1, as assessed by immunohistochemistry. More recently, predictive biomarkers have included microsatellite instability, DNA mismatch repair, and tumor mutational burden. Although these markers may be clinically relevant in predicting an immunotherapy response, cancer immunotherapy fails some patients. Improved understanding of the human immune system is necessary, as is a careful evaluation of the methods used to predict and assess response to immuno-oncology treatments. With the application of therapeutic immune-modulating agents, more comprehensive assays, and associated bioinformatics tools to accurately assess the tumor microenvironment, we may better predict responses to immuno-oncology agents and the ever-increasing complexity of their clinical use.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Instabilidade de Microssatélites , Mutação , Neoplasias/metabolismo , Neoplasias/patologia , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo
4.
Oral Oncol ; 111: 104899, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32665184

RESUMO

The current standard of care for cutaneous melanoma of the ear is surgical excision. This approach may result in unfavorable functional and cosmetic outcomes. We report here a case of recurrent melanoma of the ear that achieved complete response with talimogene laherparepvec treatment after the patient declined surgical resection.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Produtos Biológicos/administração & dosagem , Pavilhão Auricular , Neoplasias da Orelha/tratamento farmacológico , Melanoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Pavilhão Auricular/patologia , Neoplasias da Orelha/patologia , Neoplasias da Orelha/cirurgia , Herpesvirus Humano 1 , Humanos , Injeções Intralesionais , Masculino , Melanoma/patologia , Melanoma/cirurgia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia
5.
J Surg Oncol ; 113(3): 333-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26662660

RESUMO

For extremity soft tissue sarcomas, limb salvage is now standard of care. The extent of surgical margins is balanced with functionality of the resected limb. Although negative margins are the goal, the necessary width is unclear. Additional considerations for margin adequacy include presence of anatomic barriers such as fascia and periosteum, proximity of critical structures, receipt of adjuvant and neoadjuvant therapies, and histologic subtype. Multidisciplinary team discussion is critical for treatment planning.


Assuntos
Extremidades , Recidiva Local de Neoplasia/prevenção & controle , Sarcoma/prevenção & controle , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/prevenção & controle , Neoplasias de Tecidos Moles/cirurgia , Procedimentos Cirúrgicos Operatórios , Extremidades/patologia , Extremidades/cirurgia , Humanos , Salvamento de Membro , Terapia Neoadjuvante/métodos , Neoplasia Residual/prevenção & controle , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Procedimentos Cirúrgicos Operatórios/métodos , Procedimentos Cirúrgicos Operatórios/normas
6.
BMC Cancer ; 15: 886, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26555296

RESUMO

BACKGROUND: USP18 (ubiquitin-specific protease 18) removes ubiquitin-like modifier interferon stimulated gene 15 (ISG15) from conjugated proteins. USP18 null mice in a FVB/N background develop tumors as early as 2 months of age. These tumors are leiomyosarcomas and thus represent a new murine model for this disease. METHODS: Heterozygous USP18 +/- FVB/N mice were bred to generate wild-type, heterozygous and homozygous cohorts. Tumors were characterized immunohistochemically and two cell lines were derived from independent tumors. Cell lines were karyotyped and their responses to restoration of USP18 activity assessed. Drug testing and tumorigenic assays were also performed. USP18 immunohistochemical staining in a large series of human leiomyosacomas was examined. RESULTS: USP18 -/- FVB/N mice spontaneously develop tumors predominantly on the back of the neck with most tumors evident between 6-12 months (80 % penetrance). Immunohistochemical characterization of the tumors confirmed they were leiomyosarcomas, which originate from smooth muscle. Restoration of USP18 activity in sarcoma-derived cell lines did not reduce anchorage dependent or independent growth or xenograft tumor formation demonstrating that these cells no longer require USP18 suppression for tumorigenesis. Karyotyping revealed that both tumor-derived cell lines were aneuploid with extra copies of chromosomes 3 and 15. Chromosome 15 contains the Myc locus and MYC is also amplified in human leiomyosarcomas. MYC protein levels were elevated in both murine leiomyosarcoma cell lines. Stabilized P53 protein was detected in a subset of these murine tumors, another feature of human leiomyosarcomas. Immunohistochemical analyses of USP18 in human leiomyosarcomas revealed a range of staining intensities with the highest USP18 expression in normal vascular smooth muscle. USP18 tissue array analysis of primary leiomyosarcomas from 89 patients with a clinical database revealed cases with reduced USP18 levels had a significantly decreased time to metastasis (P = 0.0441). CONCLUSIONS: USP18 null mice develop leiomyosarcoma recapitulating key features of clinical leiomyosarcomas and patients with reduced-USP18 tumor levels have an unfavorable outcome. USP18 null mice and the derived cell lines represent clinically-relevant models of leiomyosarcoma and can provide insights into both leiomyosarcoma biology and therapy.


Assuntos
Carcinogênese/genética , Leiomiossarcoma/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uterinas/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leiomiossarcoma/patologia , Camundongos , Camundongos Knockout , Metástase Neoplásica , Proteína Supressora de Tumor p53/genética , Ubiquitina Tiolesterase/biossíntese , Neoplasias Uterinas/patologia
7.
Curr Oncol Rep ; 17(8): 39, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26092408

RESUMO

Management of retroperitoneal soft tissue sarcomas (RP STS) can be very challenging. In contrast to the more common extremity STS, the two predominant histologic subtypes encountered in the retroperitoneum are well-differentiated/dedifferentiated liposarcoma and leiomyosarcoma. Surgery remains the mainstay of treatment for RP STS. Preoperative planning and anticipation of the need for resection of adjacent organs/structures are critical. The extent of surgery, including the role of compartmental resection, is still controversial. Radiation therapy may be an important adjunct to surgery to provide locoregional disease control; this is currently being evaluated in the preoperative setting in the EORTC STRASS trial. Systemic therapy, tailored to the specific histologic subtype, may also be of benefit for the management of RP STS. Further investigation of novel therapies (e.g., targeted therapies, immunotherapy) is needed. Overall, multi-institutional collaboration is important moving forward, to continue to better understand and optimize management of this disease.


Assuntos
Neoplasias Retroperitoneais/terapia , Sarcoma/terapia , Antineoplásicos/uso terapêutico , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Planejamento de Assistência ao Paciente , Radioterapia Adjuvante/métodos
8.
J Clin Oncol ; 33(20): 2231-8, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25667281

RESUMO

PURPOSE: We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume. PATIENTS AND METHODS: Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years. RESULTS: In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001). CONCLUSION: The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS.


Assuntos
Terapia Neoadjuvante , Lesões por Radiação/prevenção & controle , Radioterapia Conformacional/métodos , Radioterapia Guiada por Imagem/métodos , Sarcoma/radioterapia , Carga Tumoral/efeitos da radiação , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Extremidades , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , América do Norte , Estudos Prospectivos , Lesões por Radiação/etiologia , Lesões por Radiação/mortalidade , Radioterapia Adjuvante , Radioterapia Conformacional/efeitos adversos , Radioterapia Conformacional/mortalidade , Radioterapia Guiada por Imagem/efeitos adversos , Radioterapia Guiada por Imagem/mortalidade , Radioterapia de Intensidade Modulada/métodos , Fatores de Risco , Sarcoma/mortalidade , Sarcoma/secundário , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
9.
BMC Clin Pathol ; 14: 42, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25349530

RESUMO

BACKGROUND: Liposarcoma (LS) is the second-most common type of soft-tissue sarcoma. Despite advances in knowledge and treatment of this disease, there remains a need for more effective LS therapy. Steroid hormone receptors regulate metabolism in adipocytes. Estrogen receptor alpha (ER), progesterone receptor (PR), and androgen receptor (AR) have been implicated in the pathophysiology of other cancer types. We sought to comprehensively determine temporal expression patterns of these receptors in LS. METHODS: We analyzed 561 histologically subtyped LS specimens from 354 patients for expression of ER, PR, and AR by immunohistochemistry (IHC) using diagnostic-grade reagents and protocols. The fractions of positively stained tumor cells were scored within each specimen. IHC scores were compared across LS subtypes using the Kruskal-Wallis test, and subtypes were compared using Dunn's post-hoc test. Ages of patients with receptor-positive vs. -negative LS were compared by t-test. Genders and races were compared for hormone receptor positivity using Fisher's exact test and Chi-square analysis, respectively. Recurrence-free survival was compared between receptor-positive and negative patients by log-rank test. p< 0.05 was considered significant. RESULTS: ER and AR were frequently expressed in LS, while few tumors expressed PR. Most of the ER + and AR + samples were of the well-differentiated LS subtype. A smaller fraction of de-differentiated LS expressed ER or AR, but expression was common within well-differentiated regions of tumors histologically classified as de-differentiated LS. In LS specimens from patients who underwent multiple surgeries over time, receptor expression frequently changed over time, which may be attributable in part to intratumor heterogeneity, varying degrees of de-differentiation, and biopsy bias. ER and AR were frequently co-expressed. Receptor status was not significantly associated with gender or race, but AR and PR expression were associated with earlier age at diagnosis. Receptor expression was not associated with altered recurrence-free survival. CONCLUSIONS: ER and AR are commonly expressed in LS, particularly in well-differentiated tumors. These data warrant further functional study to determine receptor function in LS, and the potential efficacy of anti-hormone therapies for the treatment of patients with LS.

10.
Breast Cancer Res Treat ; 138(1): 175-83, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23417336

RESUMO

Conjugated linoleic acid (CLA) is widely used as a "nutraceutical" for weight loss. CLA has anticancer effects in preclinical models, and we demonstrated in vitro that this can be attributed to the suppression of fatty acid (FA) synthesis. We tested the hypothesis that administration of CLA to breast cancer patients would inhibit expression of markers related to FA synthesis in tumor tissue, and that this would suppress tumor proliferation. Women with Stage I-III breast cancer were enrolled into an open label study and treated with CLA (1:1 mix of 9c,11t- and 10t,12c-CLA isomers, 7.5 g/d) for ≥ 10 days before surgery. Fasting plasma CLA concentrations measured pre- and post-CLA administration, and pre/post CLA tumor samples were examined by immunohistochemistry for Spot 14 (S14), a regulator of FA synthesis, FA synthase (FASN), an enzyme of FA synthesis, and lipoprotein lipase (LPL), the enzyme that allows FA uptake. Tumors were also analyzed for expression of Ki-67 and cleaved caspase 3. 24 women completed study treatment, and 23 tumors were evaluable for the primary endpoint. The median duration of CLA therapy was 12 days, and no significant toxicity was observed. S14 expression scores decreased (p = 0.003) after CLA administration. No significant change in FASN or LPL expression was observed. Ki-67 scores declined (p = 0.029), while cleaved caspase 3 staining was unaffected. Decrements in S14 or Ki-67 did not correlate with fasting plasma CLA concentrations at surgery. Breast tumor tissue expression of S14, but not FASN or LPL, was decreased after a short course of treatment with 7.5 g/day CLA. This was accompanied by reductions in the proliferation index. CLA consumption was well-tolerated and safe at this dose for up to 20 days. Overall, CLA may be a prototype compound to target fatty acid synthesis in breast cancers with a "lipogenic phenotype".


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Ácido Linoleico/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Ácido Linoleico/administração & dosagem , Ácido Linoleico/efeitos adversos , Pessoa de Meia-Idade , Gradação de Tumores
11.
Am J Clin Oncol ; 36(1): 89-90, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23334483

RESUMO

Although adjuvant imatinib (IM) for high risk GIST is an accepted treatment consideration, the duration of therapy remains controversial. The recently published SSGXVIII/AIO randomized clinical trial of 3 years vs. 1 year of adjuvant IM has established a benefit of RFS and OS for the 3 year cohort. Future studies are necessary to continue to further delineate risk variables for GIST recurrence.


Assuntos
Antineoplásicos/administração & dosagem , Quimioterapia Adjuvante/métodos , Ensaios Clínicos Fase III como Assunto , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/administração & dosagem , Guias de Prática Clínica como Assunto , Pirimidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Benzamidas , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib
12.
Hematol Oncol Clin North Am ; 26(6): 1239-59, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23116579

RESUMO

Gastrointestinal stromal tumor (GIST) represents the most common mesechymal tumor of the gastrointestinal tract. Discovery of the relationship between unregulated KIT kinase and GIST transformation has led to diagnostic and therapeutic targeting. Imatinib is the recommended first-line treatment of metastatic GIST. In addition, the combination of surgery and imatinib for primary GIST is indicated in the adjuvant setting of high-risk patients and there may be benefit for this combination in the neoadjuvant setting. The success of molecular targeted therapy in GIST represents an important and exciting advance in solid tumor oncology.


Assuntos
Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/terapia , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Neoplasias Gastrointestinais/epidemiologia , Tumores do Estroma Gastrointestinal/epidemiologia , Humanos , Incidência
13.
Ann Surg Oncol ; 19(4): 1074-80, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22203182

RESUMO

BACKGROUND: Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. RESULTS: Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. CONCLUSIONS: This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.


Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/secundário , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Quimioterapia Adjuvante , Progressão da Doença , Intervalo Livre de Doença , Feminino , Seguimentos , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
14.
Int J Cancer ; 129(11): 2533-42, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21671474

RESUMO

Although surgery remains the mainstay for the treatment of primary gastrointestinal stromal tumors (GIST), a significant number of patients experience disease recurrence within 5 years of surgery. The emergence of imatinib therapy for the treatment of patients with advanced GIST has offered unprecedented improvements in clinical outcomes for these patients. Prospective clinical trials have supported the efficacy and safety of imatinib before and after surgical resection of GIST. The American College of Surgeons Oncology Group Z9001 pivotal trial revealed that 1 year of adjuvant imatinib therapy provides significantly superior recurrence-free survival in patients with GIST after surgical resection, when compared to placebo. Additional trials and case studies have also begun to define the potential clinical benefit of imatinib in the neoadjuvant setting. Optimized risk stratification paradigms will be required to ensure the appropriate selection of patients to undergo treatment with imatinib in these settings. Risk stratification schemes are evolving that potentially will include mutation status and tumor rupture, and predictive nomograms have recently been proposed. The recent European Society of Medical Oncology and National Comprehensive Cancer Network guidelines mention use of adjuvant imatinib for ≥ 1 year in patients with KIT(+) , resectable GIST at high risk of recurrence. Moreover, the guidelines support the use of neoadjuvant imatinib in cases of limited disease if it would facilitate less extensive surgery and organ sparing. This article reviews pivotal efficacy and safety data for adjuvant imatinib and explores the potential clinical benefit of neoadjuvant imatinib in patients with GIST.


Assuntos
Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Terapia Neoadjuvante , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Benzamidas , Quimioterapia Adjuvante , Gerenciamento Clínico , Humanos , Mesilato de Imatinib
15.
Mol Cancer Ther ; 10(3): 427-36, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21282354

RESUMO

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA.


Assuntos
Proliferação de Células , Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Lipase Lipoproteica/metabolismo , Neoplasias/metabolismo , Animais , Antígenos CD36/genética , Linhagem Celular Tumoral , Inibidores da Síntese de Ácidos Graxos/farmacologia , Ácidos Graxos/farmacologia , Feminino , Humanos , Lipólise , Lipossarcoma/genética , Lipossarcoma/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Interferente Pequeno/genética
16.
Cancer Chemother Pharmacol ; 67 Suppl 1: S3-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21116626

RESUMO

Adjuvant therapy for primary GIST has proven benefit in extending disease free survival. Defined risk factors for recurrent disease are based on GIST size, location, and mitotic rate and provide useful guidelines for selecting patients for adjuvant therapy considerations. Neoadjuvant therapy with tyrosine kinase inhibition has potential usefulness in primary GIST, although not yet as standard of care. Advantages can include tumor downsizing to provide opportunity for less morbid surgical resection as well as to decrease risk of intra-op tumor rupture. These theoretical considerations have not been evaluated in large clinical studies.


Assuntos
Quimioterapia Adjuvante , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Terapia Neoadjuvante , Antineoplásicos/uso terapêutico , Benzamidas , Terapia Combinada , Intervalo Livre de Doença , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib , Recidiva Local de Neoplasia/epidemiologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico
17.
Int J Oncol ; 36(5): 1309-14, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20372807

RESUMO

Liposarcomas (LS) are mesenchymal tumors that can recur after surgical resection and often do not respond to presently available medical therapies. This study demonstrates the dependence of LS on de novo long-chain fatty acid synthesis for growth. Lipogenesis can be impaired by inhibiting the activities of lipogenic enzymes, including acetyl CoA-carboxylase (ACC) and fatty acid synthase (FASN), or by suppressing the expression of key genes involved in the pathway and its regulation. The FASN inhibitors cerulenin and orlistat reduced the growth of two LS cell lines (LiSa2, SW872), as did inhibition of ACC with soraphen A. CDDO-Me, a synthetic triterpenoid, suppressed expression of Spot 14 and FASN genes and likewise inhibited LS cell growth. Importantly, the anti-proliferative effect of each agent was prevented by the co-administration of palmitate, the major product of cellular long-chain fatty acid synthesis. In stark contrast to LS cells, these compounds had no effect on the growth of fibroblasts. Four biochemically distinct agents that target critical points in the fatty acid synthetic pathway exert anti-proliferative effects on LS cells, and rescue of cell growth by palmitic acid suggests that reduced tumor cell lipogenesis mediates the growth inhibition. These findings warrant further studies aimed at the clinical exploitation of the dependence of LS cell growth on fatty acids.


Assuntos
Ácidos Graxos/química , Regulação Neoplásica da Expressão Gênica , Lipossarcoma/metabolismo , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Ácido Graxo Sintases/metabolismo , Fibroblastos/metabolismo , Humanos , Lactonas/farmacologia , Lipídeos/química , Orlistate , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Genes Chromosomes Cancer ; 48(10): 886-96, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19585585

RESUMO

Gastrointestinal stromal tumors (GISTs) generally harbor activating mutations in KIT or platelet-derived growth facter receptor (PDGFRA). Mutations in these receptor tyrosine kinases lead to dysregulation of downstream signaling pathways that contribute to GIST pathogenesis. GISTs with KIT or PDGFRA mutations also undergo secondary cytogenetic alterations that may indicate the involvement of additional genes important in tumor progression. Approximately 10-15% of adult and 85% of pediatric GISTs do not have mutations in KIT or in PDGFRA. Most mutant adult GISTs display large-scale genomic alterations, but little is known about the mutation-negative tumors. Using genome-wide DNA arrays, we investigated genomic imbalances in a set of 31 GISTs, including 10 KIT/PDGFRA mutation-negative tumors from nine adults and one pediatric case and 21 mutant tumors. Although all 21 mutant GISTs exhibited multiple copy number aberrations, notably losses, eight of the 10 KIT/PDGFRA mutation-negative GISTs exhibited few or no genomic alterations. One KIT/PDGFRA mutation-negative tumor exhibiting numerous genomic changes was found to harbor an alternate activating mutation, in the serine-threonine kinase BRAF. The only other mutation-negative GIST with significant chromosomal imbalances was a recurrent metastatic tumor found to harbor a homozygous deletion in chromosome arm 9p. Similar findings in several KIT-mutant GISTs identified a minimal overlapping region of deletion of approximately 0.28 Mbp in 9p21.3 that includes only the CDKN2A/2B genes, which encode inhibitors of cell-cycle kinases. These results suggest that GISTs without activating kinase mutations, whether pediatric or adult, generally exhibit a much lower level of cytogenetic progression than that observed in mutant GISTs.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Tumores do Estroma Gastrointestinal/enzimologia , Dosagem de Genes , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
19.
Nutr Cancer ; 61(1): 114-22, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19116881

RESUMO

Spot 14 (THRSP, S14) is a nuclear protein involved in the regulation of genes required for fatty acid synthesis in normal and malignant mammary epithelial and adipose cells. Harvatine and Bauman (1) reported that conjugated linoleic acid (CLA) inhibits S14 gene expression in bovine mammary and mouse adipose tissues and reduces milk fat production in cows. We hypothesized that CLA inhibits S14 gene expression in human breast cancer and liposarcoma cells and that this will retard their growth. Exposure of T47D breast cancer cells to a mixture of CLA isomers reduced the expression of the S14 and fatty acid synthase (FAS) genes. The mixture caused a dose-related inhibition of T47D cell growth, as did pure c9, t11 and t10, c12-CLA, but not linoleic acid. Similar effects were observed in MDA-MB-231 breast cancer cells. Provision of 8 mircoM palmitate fully (CLA mix, t10, c12-CLA) or partially (c9, t11-CLA) reversed the antiproliferative effect in T47D cells. CLA likewise suppressed levels of S14 and FAS mRNAs in liposarcoma cells and caused growth inhibition that was prevented by palmitic acid. CLA did not affect the growth of nonlipogenic HeLa cells or human fibroblasts. We conclude that as in bovine mammary and mouse adipose cells, CLA suppresses S14 and FAS gene expression in human breast cancer and liposarcoma cells. Rescue from the antiproliferative effect of CLA by palmitic acid indicates that reduced tumor lipogenesis is a major mechanism for the anticancer effects of CLA.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Ácido Graxo Sintases/antagonistas & inibidores , Inibidores do Crescimento/farmacologia , Ácidos Linoleicos Conjugados/farmacologia , Lipossarcoma/tratamento farmacológico , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lipossarcoma/metabolismo , Lipossarcoma/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
20.
J Surg Oncol ; 99(1): 42-7, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18942073

RESUMO

BACKGROUND: Therapy for gastrointestinal stromal tumors (GIST) has changed significantly with the use of imatinib mesylate (IM). Despite the success of this drug in metastatic GIST, disease progression remains a perplexing clinical issue suggesting the need for multimodality management. There have been no prospective studies either evaluating the neoadjuvant use of IM in primary GIST or as a preoperative cytoreduction agent for metastatic GIST. METHODS: RTOG 0132/ACRIN 6665 was a prospective phase II study evaluating safety and efficacy of neoadjuvant IM (600 mg/day) for patients with primary GIST or the preop use of IM in patients with operable metastatic GIST. The trial continued postop IM for 2 years. RESULTS: Sixty-three patients were entered (52 analyzable), 30 patients with primary GIST (Group A) and 22 with recurrent metastatic GIST (Group B). Response (RECIST) in Group A was (7% partial, 83% stable, 10% unknown), in Group B (4.5% partial, 91% stable, 4.5% progression). Two-year progression free survival (Group A 83%, Group B 77%). Estimated overall survival (Group A 93%, Group B 91%). Complications of surgery and IM toxicity were minimal. CONCLUSION: This trial represents the first prospective report of preop IM in GIST. This approach is feasible, requires multidisciplinary consultations, and is not associated with notable postop complications.


Assuntos
Antineoplásicos/administração & dosagem , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Benzamidas , Terapia Combinada , Feminino , Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/secundário , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Estudos Prospectivos , Pirimidinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
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