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1.
Oncogene ; 36(30): 4336-4348, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28368414

RESUMO

While TGFß signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFß appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFß pathway, we first generated mouse models of neoplastic disease with TGFß receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFß led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFß-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFß-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFß signals, yet may also contribute to detrimental TGFß signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFß-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFß and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFß-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFß, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFß-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFß signaling.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Neoplasias Pancreáticas/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Western Blotting , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Imunoprecipitação , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/patologia
2.
Oncogene ; 35(25): 3249-59, 2016 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-26477314

RESUMO

The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target.


Assuntos
Transformação Celular Neoplásica/genética , Células Epiteliais/metabolismo , Ductos Pancreáticos/citologia , Receptores Proteína Tirosina Quinases/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Processamento Alternativo , Animais , Western Blotting , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Chlorocebus aethiops , Citoplasma/metabolismo , Éxons/genética , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Microscopia Confocal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosforilação , Receptores Proteína Tirosina Quinases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo
3.
Ann Surg Oncol ; 21(5): 1501-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-23793364

RESUMO

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/terapia , Consenso , Hipertermia Induzida , Neoplasias Peritoneais/terapia , Guias de Prática Clínica como Assunto/normas , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Humanos , Sociedades Científicas
4.
Oncogene ; 30(18): 2123-34, 2011 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-21242978

RESUMO

Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5-8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.


Assuntos
Oncogenes , Neoplasias Pancreáticas/fisiopatologia , Proteínas ras/fisiologia , Quinases da Família src/fisiologia , Animais , Linhagem Celular Tumoral , Instabilidade Genômica , Humanos , Camundongos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
5.
Br J Cancer ; 100(1): 24-7, 2009 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-19127264

RESUMO

Skin malignancy is an important cause of mortality in the United Kingdom and is rising in incidence every year. Most skin cancer presents in primary care, and an important determinant of outcome is initial recognition and management of the lesion. Here we present an observational study of interobserver agreement using data from a population-based randomised controlled trial of minor surgery. Trial participants comprised patients presenting in primary care and needing minor surgery in whom recruiting doctors felt to be able to offer treatment themselves or to be able to refer to a colleague in primary care. They are thus relatively unselected. The skin procedures undertaken in the randomised controlled trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or pre-malignant. Chance-corrected agreement (kappa) between general practitioner (GP) diagnosis of malignancy and histology was 0.45 (0.36-0.54) for lesions and 0.41 (0.32-0.51) for individuals affected with malignancy. Sensitivity of GPs for the detection of malignant lesions was 66.7% (95% confidence interval (CI), 50.3-79.8) for lesions and 63.6% (95% CI, 46.7-77.8) for individuals affected with malignancy. The safety of patients is of paramount importance and it is unsafe to leave the diagnosis and treatment of potential skin malignancy in the hands of doctors who have limited training and experience. However, the capacity to undertake all of the minor surgical demand works demanded in hospitals does not exist. If the capacity to undertake it is present in primary care, then the increased costs associated with enhanced training for general medical practitioners (GPs) must be borne.


Assuntos
Médicos de Família , Neoplasias Cutâneas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Gut ; 57(11): 1555-60, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18664506

RESUMO

OBJECTIVE: The chemokine CXCL12, together with its specific receptor, CXCR4, have been shown to mediate invasiveness and metastatic behaviour in pancreatic cancer cells. The expression of CXC12/CXCR4 has not been previously examined in pancreatic intraepithelial neoplasias (PanIN), the accepted precursor lesions to pancreatic duct cancer. DESIGN: In this study we sought to characterise the expression of CXCL12 and CXCR4 during the progression of PanIN using both a murine model and human tissues. RESULTS: These studies reveal that both CXCL12 and CXCR4 are expressed in PanIN and that the frequency increases during PanIN progression (0% CXCR4 expression in normal mouse and human ducts vs 100% in mouse PanIN 3 and 77% in human PanIN 3). Next we demonstrate a dose-dependent increase in the proliferation of murine PanIN cells when exposed to CXCL12. Finally, we show that expression of CXCR4 in murine PanIN cells is partially dependent on mitogen-activated protein kinase (MAPK) signalling and that the effect of CXCL12 on PanIN proliferation can be abrogated by an MAPK inhibitor. CONCLUSIONS: Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.


Assuntos
Carcinoma in Situ/metabolismo , Quimiocina CXCL12/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores CXCR4/metabolismo , Animais , Carcinoma in Situ/patologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL12/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , RNA Mensageiro/metabolismo , Receptores CXCR4/genética
7.
Health Technol Assess ; 12(23): iii-iv, ix-38, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18505669

RESUMO

OBJECTIVE: To determine whether there is equivalence in the competence of GPs and hospital doctors to perform a range of elective minor surgical procedures, in terms of the safety, quality and cost of care. DESIGN: A prospective randomised controlled equivalence trial was undertaken in consenting patients presenting at general practices and needing minor surgery. SETTING: The study was conducted in the south of England. PARTICIPANTS: Consenting patients presenting at general practices who needed minor surgery in specified categories for whom the recruiting doctor felt able to offer treatment or to be able to refer to a colleague in primary care. INTERVENTIONS: On presentation to their GP, patients were randomised to either treatment within primary care or treatment at their local hospital. Evaluation was by assessment of clinical quality and safety of outcome, supplemented by examination of patient satisfaction and cost-effectiveness. MAIN OUTCOME MEASURES: Two independent observers assessed surgical quality by blinded assessment of wound appearance, between 6 and 8 weeks postsurgery, from photographs of wounds. Other measures included satisfaction with care, safety of surgery in terms of recognition of and appropriate treatment of skin malignancies, and resource use and implications. RESULTS: The 568 patients recruited (284 primary care, 284 hospital) were randomised by 82 GPs. In total, 637 skin procedures plus 17 ingrowing toenail procedures were performed (313 primary care, 341 hospital) by 65 GPs and 60 hospital doctors. Surgical quality was assessed for 273 (87%) primary care and 316 (93%) hospital lesions. Mean visual analogue scale score in hospital was significantly higher than that in primary care [mean difference=5.46 on 100-point scale; 95% confidence interval (CI) 0.925 to 9.99], but the clinical importance of the difference was uncertain. Hospital doctors were better at achieving complete excision of malignancies, with a difference that approached statistical significance [7/16 GP (44%) versus 15/20 hospital (75%), chi(2)=3.65, p=0.056]. The proportion of patients with post-operative complications was similar in both groups. The mean cost for hospital-based minor surgery was 1222.24 pounds and for primary care 449.74 pounds. Using postoperative complications as an outcome, both effectiveness and costs of the alternative interventions are uncertain. Using completeness of excision of malignancy as an outcome, hospital minor surgery becomes more cost-effective. The 705 skin procedures undertaken in this trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or premalignant. Chance-corrected agreement (kappa) between GP diagnosis of malignancy and histology was 0.45 (95% CI 0.36 to 0.54) for lesions and 0.41 (95% CI 0.32 to 0.51) for individuals affected by malignancy. Sensitivity of GPs for detection of malignant lesions was 66.7% (95% CI 50.3 to 79.8) for lesions and 63.6% (95% CI 46.7 to 77.8) for individuals affected by malignancy. CONCLUSIONS: The quality of minor surgery carried out in general practice is not as high as that carried out in hospital, using surgical quality as the primary outcome, although the difference is not large. Patients are more satisfied if their procedure is performed in primary care, largely because of convenience. However, there are clear deficiencies in GPs' ability to recognise malignant lesions, and there may be differences in completeness of excision when compared with hospital doctors. The safety of patients is of paramount importance and this study does not demonstrate that minor surgery carried out in primary care is safe as it is currently practised. There are several alternative models of minor surgery provision worthy of consideration, including ones based in primary care that require all excised tissue to be sent for histological examination, or that require further training of GPs to undertake the necessary work. The results of this study suggest that a hospital-based service is more cost-effective. It must be concluded that it is unsafe to leave minor surgery in the hands of doctors who have never been trained to do it. Further work is required to determine GPs' management of a range of skin conditions (including potentially life-threatening malignancies), rather than just their recognition of them. Further economic modelling work is required to look at the potential costs of training sufficient numbers of GPs and GPs with special interests to meet the demand for minor surgery safely in primary care, and of the alternative of transferring minor surgery large-scale to the hospital sector. Different models of provision need thorough testing before widespread introduction.


Assuntos
Assistência Ambulatorial , Hospitalização , Procedimentos Cirúrgicos Menores/normas , Atenção Primária à Saúde , Procedimentos Cirúrgicos Eletivos/normas , Inglaterra , Feminino , Gastos em Saúde , Humanos , Masculino , Corpo Clínico Hospitalar , Pessoa de Meia-Idade , Unhas Encravadas/cirurgia , Medição da Dor , Médicos de Família , Competência Profissional , Estudos Prospectivos , Qualidade da Assistência à Saúde , Segurança , Dermatopatias/cirurgia
8.
J Chemother ; 19(4): 451-4, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17855191

RESUMO

The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment.


Assuntos
Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/cirurgia , Neoplasias do Apêndice/diagnóstico , Neoplasias do Apêndice/cirurgia , Apêndice , Adenocarcinoma Mucinoso/patologia , Idoso , Neoplasias do Apêndice/patologia , Apêndice/patologia , Antígeno CA-19-9/análise , Antígeno Carcinoembrionário/análise , Evolução Fatal , Feminino , Humanos
9.
Ann Surg Oncol ; 12(5): 374-80, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15915371

RESUMO

BACKGROUND: Prognosis after resection of colorectal liver metastases is influenced by various factors. A positive margin of resection (MOR) has been shown to adversely influence prognosis. Although a 1-cm MOR has been accepted as adequate, the data to support this guideline are sparse. METHODS: Our hepatobiliary database was queried for patients who underwent liver resection for colorectal metastases between January 1992 and July 2003. All patients were divided into three groups: MOR <.5 cm (group A), .5 to 1 cm (group B), and >1 cm (group C). Operative reports from each hepatic resection were analyzed to determine local factors that may have contributed to a subcentimeter MOR. RESULTS: A total of 112 patients (67 men and 45 women) underwent liver resection for colorectal metastases with negative margins. Fifty-three patients were in group A, 26 patients were in group B, and 33 patients were in group C. Group C demonstrated decreased local recurrence (LR; P = .003), distant recurrence (DR; P = .008), and disease-free recurrence (P = .002). A significant difference in the overall time to LR (P = .003), time to DR (P = .003), and disease-free survival (P = .002) was also demonstrated. Factors associated with a subcentimeter MOR included nonanatomical resection (P = .043), proximity to a major vessel (P = .003), and central location (P = .002). CONCLUSIONS: A <1-cm resection for colorectal liver metastases is associated with increased LR and DR, as well as decreased disease-free survival. When a nonanatomical resection is performed, a MOR >1 cm should be attempted, because an adequate margin is often underestimated. Considerations should be made for extended resections when tumors are centrally located or near major vessels.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Recidiva Local de Neoplasia/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Hepatectomia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Análise de Sobrevida
10.
Br J Cancer ; 87(6): 630-4, 2002 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-12237773

RESUMO

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Fluoruracila/uso terapêutico , Dosagem de Genes , Transativadores/genética , Biomarcadores , Quimioterapia Adjuvante , Deleção Cromossômica , Primers do DNA/química , DNA de Neoplasias/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais/genética , Proteína Smad4 , Taxa de Sobrevida , Fator de Crescimento Transformador beta/genética
11.
Eur J Cancer ; 37(14): 1729-35, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11549425

RESUMO

We previously showed that patients with newly diagnosed colon cancer change the internal standards on which they base their quality of life estimation. In the present investigation, we explored whether this response shift similarly affects the perception of health for utility evaluation in cancer clinical trials. After radical resection of adenocarcinoma of the colon (pT1-4 pN>0 M0 and pT3-4 pN0 M0) and perioperative chemotherapy, patients were randomised to three treatment arms: observation only (A), 5-fluorouracil (5-FU) 450 mg/m(2) plus levamisol (B), or 5-FU 600 mg/m(2) (C). Subjective health was assessed by a linear analogue self-assessment (LASA) scale anchored at 'perfect health-worst health' developed for serial assessment of utility values (Hürny C, van Wegberg B, Bacchi M, et al. Subjective health estimations (SHE) in patients with advanced breast cancer: an adapted utility concept for clinical trials. Br J Cancer 1998, 77, 985-991). Patients estimated their pre-surgery health among various quality of life indicators both before surgery and retrospectively thereafter, and their pre-adjuvant health both at the beginning of randomly assigned chemotherapy or observation and retrospectively approximately 2 months later. Thereafter, current subjective health was assessed. Paired t-tests were used to test the hypotheses of no change. Patients' estimated pre-surgery health was worse after surgery than before (n=127, mean change=-6.7, standard deviation (S.D.)=30, P=0.01), and their estimated pre-adjuvant health was worse under treatment or observation than at the beginning (n=132, mean change=-7.1, S.D.=23.8, P=0.001), in agreement with the quality of life indicators. Chemotherapy had no impact on these changes attributed to a response shift. Conventionally assessed changes between the beginning of adjuvant treatment or observation and 2 months later indicated no change in subjective health. Change scores relative to patients' retrospective estimation revealed an improvement (n=122, mean change=6.6, S.D.=24.8, P=0.004) in this period. Patients with colon cancer substantially reframe their internal standard of health as they do for quality of life. This explorative finding questions the assumption, generally made in decision models, that health estimates for utility evaluation are independent of time. Given that patients may change their standards, comparisons of health estimates across different populations and clinical situations are to be interpreted with caution.


Assuntos
Adenocarcinoma/psicologia , Neoplasias do Colo/psicologia , Indicadores Básicos de Saúde , Qualidade de Vida , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Atitude Frente a Saúde , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Feminino , Fluoruracila/uso terapêutico , Humanos , Levamisol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Suíça
12.
Obes Res ; 9(9): 535-43, 2001 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11557834

RESUMO

OBJECTIVE: Insulin resistance is closely associated with two disparate aspects of lipid storage: the intracellular lipid content of skeletal muscle and the magnitude of central adipose beds. Our aim was to determine their relative contribution to impaired insulin action. RESEARCH METHODS AND PROCEDURES: Eighteen older (56 to 75 years of age) men were studied before elective knee surgery. Insulin sensitivity (M/Delta I) was determined by hyperinsulinemic-euglycemic clamp. Central abdominal fat (CF) was assessed by DXA. Skeletal muscle was excised at surgery and assayed for content of metabolically active long-chain acyl-CoA esters (LCAC). RESULTS: Significant inverse relationships were observed between LCAC and M/Delta I (R(2) = 0.34, p = 0.01) and between CF and M/Delta I (R(2) = 0.38, p = 0.006), but not between CF and LCAC (R(2) = 0.0005, p = 0.93). In a multiple regression model (R(2) = 0.71, p < 0.0001), both CF (p = 0.0006) and LCAC (p = 0.0009) were independent statistical predictors of M/Delta I. Leptin levels correlated inversely with M/Delta I (R(2) = 0.60, p = 0.0002) and positively with central (R(2) = 0.41, p = 0.006) and total body fat (R(2) = 0.63, p = 0.0001). DISCUSSION: The mechanisms by which altered lipid metabolism in skeletal muscle influences insulin action may not be related directly to those linking central fat and insulin sensitivity. In particular, it is unlikely that muscle accumulation of lipids directly derived from labile central fat depots is a principal contributor to peripheral insulin resistance. Instead, our results imply that circulating factors, other than nonesterified fatty acids or triglyceride, mediate between central fat depots and skeletal muscle tissue. Leptin was not exclusively associated with central fat, but other factors, secreted specifically from central fat cells, could modulate muscle insulin sensitivity.


Assuntos
Acil Coenzima A/metabolismo , Insulina/farmacologia , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Absorciometria de Fóton , Tecido Adiposo/anatomia & histologia , Tecido Adiposo/metabolismo , Idoso , Composição Corporal , Ésteres , Técnica Clamp de Glucose , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Triglicerídeos/metabolismo
13.
Gastroenterology ; 121(2): 435-9, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11487553

RESUMO

Bloom's syndrome (BS) is a rare recessive disorder caused by germline mutation of the BLM gene. Individuals with BS manifest growth retardation, immunodeficiency, and a predisposition to cancer. In this report, we describe an individual with BS and multiple colonic adenomas reminiscent of familial adenomatous polyposis coli (FAP). Molecular studies revealed APC mutations in 4 of 6 adenomas, including 2 adenomas with the identical APC mutation and microsatellite instability in 1 of 6 adenomas. These results demonstrate similar pathways to colorectal neoplasia in BS as in the normal population and suggest that individuals with BS may be particularly susceptible to colorectal neoplasia.


Assuntos
Adenoma/patologia , Síndrome de Bloom/patologia , Neoplasias do Colo/patologia , Adenoma/etiologia , Adenoma/genética , Adulto , Síndrome de Bloom/complicações , Síndrome de Bloom/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , Humanos , Masculino , Repetições de Microssatélites
15.
Ann Surg Oncol ; 8(6): 519-24, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11456051

RESUMO

BACKGROUND: The goals of this study were to assess the feasibility and toxicity of a regimen of preoperative chemoradiotherapy, surgery, and intraoperative radiotherapy in the treatment of patients with potentially resectable gastric cancer. A secondary objective was to assess pathologic response to chemoradiotherapy in the treated tumors. METHODS: Twenty-four patients were entered in the protocol. Treatment regimen consisted of 45 Gy of external beam radiotherapy with concurrent 5-FU given as a continuous infusion at a dose of 300 mg/m2. Patients were restaged 4-6 weeks after chemoradiotherapy and then underwent surgical resection and intraoperative radiotherapy to a dose of 10 Gy. RESULTS: Twenty-three patients (96%) completed chemoradiotherapy in accordance with the study protocol. Nineteen (83%) of 23 patients who completed chemoradiotherapy underwent surgical resection with D2 lymphadenectomy. Four patients (17%) had progressive disease and were not resected. The morbidity and mortality rates were 32% and 5%, respectively. Of the resected patients, two (11%) had complete pathologic responses while 12 (63%) had pathologic evidence of significant treatment effect. CONCLUSIONS: Preoperative chemoradiotherapy for gastric cancer can be delivered safely and is well tolerated. The rate of surgical complications is consistent with that of other recently reported prospective trials of gastrectomy alone. Preoperative chemoradiotherapy resulted in significant pathologic responses in the majority of treated tumors, and complete pathologic responses were achieved in some patients.


Assuntos
Adenocarcinoma/terapia , Neoplasias Gástricas/terapia , Adenocarcinoma/patologia , Adulto , Idoso , Quimioterapia Adjuvante/efeitos adversos , Estudos de Viabilidade , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Gastrectomia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Projetos Piloto , Radioterapia Adjuvante/efeitos adversos , Neoplasias Gástricas/patologia , Resultado do Tratamento
16.
Genes Chromosomes Cancer ; 31(3): 240-7, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11391794

RESUMO

Deletions of chromosome band 18q21 appear with very high frequency in a variety of carcinomas, especially in colorectal cancer. Potent tumor suppressor genes located in this region encode transforming growth factor beta (TGF-beta) signal transducers SMAD2 and SMAD4, and inactivation of either one leads to impaired TGF-beta-mediated cell growth/apoptosis. Following the assignment of SMAD7 to 18q21, we first refined the SMAD7 gene position within this region by genetically mapping SMAD7 between SMAD2 and SMAD4. Further, to compare the respective frequencies of genetic alterations of these three SMAD genes in colorectal cancer, we undertook a large-scale evaluation of the copy status of each of these genes on DNA samples from colorectal tumor biopsy material. Among a subset of 233 DNA samples for which data were available for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed high deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was deleted in only 48% of the tumors. Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4-7%). Compiled data for SMAD genes in each tumor show that the most common combination (26% of all the tumors) consists of the simultaneous deletions of SMAD2 and SMAD4 associated with normal diploidy or even duplication of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF-beta signaling, we hypothesize that the tumor might not benefit from simultaneous SMAD7 inactivation, thereby exerting selective pressure to retain or even to duplicate the SMAD7 gene.


Assuntos
Cromossomos Humanos Par 18/genética , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Dosagem de Genes , Transativadores/genética , Deleção Cromossômica , Mapeamento Cromossômico , Ordem dos Genes , Homologia de Genes/genética , Genes Supressores de Tumor/genética , Humanos , Transdução de Sinais/genética , Proteína Smad2 , Proteína Smad4 , Proteína Smad7 , Fator de Crescimento Transformador beta/genética
19.
J Clin Endocrinol Metab ; 85(11): 4293-7, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11095470

RESUMO

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation in adipose tissue is known to regulate genes involved in adipocyte differentiation and lipid metabolism. However, the role of PPAR-gamma in muscle remains unclear. To examine the potential regulation of genes by PPAR-gamma in human skeletal muscle, we used semiquantitative RT-PCR to determine the expression of PPAR-gamma, lipoprotein lipase (LPL), muscle carnitine palmitoyl transferase-1 (mCPT1), fatty acid-binding protein (FABP), carnitine acylcarnitine transferase (CACT), and glucose transporter-4 (GLUT4) in freeze-dried muscle samples from 14 male subjects. These samples were dissected free of adipose and other tissue contamination, as confirmed by minimal or absent adipsin expression. Between individuals, the messenger ribonucleic acid concentration of PPAR-gamma varied up to 3-fold, whereas LPL varied up to 6.5-fold, mCPT1 13-fold, FABP 4-fold, CACT 4-fold, and GLUT4 up to 3-fold. The expression of LPL (r2 = 0.54; P = 0.003), mCPT1 (r2 = 0.42; P = 0.012), and FABP (r2 = 0.324; P = 0.034) all correlated significantly with PPAR-gamma expression in the same samples. No significant correlation was observed between the expression of CACT and PPAR-gamma or between GLUT4 and PPAR-gamma. These findings demonstrate a relationship between PPAR-gamma expression and the expression of other genes of lipid metabolism in muscle and support the hypothesis that PPAR-gamma activators such as the antidiabetic thiazolidinediones may regulate fatty acid metabolism in skeletal muscle as well as in adipose tissue.


Assuntos
Carnitina Aciltransferases/genética , Proteínas de Transporte/genética , Regulação da Expressão Gênica , Lipase Lipoproteica/genética , Proteínas de Transporte de Monossacarídeos/genética , Proteínas Musculares , Músculo Esquelético/metabolismo , Proteínas de Neoplasias , Receptores Citoplasmáticos e Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Supressoras de Tumor , Idoso , Glicemia/metabolismo , Fator D do Complemento , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos não Esterificados/sangue , Transportador de Glucose Tipo 4 , Humanos , Insulina/sangue , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/genética , Valores de Referência , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue
20.
Med Clin North Am ; 84(3): 749-59, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10872430

RESUMO

Pancreatic cancer continues to be a leading cause of cancer death in the United States. Seven genetic syndromes are now known to be associated with an increased incidence of pancreatic cancer. Other familial forms of pancreatic cancer exist although the genetic basis for this predisposition remains elusive. The similarities in the genetic and clinical manifestations of the sporadic and familial forms of pancreatic cancer suggest that pretreatment staging and management of patients with established pancreatic cancer should be similar. For carcinomas of the pancreatic head, pancreaticoduodenectomy should be performed according to current surgical practice, whereas the use of total pancreatectomy should be limited to cases in which margins are found to be positive or if the anatomy precludes a safe pancreaticojejunostomy. Total pancreatectomy may be considered in high-risk kindreds who strongly desire prophylactic surgery and in those with premalignant lesions. Identification of the precise genetic basis for inherited pancreatic cancer will someday make it possible to examine scientifically the effectiveness of specific management strategies.


Assuntos
Adenocarcinoma/genética , Predisposição Genética para Doença/genética , Pancreatectomia , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Síndrome
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