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1.
Clin Radiol ; 79(1): 33-40, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38008662

RESUMO

Median sternotomy is widely recognised as the primary incision technique in cardiac surgery. This surgical procedure involves dividing the sternum to gain access to the heart and lungs, making it invaluable in correcting congenital heart defects. Furthermore, it is frequently employed in adult patients, particularly during coronary artery bypass graft (CABG) procedures. In this imaging review, we present a comprehensive overview of the pre-procedural assessment and various post-sternotomy complications encountered within our clinical experience at a tertiary cardiothoracic centre. The focus of this review is to outline the imaging features associated with mediastinal adhesions and establish the minimal safe distance between the sternum and common mediastinal structures when considering re-sternotomy. By providing visual examples, we aim to facilitate a better understanding of these key concepts. Moreover, we delve into a detailed discussion of a spectrum of postoperative complications that may arise following median sternotomy including those related to metalwork (sternal wire fracture), bone (sternal dehiscence, non-union and osteomyelitis), and soft tissue (abscess, haematoma).


Assuntos
Esternotomia , Deiscência da Ferida Operatória , Adulto , Humanos , Esternotomia/efeitos adversos , Esternotomia/métodos , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/cirurgia , Esterno/diagnóstico por imagem , Esterno/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Radiologistas
2.
Cancer Epidemiol ; 86: 102433, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37531729

RESUMO

OBJECTIVE: To provide updated estimates of childhood cancer incidence and survival in Aotearoa, New Zealand. METHOD: Registrations for children under the age of 15 years diagnosed with cancer between 2010 and 2019 were extracted from the New Zealand Children's Cancer Registry. Cases were stratified by age, sex, prioritised ethnicity (Maori, Pacific peoples, and non-Maori) and cancer type. Age-standardised incidence rates (ASRs) per million person years and observed survival rates were calculated. RESULTS: During the study period, 1522 children were diagnosed with cancer providing an ASR of 169.1 per million per year (95 % Confidence Interval, CI: 157.0-181.2). For all childhood cancers combined, survival at 5-years was 85.6 % (95 % CI 83.7-87.3). There was a gap in 5-year survival between Maori (80.9 %, 95 % CI 76.5-84.6), Pacific peoples (82.6 %, 95 % CI 75.6-87,7) and Non-Maori (87.8 %, 95 % CI 85.6-89.7) In both adjusted and unadjusted models, this difference in survival was most marked (p < 0.05) among children who were 10-14 years of age at diagnosis. CONCLUSION: Childhood cancer incidence and survival rates in Aotearoa, New Zealand remain comparable to other high-income countries. Further research is required to understand the survival difference between ethnic groups.


Assuntos
Neoplasias , Criança , Humanos , Adolescente , Nova Zelândia/epidemiologia , Incidência , Povo Maori , Etnicidade
3.
Tech Coloproctol ; 26(12): 941-952, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35588336

RESUMO

BACKGROUND: The effectiveness of laparoscopic ventral mesh rectopexy (LVMR) in patients with defecatory disorders secondary to internal rectal prolapse is poorly evidenced. A UK-based multicenter randomized controlled trial was designed to determine the clinical efficacy of LVMR compared to controls at medium-term follow-up. METHODS: The randomized controlled trial was conducted from March 1, 2015 TO January 31, 2019. A stepped-wedge RCT design permitted observer-masked data comparisons between patients awaiting LVMR (controls) with those who had undergone surgery. Adult participants with radiologically confirmed IRP refractory to conservative treatment were randomized to three arms with different delays before surgery. Efficacy outcome data were collected at equally stepped time points (12, 24, 36, 48, 60, and 72 weeks). Clinical efficacy of LVMR compared to controls was defined as ≥ 1.0-point reduction in Patient Assessment of Constipation-Quality of Life and/or Symptoms (PAC-QOL and/or PAC-SYM) scores at 24 weeks. Secondary outcome measures included 14-day diary data, the Generalized Anxiety Disorder scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), St Marks incontinence score, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), the chronic constipation Behavioral Response to Illness Questionnaire (CC-BRQ), and the Brief Illness Perception Questionnaire (BIPQ). RESULTS: Of a calculated sample size of 114, only 28 patients (100% female) were randomized from 6 institutions (due mainly to national pause on mesh-related surgery). Nine were assigned to the T0 arm, 10 to T12, and 9 to T24. There were no substantial differences in baseline characteristics between the three arms. Compared to baseline, significant reduction (improvement) in PAC-QOL and PAC-SYM scores were observed at 24 weeks post-surgery (- 1.09 [95% CI - 1.76, - 0.41], p = 0.0019, and - 0.92 [- 1.52, - 0.32], p = 0.0029, respectively) in the 19 patients available for analysis (9 were excluded for dropout [n = 2] or missing primary outcome [n = 7]). There was a clinically significant long-term reduction in PAC-QOL scores (- 1.38 [- 2.94, 0.19], p = 0.0840 at 72 weeks). Statistically significant improvements in PAC-SYM scores persisted to 72 weeks (- 1.51 [- 2.87, - 0.16], p = 0.0289). Compared to baseline, no differences were found in secondary outcomes, except for significant improvements at 24 and 48 weeks on CC-BRQ avoidance behavior (- 14.3 [95% CI - 23.3, - 5.4], and - 0.92 [- 1.52, - 0.32], respectively), CC-BRQ safety behavior (- 13.7 [95% CI - 20.5, - 7.0], and - 13.0 [- 19.8, - 6.1], respectively), and BIPQ negative perceptions (- 16.3 [95% CI - 23.5, - 9.0], and - 10.5 [- 17.9, - 3.2], respectively). CONCLUSIONS: With the caveat of under-powering due to poor recruitment, the study presents the first randomized trial evidence of short-term benefit of LVMR for internal rectal prolapse. TRIAL REGISTRATION: ISRCTN Registry (ISRCTN11747152).


Assuntos
Laparoscopia , Prolapso Retal , Adulto , Humanos , Feminino , Masculino , Prolapso Retal/complicações , Prolapso Retal/cirurgia , Prolapso Retal/diagnóstico , Qualidade de Vida , Telas Cirúrgicas , Laparoscopia/efeitos adversos , Constipação Intestinal/cirurgia , Constipação Intestinal/complicações , Resultado do Tratamento , Doença Crônica
4.
Clin Oncol (R Coll Radiol) ; 29(7): 421-428, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28202212

RESUMO

INTRODUCTION: This study reports long-term patient reported urinary function and urinary-related quality of life (uQoL) after external beam radiotherapy (EBRT) for localized prostate cancer. METHODS: 574 men underwent definitive prostate EBRT to 70-78 Gy±androgen deprivation therapy between 2000 and 2009. The median follow-up from EBRT was 44 months. Patients were evaluated at baseline (pre-EBRT) and at intervals post-treatment using the International Prostate Symptom Score (IPSS) instrument. RESULTS: Patients with mild IPSS at baseline (total 0-7) reported median total scores of 3, 4 and 3 at baseline, 6 and 48 months respectively post-EBRT. For patients with moderate IPSS at baseline (total 8-19), median total IPSS was 12 at baseline and 9 at both 6 and 48 months. For the severe IPSS group at baseline (total 20-35), the median total IPSS was 24, 12 and 14 at baseline, 6 and 48 months post-EBRT. The cumulative risk of persistent IPSS increase (greater than 5 points above baseline) at 48 months was 16%, 10% and 6% for patients with mild, moderate and severe baseline IPSS respectively. 94%, 54% and 11% of patients with mild, moderate and severe baseline IPSS reported good uQoL at baseline respectively, with these proportions increasing to 95%, 83% and 69% at 48 months. CONCLUSION: Urinary symptoms and uQoL as measured by the IPSS instrument remained stable or improved for the majority of men after definitive EBRT with or without ADT for prostate cancer. This was especially notable for the group of men with worse baseline symptoms or uQoL, with risk of persistent worsening of urinary symptoms decreasing with higher baseline IPSS category. Understanding the expected pattern of urinary symptoms and related uQoL in the months and years following EBRT taking into account baseline urinary function is highly valuable for counselling men as part of the therapeutic decision-making process.


Assuntos
Neoplasias da Próstata/radioterapia , Qualidade de Vida/psicologia , Transtornos Urinários/etiologia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Tempo
5.
J Crohns Colitis ; 11(12): 1456-1462, 2017 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25311864

RESUMO

BACKGROUND AND AIMS: Outcomes of cessation of anti-TNF therapy for Crohn's disease (CD) in clinical and/or endoscopic remission in routine clinical practice is uncertain. This study aimed to evaluate clinical outcomes and factors associated with relapse in CD patients following formal disease assessment and elective anti-TNF withdrawal. METHODS: Prospective observational study of CD patients in whom anti-TNF therapy was stopped electively after ≥12months and follow-up of ≥6months. Investigations at assessment prior to cessation included ≥1 of clinical assessment, endoscopic and/or imaging. Relapse was defined as recurrent symptoms of CD requiring medical or surgical therapy. RESULTS: Eighty-six patients received anti-TNF for a median duration of 23 (12-80) months for severe active luminal (70%), fistulating perianal (25.5%) and other fistulating disease (4.5%). Relapse rates at 90,180 and 365days were 4.7%, 18.6% and 36%, respectively. If anti-TNF dose escalation occurred 6months prior to withdrawal, 88% (7/8) relapsed. Based on multivariate analysis, risk factors for relapse include ileocolonic disease at diagnosis and previous anti-TNF therapy. An elevated faecal calprotectin (FC) is likely to predict relapse (p=0.02), with a PPV of 66.7% at >50µg/g. Of 36 patients who relapsed, 31 were retreated with anti-TNF, with an overall recapture rate of 93%. CONCLUSION: Relapse rates at 1year following elective withdrawal of anti-TNF are 36%, with high retreatment response rate. Predictors of relapse include ileocolonic involvement, previous anti-TNF therapy and raised FC. Endoscopic/radiologic assessment prior to cessation of therapy does not appear to predict those at lower risk of relapse.


Assuntos
Adalimumab/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Doença de Crohn/tratamento farmacológico , Infliximab/uso terapêutico , Suspensão de Tratamento , Adolescente , Adulto , Idoso , Criança , Colo , Colonoscopia , Doença de Crohn/diagnóstico por imagem , Fezes/química , Feminino , Seguimentos , Humanos , Íleo , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Indução de Remissão , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
6.
Vasc Endovascular Surg ; 49(8): 220-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26574485

RESUMO

A pilot randomized controlled trial that evaluated the effect of remote ischemic preconditioning (RIPC) on clinical outcomes following major vascular surgery was performed. Eligible patients were those scheduled to undergo open abdominal aortic aneurysm repair, endovascular aortic aneurysm repair, carotid endarterectomy, and lower limb revascularization procedures. Patients were randomized to RIPC or to control groups. The primary outcome was a composite clinical end point comprising any of cardiovascular death, myocardial infarction, new-onset arrhythmia, cardiac arrest, congestive cardiac failure, cerebrovascular accident, renal failure requiring renal replacement therapy, mesenteric ischemia, and urgent cardiac revascularization. Secondary outcomes were components of the primary outcome and myocardial injury as assessed by serum troponin values. The primary outcome occurred in 19 (19.2%) of 99 controls and 14 (14.1%) of 99 RIPC group patients (P = .446). There were no significant differences in secondary outcomes. Our trial generated data that will guide future trials. Further trials are urgently needed.


Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Doenças das Artérias Carótidas/cirurgia , Antebraço/irrigação sanguínea , Precondicionamento Isquêmico/métodos , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/cirurgia , Procedimentos Cirúrgicos Vasculares , Idoso , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/mortalidade , Implante de Prótese Vascular , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/mortalidade , Endarterectomia das Carótidas , Procedimentos Endovasculares , Feminino , Humanos , Irlanda , Precondicionamento Isquêmico/efeitos adversos , Precondicionamento Isquêmico/mortalidade , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Projetos Piloto , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/prevenção & controle , Estudos Prospectivos , Fluxo Sanguíneo Regional , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Procedimentos Cirúrgicos Vasculares/mortalidade
7.
Sci Rep ; 3: 2792, 2013 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-24077328

RESUMO

Dystroglycan is frequently lost in adenocarcinoma, but the mechanisms and consequences are poorly understood. We report an analysis of ß-dystroglycan in prostate cancer in human tissue samples and in LNCaP cells in vitro. There is progressive loss of ß-dystroglycan immunoreactivity from basal and lateral surfaces of prostate epithelia which correlates significantly with increasing Gleason grade. In about half of matched bone metastases there is significant dystroglycan re-expression. In tumour tissue and in LNCaP cells there is also a tyrosine phosphorylation-dependent translocation of ß-dystroglycan to the nucleus. Analysis of gene expression data by microarray, reveals that nuclear targeting of ß-dystroglycan in LNCaP cells alters the transcription of relatively few genes, the most unregulated being the transcription factor ETV1. These data suggest that proteolysis, tyrosine phosphorylation and translocation of dystroglycan to the nucleus resulting in altered gene transcription could be important mechanisms in the progression of prostate cancer.


Assuntos
Androgênios/farmacologia , Núcleo Celular/metabolismo , Distroglicanas/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Distroglicanas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Ácido Mirístico/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Transporte Proteico/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos
8.
Leukemia ; 27(7): 1497-503, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23407458

RESUMO

Children with acute lymphoblastic leukemia (ALL) and high minimal residual disease (MRD) levels after initial chemotherapy have a poor clinical outcome. In this prospective, single arm, Phase 2 trial, 111 Dutch and Australian children aged 1-18 years with newly diagnosed, t(9;22)-negative ALL, were identified among 1041 consecutively enrolled patients as high risk (HR) based on clinical features or high MRD. The HR cohort received the AIEOP-BFM (Associazione Italiana di Ematologia ed Oncologia Pediatrica (Italy)-Berlin-Frankfurt-Münster ALL Study Group) 2000 ALL Protocol I, then three novel HR chemotherapy blocks, followed by allogeneic transplant or chemotherapy. Of the 111 HR patients, 91 began HR treatment blocks, while 79 completed the protocol. There were 3 remission failures, 12 relapses, 7 toxic deaths in remission and 10 patients who changed protocol due to toxicity or clinician/parent preference. For the 111 HR patients, 5-year event-free survival (EFS) was 66.8% (±5.5) and overall survival (OS) was 75.6% (±4.3). The 30 patients treated as HR solely on the basis of high MRD levels had a 5-year EFS of 63% (±9.4%). All patients experienced grade 3 or 4 toxicities during HR block therapy. Although cure rates were improved compared with previous studies, high treatment toxicity suggested that novel agents are needed to achieve further improvement.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/administração & dosagem , Asparaginase/efeitos adversos , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Prospectivos , Indução de Remissão , Fatores de Risco , Transplante Homólogo , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
9.
Prostate ; 73(4): 398-408, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22996647

RESUMO

BACKGROUND: Dystroglycan is a ubiquitously expressed cell adhesion molecule frequently found to be altered or reduced in adenocarcinomas, however the mechanisms or consequences of dystroglycan loss have not been studied extensively. METHODS: We examined the consequence of overexpression or RNAi depletion of dystroglycan on properties of in vitro growth migration and invasion of LNCaP, PC3, and DU145 prostate cancer cell lines. RESULTS: Using LNCaP cells we observed cell density-dependent changes in ß-dystroglycan with the appearance of several lower molecular weight species ranging in size from 43 to 26 kDa. The bands of 31 and 26 kDa were attributed to proteolysis, whereas bands between 43 and 38 kDa were a consequence of mis-glycosylation. The localization of ß-dystroglycan in LNCaP colonies in culture also varied, cells with a mesenchymal appearance at the periphery of the colony had more pronounced membrane localization of dystroglycan. Whereas some cells demonstrated nuclear dystroglycan. Increased dystroglycan levels were inhibitory to growth in soft agar but promoted Matrigel invasion, whereas reduced dystroglycan levels promoted growth in soft agar but inhibited invasion. Similar results were also obtained for PC3 and DU145 cells. CONCLUSIONS: This study suggests that changes in ß-dystroglycan distribution within the cell and/or the loss of dystroglycan during tumorigenesis, through a combination of proteolysis and altered glycosylation, leads to an increased ability to grow in an anchorage independent manner, however dystroglycan may need to be re-expressed for cell invasion and metastasis to occur.


Assuntos
Distroglicanas/fisiologia , Invasividade Neoplásica/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/fisiopatologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Masculino , Neoplasias da Próstata/fisiopatologia , Células Tumorais Cultivadas
10.
Br J Cancer ; 107(5): 800-7, 2012 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-22850554

RESUMO

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Modelos Estatísticos , Receptor ErbB-2/biossíntese , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Adulto Jovem
11.
Br J Surg ; 96(12): 1484-91, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19918856

RESUMO

BACKGROUND: Angiogenesis plays an essential role in tissue repair. Vascular endothelial growth factor (VEGF) mediates angiogenesis through receptor kinases VEGF-R1 and VEGF-R2, and co-receptors, neuropilins Np1 and Np2. This study examined the spatial and temporal expression of these factors in relation to angiogenesis in surgical wounds. METHODS: Scar biopsies were obtained from patients between 3 days and 2 years after surgery. Normal skin control biopsies were taken during surgery. Microvessel density (MVD) was quantified using a Chalkley grid. VEGF, VEGF-R1, VEGF-R2, Np1 and Np2 endothelial expression was determined by immunohistochemistry, and correlated with MVD and scar age. RESULTS: Cumulative MVD was significantly greater in scars than controls (P = 0.011), and was related to scar age (P = 0.007). Expression of VEGF, VEGF-R2, Np1 and Np2 was increased significantly in all scars and correlated with MVD. In contrast, scar VEGF-R1 expression was decreased, and correlated with increased VEGF and VEGF-R2. CONCLUSION: Levels of VEGF, VEGF-R2, Np1 and Np2 are increased, whereas VEGF-R1 expression is decreased in angiogenesis, suggesting a role for VEGF-receptor complexes in early wound healing. This altered protein expression and increased presence of vessels is prolonged, suggesting that structural remodelling continues for at least 2 years after surgery.


Assuntos
Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Doenças Mamárias/metabolismo , Doenças Mamárias/patologia , Cicatriz/metabolismo , Cicatriz/patologia , Feminino , Humanos , Imuno-Histoquímica , Microcirculação/fisiologia , Neuropilinas/metabolismo , Variações Dependentes do Observador , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/fisiologia
12.
Br J Cancer ; 101(10): 1692-8, 2009 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-19861963

RESUMO

INTRODUCTION: The tumour microenvironment is hypoglycaemic, hypoxic and acidotic. This activates a stress signalling pathway: the unfolded protein response (UPR). The UPR is cytoprotective if the stressor is mild, but may initiate apoptosis if severe.Activation of the UPR in breast carcinoma is induced by microenvironmental stress such as glucose and oxygen deprivation, but may also be linked to oestrogen stimulation. It may be clinically significant as it may alter chemosensitivity to doxorubicin. METHODS: 395 human breast adenocarcinomas were immunohistochemically stained for UPR activation markers (glucose-regulated protein (GRP-78 and XBP-1). A model of UPR activation in vitro by glucose deprivation of T47D breast cancer cells was developed to determine how the UPR affects cellular sensitivity to doxorubicin and 5-fluorouracil. Cytotoxicity was assessed using a colorimetric cytotoxicity assay (MTT). The effect of oestrogen stimulation and tamoxifen exposure on UPR activation by T47D cells was determined by western blotting measurement of the key UPR protein, GRP-78. RESULTS: Expression of GRP78 and XBP-1 was demonstrated in 76% and 90% of the breast cancers, respectively, and correlated with oestrogen receptor positivity (P=0.045 and 0.017, respectively). In vitro UPR activation induced resistance to both doxorubicin and 5-flurouracil, (P<0.05). Oestrogen stimulation induced GRP78 and XBP1 over-expression on western blotting. Tamoxifen did not block this response and may induce UPR activation in its own right. CONCLUSIONS: The UPR is activated in the majority of breast cancers and confers resistance to chemotherapy. In vitro oestrogen stimulates UPR induction. UPR activation may contribute to breast cancer chemoresistance and interact with oestrogen response elements.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias da Mama/metabolismo , Resposta a Proteínas não Dobradas , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Chaperona BiP do Retículo Endoplasmático , Moduladores de Receptor Estrogênico/farmacologia , Feminino , Glucose/genética , Glucose/metabolismo , Humanos , Imuno-Histoquímica , Tamoxifeno/farmacologia
13.
Gene Ther ; 16(12): 1452-64, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19657370

RESUMO

X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency with absent phagocyte NADPH-oxidase activity caused by defects in the gene-encoding gp91(phox). Here, we evaluated strategies for less intensive conditioning for gene therapy of genetic blood disorders without selective advantage for gene correction, such as might be used in a human X-CGD protocol. We compared submyeloablative with ablative irradiation as conditioning in murine X-CGD, examining engraftment, oxidase activity and vector integration in mice transplanted with marrow transduced with a gamma-retroviral vector for gp91(phox) expression. The frequency of oxidase-positive neutrophils in the donor population was unexpectedly higher in many 300 cGy-conditioned mice compared with lethally irradiated recipients, as was the fraction of vector-marked donor secondary CFU-S12. Vector integration sites in marrow, spleen and secondary CFU-S12 DNA from primary recipients were enriched for cancer-associated genes, including Evi1, and integrations in or near cancer-associated genes were more frequent in marrow and secondary CFU-S12 from 300 cGy-conditioned mice compared with fully ablated mice. These findings support the concept that vector integration can confer a selection bias, and suggest that the intensity of the conditioning regimen may further influence the effects of vector integration on clonal selection in post-transplant engraftment and hematopoiesis.


Assuntos
Medula Óssea/efeitos da radiação , Técnicas de Transferência de Genes , Vetores Genéticos , Doença Granulomatosa Crônica/terapia , Hematopoese , Retroviridae/genética , Condicionamento Pré-Transplante/métodos , Animais , Feminino , Doença Granulomatosa Crônica/genética , Transplante de Células-Tronco Hematopoéticas , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidase 2 , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Neoplasias/genética , Neutrófilos/metabolismo , Células-Tronco , Transdução Genética , Integração Viral
14.
Br J Cancer ; 101(4): 666-72, 2009 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-19623180

RESUMO

BACKGROUND: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown. METHODS: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens. RESULTS: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01). CONCLUSIONS: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.


Assuntos
Neoplasias da Mama/patologia , Neovascularização Patológica/patologia , Lesões Pré-Cancerosas/patologia , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Proliferação de Células , Células Endoteliais/metabolismo , Feminino , Humanos , Hiperplasia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Imuno-Histoquímica , Neovascularização Patológica/metabolismo , Lesões Pré-Cancerosas/metabolismo , Prognóstico , Tromboplastina/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese
15.
Histopathology ; 53(5): 561-6, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18983465

RESUMO

AIMS: Dystroglycan is an important structural and signalling protein that is expressed in most human cells. alpha-Dystroglycan has been investigated and found to be reduced in human cancers, but there is only one published study on the expression of beta-dystroglycan in human cancer and that was only on small numbers of breast and prostatic cancers. The aim was to conduct a comprehensive immunohistochemical survey of the expression of beta-dystroglycan in normal human tissues and common cancers. METHODS AND RESULTS: Triplicate tissue microarrays of 681 samples of normal human tissues and common cancers were stained using an antibody directed against the cytoplasmic component of beta-dystroglycan. beta-Dystroglycan was strongly expressed at the intercellular junctions and basement membranes of all normal human epithelia. Expression of beta-dystroglycan was absent or markedly reduced in 100% of oesophageal adenocarcinomas, 97% of colonic cancers, 100% of transitional cell carcinomas of the urothelium and 94% of breast cancers. In the breast cancers, the only tumours that showed any retention of beta-dystroglycan expression were small low-grade oestrogen receptor-positive tumours. The only cancers that showed retention of beta-dystroglycan expression were cutaneous basal cell carcinomas. CONCLUSIONS: There is loss or marked reduction of beta-dystroglycan expression (by immunohistochemistry) in the vast majority of human cancers surveyed. Since beta-dystroglycan is postulated to have a tumour suppressor effect, this loss may have important functional significance.


Assuntos
Carcinoma/metabolismo , Distroglicanas/metabolismo , Linhagem Celular Tumoral , Epitélio/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Modelos Biológicos , Análise Serial de Tecidos
16.
Gene Ther ; 15(18): 1294-8, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18580967

RESUMO

Research in gene therapy involving genome-integrating vectors now often includes analysis of vector integration sites across the genome using methods such as ligation-mediated PCR (LM-PCR) or linear amplification-mediated PCR (LAM-PCR). To help researchers analyze these sites and the functions of nearby genes, we have developed SeqMap (http://seqmap.compbio.iupui.edu/) a secure, web-based comprehensive vector integration site management tool that automatically analyzes and annotates large numbers of vector integration sites derived from LM-PCR experiments in human and model organisms upon a common genome database. We believe the use of this resource will enable better reproducibility and understanding of this important data.


Assuntos
Mapeamento Cromossômico/métodos , Terapia Genética , Integrases/genética , Internet , Integração Viral/genética , Animais , Bases de Dados Genéticas , Genoma , Humanos , Reação em Cadeia da Polimerase/métodos , Pesquisa , Retroviridae/genética , Software
17.
Colorectal Dis ; 10(9): 891-7, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18355372

RESUMO

OBJECTIVE: A prospective technical feasibility study of cap assisted ESD for 'curative intent' in patients with residual or local neoplastic recurrence following EMR. Primary end points were second stage R0 resection rate, safety and recurrence. METHOD: Salvage ESD was performed using the Olympus GIF-XQ240 gastroscope and KD-630L insulation tipped knife. Thirty-day mortality, re-admission rates, complications and histological resection status were collected prospectively up to 9 months following index resection. RESULTS: Thirty patients met eligibility criteria. Index R0 resection was achieved in 25/30 (83%) lesions. One patient underwent surgical excision with a second receiving a curative second stage dissection. Ninety-six per cent (29/30) patients were discharged within 24 h of the procedure with a 0% 30-day mortality and re-admission rate. Bleeding occurred in 5/30 (16%) treated successfully with endoluminal haemostasis. There were no perforations. Overall 'cure' rates at short-term follow-up [median 6/12 (range; 3-18)] was 96%. CONCLUSION: This novel application of ESD for first line 'salvage' therapy in treating residual or locally recurrent neoplastic disease may be a safe, minimally invasive and cost effective alternative to direct surgical resection in a select patient cohort.


Assuntos
Carcinoma in Situ/cirurgia , Neoplasias Colorretais/cirurgia , Mucosa Intestinal/cirurgia , Recidiva Local de Neoplasia/cirurgia , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos do Sistema Digestório , Dissecação/métodos , Endoscopia , Endoscopia do Sistema Digestório , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Estudos Prospectivos
18.
Br J Surg ; 95(5): 636-45, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18324640

RESUMO

BACKGROUND: Conventional colonoscopy has a significant false-negative rate for intraepithelial neoplasia. Chromoendoscopy increases sensitivity but lacks specificity. The aim was to assess prospectively the clinical applicability and predictive power of the EC3870CIFK confocal laser endomicroscope (CLE) for the in vivo diagnosis of intraepithelial neoplasia during colonoscopy. METHODS: Lesions were identified using chromoscopy followed by CLE imaging and graded according to vascular and cellular changes. CLE imaging of circumscribed lesions and four segmental 'normal' colorectal quadrants was performed. Targeted biopsy specimens were then compared with histopathological results. RESULTS: Forty patients completed the protocol (22 men and 18 women; median age 62 (range 39-82) years). The median duration of ileal intubation and total procedure time were 12 (range 5-26) and 55 (range 28-92) min respectively. Chromoscopic colonoscopy revealed 162 lesions in 39 patients. CLE imaging was obtained on all 162 lesions. Some 5422 confocal images were compared with 802 targeted biopsy specimens. Intraepithelial neoplasia was predicted with an accuracy of 99.1 per cent (sensitivity 97.4 per cent and specificity 99.3 per cent) (P = 0.711). CONCLUSION: Confocal laser endomicroscopy permits high-quality cellular, subsurface vascular and stromal imaging, enabling prediction of intraepithelial neoplasia with a high level of accuracy.


Assuntos
Colonoscopia/métodos , Neoplasias Colorretais/patologia , Mucosa Intestinal/patologia , Microscopia Confocal/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Estudos Prospectivos , Sensibilidade e Especificidade
19.
Endoscopy ; 40(2): 110-4, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18253905

RESUMO

BACKGROUND AND AIMS: Loss of mucosal 'lift' prior to submucosal dissection or endoscopic mucosal resection (EMR) increases the risk of complications. We conducted a randomized controlled trial comparing dextrose solution with sodium hyaluronic acid (SHA) for the EN BLOC resection of Paris type I/0-II and lateral spreading lesions of the colorectum. PATIENTS AND METHODS: Patients with Paris type I/0-II or lateral spreading tumor lesions of < 30 mm were randomized in a 1 : 1 ratio to undergo EMR using either dextrose solution or SHA. The primary study outcome was complete resection. Secondary outcomes were endoscopic complications (i. e. perforation or bleeding) and polyp recurrence rates. RESULTS: A total of 174 patients were randomized. R0 resection was achieved in 59 of the 82 lesions (72 %) in the dextrose group and 56 of the 81 lesions (69 %) in the SHA group ( P > 0.1), with no significant difference in median lesion diameter ( P > 0.1). The median number of post resection surveillance colonoscopies was 3 (range 2 - 7) in the dextrose group and 4 (range 2 - 6) in the SHA group ( P = NS). The median post index EMR resection follow-up period was 20 months (range 4 - 26) in the DS group and 18 months (range 3 - 22) in the SHA group ( P = NS). Recurrence rates were 1/82 (1.21 %) in the dextrose group and 1/81 (1.23 %) in the SHA group ( P = NS). CONCLUSIONS: EMR using dextrose solution is as effective as SHA in terms of resection completion, recurrence rates, and complications.


Assuntos
Adenoma/cirurgia , Colonoscopia/métodos , Neoplasias Colorretais/cirurgia , Glucose/farmacologia , Ácido Hialurônico/farmacologia , Mucosa Intestinal/cirurgia , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Distribuição de Qui-Quadrado , Neoplasias Colorretais/patologia , Método Duplo-Cego , Feminino , Humanos , Imuno-Histoquímica , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Medição de Risco , Sensibilidade e Especificidade , Resultado do Tratamento
20.
J Clin Pathol ; 61(3): 322-6, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18256118

RESUMO

AIMS: To investigate whether patient opinion about the uses of tissue removed at therapeutic operations has changed since the adverse publicity surrounding the Alder Hey and Bristol Royal Infirmary Inquiries, and to see whether it aligns with the Human Tissue Act 2004. METHODS: A questionnaire was given to 220 postoperative patients in a teaching hospital during an 11 week period. Aggregated responses to each question were ranked in frequency order. Unweighted centroid linkage hierarchical clustering analysis was performed with dendrogram display for the main data on tissue usage. RESULTS: 203 completed questionnaires were collected (compliance rate 92.3%). 96.3% of patients indicated that they would not object to their tissue being used in research, significantly higher than in the 1996 study (89.1%) with no overlap of the 95% CIs. 29.1% of patients believed that the hospital had ownership of tissue once it has been removed during surgery, 23.2% believed they had ownership, 19.7% believed that the pathology laboratory had ownership, and 15.3% believed that nobody had ownership rights in the case of tissue samples. CONCLUSIONS: This new survey indicates that despite a turbulent decade for those involved in human tissue retention in the UK, public support for a wide range of human tissue based activities, especially biomedical research, has not diminished and that patient opinion aligns well with the Human Tissue Act 2004.


Assuntos
Atitude , Pacientes Internados/psicologia , Propriedade , Procedimentos Cirúrgicos Operatórios , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Consentimento Livre e Esclarecido , Legislação Médica , Masculino , Pessoa de Meia-Idade , Pesquisa , Inquéritos e Questionários , Doadores de Tecidos/psicologia , Obtenção de Tecidos e Órgãos/legislação & jurisprudência , Reino Unido
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