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Background and study aims Barrett's esophagus (BE) with low-grade dysplasia (LGD) is considered usually endoscopically invisible and the endoscopic features are not well described. This study aimed to: 1) evaluate the frequency of visible BE-LGD; 2) compare rates of BE-LGD detection in the community versus a Barrett's referral unit (BRU); and 3) evaluate the endoscopic features of BE-LGD. Patients and methods This was a retrospective analysis of a prospectively observed cohort of 497 patients referred to a BRU with dysplastic BE between 2008 and 2022. BE-LGD was defined as confirmation of LGD by expert gastrointestinal pathologist(s). Endoscopy reports, images and histology reports were reviewed to evaluate the frequency of endoscopically identifiable BE-LGD and their endoscopic features. Results A total of 135 patients (27.2%) had confirmed BE-LGD, of whom 15 (11.1%) had visible LGD identified in the community. After BRU assessment, visible LGD was detected in 68 patients (50.4%). Three phenotypes were observed: (A) Non-visible LGD; (B) Elevated (Paris 0-IIa) lesions; and (C) Flat (Paris 0-IIb) lesions with abnormal mucosal and/or vascular patterns with clear demarcation from regular flat BE. The majority (64.7%) of visible LGD was flat lesions with abnormal mucosal and vascular patterns. Endoscopic detection of BE-LGD increased over time (38.7% (2009-2012) vs. 54.3% (2018-2022)). Conclusions In this cohort, 50.4% of true BE-LGD was endoscopically visible, with increased recognition endoscopically over time and a higher rate of visible LGD detected at a BRU when compared with the community. BRU assessment of BE-LGD remains crucial; however, improving endoscopy surveillance quality in the community is equally important.
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BACKGROUND: Comparative gene expression is commonly determined with reference to the expression of a housekeeping gene (HKG), the level of which is assumed to be unregulated. There are little data to date on the effect of disease on the expression of classic HKGs in hepatitis C virus (HCV)-infected human liver. AIMS: To identity HKGs stable across a wide spectrum of disease in human HCV-infected liver. METHODS: ß-Actin, hypoxanthine phosphoribosyltransferase 1 (HPRT1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), splicing factor arginine/serine-rich 4, ß-glucuronidase and 18S ribosomal RNA (18S rRNA) were measured by real-time polymerase chain reaction in liver biopsy tissue. Samples were categorised for inflammation, fibrosis and steatosis, and allocated into groups with mild or severe liver disease. Values were analysed using Spearman's rank correlation, NormFinder, BestKeeper and geNorm programs. RESULTS: All genes performed well in the samples of patients with low disease activity, but HPRT1, ß-actin, GAPDH and 18S rRNA ranked poorly in samples with severe fibrosis or inflammation. CONCLUSIONS: Our results indicate that liver disease affects the expression of common HKGs and that ß-glucuronidase and splicing factor arginine/serine-rich 4 are the most stable HKGs from this group for studies of gene expression in HCV-infected human liver.
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Regulação da Expressão Gênica , Genes Essenciais , Hepatite C Crônica/genética , Fígado/virologia , Adulto , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Perfilação da Expressão Gênica , Glucuronidase/genética , Glucuronidase/metabolismo , Hepacivirus , Hepatite/genética , Hepatite/metabolismo , Hepatite/patologia , Hepatite C Crônica/metabolismo , Hepatite C Crônica/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Masculino , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-ArgininaRESUMO
The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.
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Neoplasias Ósseas/metabolismo , Proteínas de Transporte/metabolismo , Diferenciação Celular/genética , Proteínas de Ligação a DNA/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Osteoblastos/metabolismo , Osteossarcoma/metabolismo , Fatores de Transcrição/metabolismo , Animais , Neoplasias Ósseas/genética , Proteínas de Transporte/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core , Inibidor de Quinase Dependente de Ciclina p27 , Ciclinas/genética , Ciclinas/metabolismo , Proteínas de Ligação a DNA/genética , Retroalimentação Fisiológica/genética , Fase G1/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes cdc/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Células NIH 3T3 , Osteocalcina/metabolismo , Osteossarcoma/genética , Fenótipo , Fosforilação , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Fator de Transcrição AP-2 , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: It has been hypothesised, mainly from studies with animal models of liver disease, that the transport of substrates for metabolic enzymes and their subsequent metabolism and elimination in hepatic bile or blood is co-ordinated, but there is little information on this process in diseased human liver. METHODS: In this study we have measured by reverse transcription polymerase chain reaction (RT-PCR) major genes involved in drug metabolism from UDP-glucuronosyltransferases (UGT1A1, UGT1A6, UGT1A9, and UGT2B4) and cytochrome P450 (CYP) families (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4), transport (OATP-C, MRP2, MRP3, and MDR1) and major transcription factors (PXR, CAR, HNF1alpha, HNF4alpha, RXR, and AHR) involved in their regulation. Liver biopsy tissue from patients with viral hepatitis was scored for inflammation and fibrosis by the METAVIR system, and separated into groups with mild (A0-1; F0-1, n = 20) or severe (A2-3; F3-4, n = 19) liver disease. Correlation analysis (Spearman rank-test, P < 0.05) was used to identify metabolic enzymes and transporters which shared significant correlation with transcription factors. RESULTS: Our results show an extensive correlation between transcription factors, transporters, and metabolic enzymes. An unexpected finding was that this was substantially greater in the severely diseased liver. Cross-talk between transcription factors was markedly increased in tissue from patients with severe liver disease, particularly between CAR, HNF4alpha, and PXR. CONCLUSION: Our results support the hypothesis of co-ordinate regulation of metabolic enzymes and transporters in diseased human liver, as part of a widespread co-ordinated process under the control of nuclear receptor transcription factors.
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Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Hepatite Viral Humana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Biópsia , Sistema Enzimático do Citocromo P-450/genética , Feminino , Glucuronosiltransferase/genética , Hepatite Viral Humana/enzimologia , Hepatite Viral Humana/genética , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-Idade , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Fatores de Transcrição/genéticaRESUMO
A presacral mass can present a diagnostic dilemma for the surgical oncologist. Differential diagnoses include congenital causes such as teratoma or chordoma, neurological causes such as neurilemoma or neurofibroma or other malignancies such as lymphoma or sarcoma. Diagnosis usually requires imaging such as CT and MRI and tissue biopsy. We present an unusual cause of a presacral mass being extramedullary haematopoiesis, found incidentally in a 71 year old female. Extramedullary haematopoiesis is defined as the production of myeloid and erythroid elements outside of the bone-marrow. This diagnosis is extremely rare in the presacral area especially in a patient with no haematological abnormalities. A review of the literature is presented.
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Angiosarcoma of bone is an exceedingly rare primary bone malignancy that can present as an aggressive osteolytic lesion. Histological diagnosis can be extremely challenging, as the pathological features often resemble that of aneurysmal bone cysts. We report an interesting and peculiar case of an intraosseous angiosarcoma that presented as a diagnostic dilemma and discuss the relevant radiological and pathologic findings.
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Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Pr1 (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Pr1 series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth.
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Carcinoma de Células de Transição/patologia , Células Epiteliais/patologia , Mesoderma/patologia , Neoplasias da Bexiga Urinária/patologia , Animais , Western Blotting , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinas/metabolismo , Mesoderma/metabolismo , Camundongos , Metástase Neoplásica , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Fatores de Tempo , Transplante Heterólogo , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Vimentina/metabolismoRESUMO
In a prospective study of 526 consecutive patients with operable breast cancer, the significance of positive parathyroid hormone-related protein (PTHrP) staining by immunohistology has been evaluated for a median of 10-year follow-up. Improved survival was observed for the 79% of tumors which stained positively for PTHrP [estimated univariate hazard ratio, 0.43; 95% confidence interval (95% CI), 0.30-0.62; P < 0.001]. Adjustments for N stage, progesterone receptor status, and log tumor size changed this estimate only slightly to 0.47 (95% CI, 0.63-0.69; P = 0.001). Patients with PTHrP-positive primary tumors were less likely to develop bone metastases (hazard ratio, 0.63; 95% CI, 0.41-0.98; P = 0.04). PTHrP status was associated with estrogen receptor (P = 0.01), progesterone receptor (P = 0.03), and menopausal status (P = 0.006) but was not significantly associated with tumor size, vascular invasion, tumor grade, or patient age. Of 19 patients requiring surgery for bone metastases, the primary cancers were PTHrP negative in seven, all but one of whom had PTHrP-positive bone metastases. All 12 patients with PTHrP-positive primary cancers also had positive bone metastases. We conclude that increased production of PTHrP by breast cancers confers on them a less invasive phenotype, an effect distinct from the bone resorption-stimulating action that favors bone metastasis. It is likely that the latter property is influenced by factors in the bone microenvironment.
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Neoplasias da Mama/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos ProspectivosRESUMO
A novel method of spontaneous generation of new adipose tissue from an existing fat flap is described. A defined volume of fat flap based on the superficial inferior epigastric vascular pedicle in the rat was elevated and inset into a hollow plastic chamber implanted subcutaneously in the groin of the rat. The chamber walls were either perforated or solid and the chambers either contained poly(D,L-lactic-co-glycolic acid) (PLGA) sponge matrix or not. The contents were analyzed after being in situ for 6 weeks. The total volume of the flap tissue in all groups except the control groups, where the flap was not inserted into the chambers, increased significantly, especially in the perforated chambers (0.08 +/- 0.007 mL baseline compared to 1.2 +/- 0.08 mL in the intact ones). Volume analysis of individual component tissues within the flaps revealed that the adipocyte volume increased and was at a maximum in the chambers without PLGA, where it expanded from 0.04 +/- 0.003 mL at insertion to 0.5 +/- 0.08 mL (1250% increase) in the perforated chambers and to 0.16 +/- 0.03 mL (400% increase) in the intact chambers. Addition of PLGA scaffolds resulted in less fat growth. Histomorphometric analysis rather than simple hypertrophy documented an increased number of adipocytes. The new tissue was highly vascularized and no fat necrosis or atypical changes were observed.
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Tecido Adiposo/anatomia & histologia , Tecido Adiposo/crescimento & desenvolvimento , Retalhos Cirúrgicos/patologia , Retalhos Cirúrgicos/fisiologia , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos , Tecido Adiposo/irrigação sanguínea , Animais , Desenho de Equipamento , Análise de Falha de Equipamento , Masculino , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos/instrumentação , Técnicas de Cultura de Tecidos/métodosRESUMO
BACKGROUND: Obtaining a histological diagnosis is essential for appropriate management of pathological fractures. Computed tomography (CT) is an accurate method of obtaining diagnosis for musculoskeletal tumours. We analysed whether diagnostic accuracy was maintained in the evaluation of pathological fractures. METHODS: A retrospective review of 101 consecutive patients presenting to our tertiary musculoskeletal tumour centre with pathological fracture was performed. Patients underwent core needle biopsy under CT guidance of pathological fractures diagnosed by plain radiography and either CT or magnetic resonance imaging. The histopathology of the CT-guided biopsy was compared with the sample obtained from open biopsy or definitive surgery to determine diagnostic accuracy. RESULTS: The mean age at diagnosis was 52 ± 20 years (range: 18-85) in a cohort of 46 men and 55 women. Diagnostic accuracy of CT-guided biopsy was 82.18%. There were 65 malignant and 36 benign tumours with diagnostic accuracy of 86.15% and 80.56%, respectively. The positive predictive value for a malignant tumour was 98.21% whilst it was 93.1% for benign tumours. The femur (53 cases) and humerus (25 cases) were the commonest bones fractured. The most frequent diagnoses were metastasis (20.79%), giant cell tumour (17.82%), osteosarcoma (9.90%) and myeloma (9.90%). There were no complications of CT-guided biopsy. CONCLUSION: Pathological fracture does not confound the diagnosis of musculoskeletal tumours. CT-guided biopsy is an accurate diagnostic tool in the evaluation of pathological fractures. Final diagnosis and management should be made in the context of appropriate anatomical and functional imaging using a multidisciplinary approach.
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Neoplasias Ósseas/patologia , Fraturas Espontâneas/patologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Ósseas/complicações , Neoplasias Ósseas/diagnóstico por imagem , Feminino , Fraturas Espontâneas/diagnóstico por imagem , Fraturas Espontâneas/etiologia , Humanos , Biópsia Guiada por Imagem , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Osteosarcoma is the most common primary malignant bone tumour in children and young adults. Despite advances in the diagnosis and management of osteosarcoma, there have been few recent studies describing the experiences of tertiary referral centres. This paper aims to describe and discuss the clinical features, pre-operative work-up, management and outcomes of these patients at St Vincent's Hospital (Melbourne, Australia). METHODS: Retrospective study of fifty-nine consecutive patients managed for osteosarcoma at St Vincent's Hospital between 1995 and 2005. RESULTS: Median age at diagnosis was 21 (range, 11-84) years. Gender distribution was similar, with thirty-one male and twenty-eight female patients.Twenty-five patients had osteosarcoma in the femur, eleven each were located in the humerus and tibia, six were identified in the pelvis, and one each in the clavicle, maxilla, fibula, sacrum, ulna and radius.Pre-operative tissue diagnosis of osteosarcoma was obtained through computed tomography-guided percutaneous biopsy in over ninety percent of patients. Following initial therapy, over fifty percent of patients remained relapse-free during the follow-up period, with twelve percent and twenty-seven percent of patients documented as having local and distant disease recurrence, respectively. Of patients with recurrent disease, sixty-two percent remained disease-free following subsequent surgical intervention (most commonly, pulmonary metastatectomy). CONCLUSION: Patient outcomes can be optimised through a multidisciplinary approach in a tertiary referral centre. At St Vincent's Hospital, survival and relapse rates of patients managed for osteosarcoma compare favourably with the published literature.
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Bone and soft-tissue sarcomas are rare and heterogeneous malignancies arising from tissues of mesenchymal origin. Treatment planning is informed by accurate diagnosis for which biopsy is the diagnostic standard. Biopsy in the setting of suspected malignancy is a technically challenging procedure that should only be performed at specialist institutions. Without the requisite expertise, they can compromise the viability of reconstructive procedures and may make necessary amputation to achieve adequate surgical margins. The risk of complications arising from the procedure must be minimized and therefore biopsy should always be preceded by imaging. There must be no attempt at biopsy or excision prior to referral if there is any suspicion of malignancy. Patients with suspected bone and soft-tissue tumours are best evaluated and treated at specialist sarcoma centres under the care of expert multidisciplinary teams. Prompt referral to a specialist sarcoma centre should always be made prior to biopsy for any suspicious mass that is painful, progressively increasing in size, greater than 5 cm in diameter, deep to deep fascia or recurs following inadvertent excision.
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Neoplasias Ósseas/patologia , Sarcoma/patologia , Biópsia , Neoplasias Ósseas/diagnóstico por imagem , Humanos , Guias de Prática Clínica como Assunto , Sarcoma/diagnóstico por imagemRESUMO
Increased and deregulated expression of glucose transporters is a characteristic of cancer cells. We previously identified a novel glucose transporter protein, GLUT12, in the MCF7 malignant breast epithelial cell line. Here we present the first demonstration of GLUT12 expression in human breast tumours. Using immunohistochemistry and reverse transcription polymerase chain reaction, GLUT12 was detected in eight of ten invasive tumours. Ductal cell carcinoma in situ cells also stained strongly for GLUT12. Immunohistochemical staining for GLUT12 in benign ducts was less intense, with few positively stained cells. GLUT12 may have a role in hexose supply to breast cancer cells.
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Neoplasias da Mama/metabolismo , Mama/metabolismo , Proteínas de Transporte de Monossacarídeos/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Carcinoma Intraductal não Infiltrante/metabolismo , Epitélio/metabolismo , Feminino , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
AIM: Parathyroid hormone-related protein (PTHrP) is one of the critical factors for the differentiation and growth of chondrocytes. We examined the correlation between the co-expression of PTHrP and PTH/PTHrP receptor and the grade of malignancy in cartilaginous tumours. METHODS: We analysed PTHrP and PTH/PTHrP receptor expression in chondrosarcoma by immunohistochemistry and compared specific staining with the expression in benign cartilaginous tumours. There were 38 cartilaginous bone tumours consisting of 26 chondrosarcoma, six enchondroma and six osteochondroma. Chondrosarcoma were composed of 20 conventional chondrosarcoma (10 grade 1, seven grade 2, and three grade 3), two dedifferentiated chondrosarcoma, two clear cell chondrosarcoma, and two myxoid chondrosarcoma. We performed the standard peroxidase-labelled streptavidin-biotin detection method for immunohistochemistry using an antibody raised against PTHrP (1-14) and PTH/PTHrP receptor. The magnitude of receptor positivity of PTHrP and PTH/ PTHrP in each tumour was assessed as a percentage of PTHrP and PTH/PTHrP-positive cells per thousand tumour cells in the most histologically aggressive area of the tumour. RESULTS: All chondrosarcoma, five of six enchondroma, and four of six osteochondroma showed PTHrP-positive cells, and all chondrosarcoma, five of six enchondroma and five of six osteochondroma showed PTHrP receptor-positive cells. The grade of malignancy correlated with the percentage of both PTHrP and PTH/PTHrP receptor-positive tumour cells (P < 0.0001, either). Each grade of chondrosarcoma showed statistically higher expression of both PTHrP and PTH/PTHrP receptor than benign cartilaginous tumour. CONCLUSION: This is the first report of the co-expression of PTHrP and PTH/PTHrP receptor in chondrosarcoma. PTHrP and PTH/PTHrP receptor positivity may be valuable for differentiating between benign and malignant cartilaginous tumours.
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Neoplasias Ósseas/metabolismo , Condrossarcoma/metabolismo , Hormônio Paratireóideo/metabolismo , Hormônios Peptídicos/metabolismo , Receptores de Hormônios Paratireóideos/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Ósseas/patologia , Contagem de Células , Condrossarcoma/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo , Receptor Tipo 1 de Hormônio ParatireóideoRESUMO
Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer.
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Linhagem da Célula/genética , Integrases/metabolismo , Modelos Biológicos , Osteossarcoma/classificação , Osteossarcoma/genética , RNA Interferente Pequeno/metabolismo , Transgenes/genética , Animais , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Membrana Celular/metabolismo , Cromossomos de Mamíferos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Cariotipagem , Camundongos , Camundongos Transgênicos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/patologia , Penetrância , Fenótipo , Radiografia , Transdução de Sinais , Análise de Sobrevida , Proteína Supressora de Tumor p53/metabolismoAssuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/genética , Lipossarcoma/genética , Técnicas de Diagnóstico Molecular , Neoplasias de Tecidos Moles/genética , Biomarcadores Tumorais/genética , Marcadores Genéticos , Humanos , Lipossarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnósticoRESUMO
Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non-cell-autonomous tumor suppressor pathway.
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Neoplasias da Mama/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Monócitos/imunologia , Proteína Relacionada ao Hormônio Paratireóideo/biossíntese , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/imunologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Masculino , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Monócitos/patologia , Proteína Relacionada ao Hormônio Paratireóideo/deficiência , Proteína Relacionada ao Hormônio Paratireóideo/genética , Receptor ErbB-2/biossínteseRESUMO
Parosteal lipomas are rare benign tumours of mature adipose tissue that arise in continuity with the underlying bone. These lesions represent less than 0.3% of all lipomas and commonly arise in the femur, tibia, humerus and radius. There have been no reported cases of such lesions arising in the foot. Hence, we report the first case of a parosteal lipoma arising in the great toe in association with an underlying osteochondroma.
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Neoplasias Ósseas/diagnóstico , Hallux/diagnóstico por imagem , Lipoma/diagnóstico , Neoplasias Lipomatosas/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Osteocondroma/diagnóstico , Idoso , Neoplasias Ósseas/cirurgia , Feminino , Hallux/cirurgia , Humanos , Lipoma/cirurgia , Neoplasias Lipomatosas/cirurgia , Neoplasias Primárias Múltiplas/cirurgia , Osteocondroma/cirurgia , Doenças Raras , Tomografia Computadorizada por Raios X/métodosRESUMO
BACKGROUND: The choice of performing surgery when tumors encroach onto joints remains a challenging and controversial issue. Pre-operative assessment by magnetic resonance imaging (MRI) is of critical importance in dictating surgical management and subsequent functional outcome. METHODS: We examined archival samples from 27 patients with osteosarcoma, adjacent to synovial joints for the incidence and mechanism of osteosarcoma extension into the joint space. Histopathologic findings were correlated with pre-operative MRI findings and choice of operation. RESULTS: There was no evidence of penetration across the entire thickness of articular cartilage into the joint cavity in all of the 27 cases. When pre-operative MRI confidently excluded joint involvement by tumor, enabling an intra-articular surgical approach, histopathologic correlation confirmed the absence of joint involvement in all cases. The low incidence of joint involvement was despite the presence of extensive bone and soft tissue involvement in most cases, a tendency for peripheral extension of tumor around the articular margin of the bone, and evidence of joint effusions pre-operatively in more than one-third of cases. CONCLUSIONS: Joint involvement by osteosarcoma is uncommon, with articular cartilage being a relative barrier to tumor invasion. If pre-operative MRI does not show definite evidence of intra-articular tumor involvement, it is likely to be safe to proceed with intra-articular resection.