RESUMO
AIM: Squamous cell carcinomas of the anus are normally treated with synchronous chemoradiotherapy (CRT). Small, localized anal margin tumours may be adequately treated by local excision (LE) alone. This study aims to investigate the outcomes of patients with anal margin tumours treated with LE alone, reserving the use of CRT for salvage on local recurrence (LR). METHODS: Patients with small, localized (stage I/IIA) anal margin tumours treated by LE from October 1999 to September 2018 were identified. The effect of tumour size and resection margin on LR risk was analysed. Outcomes of overall survival and disease-free survival were measured. RESULTS: Fifty-five patients with anal margin tumours were identified. Overall 5-year LR, overall survival and disease-free survival rates were 8%, 86% and 82% respectively. Of the seven LRs, five were successfully salvaged with CRT with no further recurrence and two were not fit for CRT. Resection margins in non-fragmented tumours and tumour size did not significantly influence LR risk. CONCLUSIONS: Most small, localized anal margin tumours can be adequately treated by LE alone with low LR rates. Most patients who developed LR were salvaged using CRT, with no cancer-related deaths reported.
Assuntos
Neoplasias do Ânus , Carcinoma de Células Escamosas , Humanos , Estadiamento de Neoplasias , Neoplasias do Ânus/cirurgia , Neoplasias do Ânus/patologia , Quimiorradioterapia , Intervalo Livre de Doença , Carcinoma de Células Escamosas/cirurgia , Recidiva Local de Neoplasia/patologia , Estudos RetrospectivosRESUMO
BACKGROUND: Despite advances in the management of and changes in clinical practice, little is known about the epidemiology, patterns of care and outcomes of gastrointestinal stromal tumour (GIST) patients in the UK. Patient registries are receiving increasing attention as they can provide important information on clinical practice and patient outcomes. The rationale and study design of the GIST Epidemiology and Management (GEM) Registry, which forms part of the routine clinical practice for GISTs in several UK centres, are described. METHODS: The GEM Registry is a secure web-based registry system designed around a Microsoft Access core using SQL interface. Demographic, surgical, histopathological and clinical data will be captured including treatment outcomes and survival. The registry was piloted in six centres and following further fine tuning of the data sets, ethical committee submission and approval was completed. RESULTS: The GEM National Registry is the first of its kind to be implemented in rare cancers in UK. The registry is being rolled out initially in selected centres with the aim to expand to other centres. The first publication reporting analyses of the central data set is anticipated for the summer of 2013. CONCLUSION: GEM Registry will enable us to obtain a clear picture of incidence/prevalence of GISTS in UK. Clinicians will be able to review the prognostic and predictive value of variables in a large prospective data set. The data can be used for planning the delivery and improving the quality of care. This information is likely to inform clinical practice and, in years to come, guide the development and implementation of clinical trials for novel tyrosine kinase inhibitors. The results will not only benefit the GIST community, but also serve as a basis for the study of other rare tumour types.
Assuntos
Bases de Dados Factuais , Tumores do Estroma Gastrointestinal/epidemiologia , Sistema de Registros , Adulto , Coleta de Dados , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Incidência , Masculino , Prevalência , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Indóis/uso terapêutico , Melanoma/tratamento farmacológico , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Algoritmos , Odontologia Baseada em Evidências , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Melanoma/genética , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Neoplasias Cutâneas/genética , VemurafenibRESUMO
BACKGROUND: The prognostic significance of histological organ involvement by retroperitoneal sarcoma subtype is unknown. The present study aimed to describe organ involvement across the subtypes, and the implications for survival. METHODS: Patients undergoing surgery for primary retroperitoneal sarcoma at the Queen Elizabeth Hospital, Birmingham from April 2005 to September 2018 were identified retrospectively. Histological organ involvement was classed as pushing, infiltrative or neither. Univariable and multivariable Cox regression models were produced to analyse the association between histological organ involvement and both overall (OS) and recurrence-free (RFS) survival for the cohort as a whole, and by histological subtype. RESULTS: Data were available for a total of 197 patients, of whom 171 (86.8 per cent) had at least one organ resected. Infiltrative organ behaviour was seen in 37 patients (18.8 per cent), and pushing behaviour in 67 (34.0 per cent). For the cohort as a whole, infiltration (hazard ratio (HR) 4.32, 95 per cent c.i. 2.35 to 7.93; P < 0.001), but not pushing (HR 1.62, 0.90 to 2.92; P = 0.106), was associated with significantly shorter OS, in comparisons with a group with neither of these behaviours. However, this effect was found to differ significantly by histological subtype (P = 0.009). For patients with dedifferentiated liposarcoma, there was no significant association between tumour behaviour and either OS (P = 0.508) or RFS (P = 0.313). However, in leiomyosarcoma, infiltrative behaviour was associated with shorter OS (P = 0.002), and both infiltrative (P < 0.001) and pushing (P = 0.010) behaviours were associated with shorter RFS, compared with tumours with neither behaviour. Multivariable analyses of both OS and RFS returned similar results. CONCLUSION: The prognostic implications of organ involvement in retroperitoneal sarcoma vary by histological subtype.
Assuntos
Neoplasias Retroperitoneais , Sarcoma , Intervalo Livre de Doença , Humanos , Prognóstico , Neoplasias Retroperitoneais/cirurgia , Estudos RetrospectivosRESUMO
Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.
Assuntos
Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Antígeno Ki-67/metabolismo , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/tratamento farmacológico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/mortalidade , Carcinoma Neuroendócrino/patologia , Feminino , Seguimentos , Humanos , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Adulto JovemRESUMO
Rectal squamous-cell carcinoma is a rare tumour with an incidence of less than 1 per 1000 cases. We report such a case treated with chemoradiotherapy. The patient developed a metastasis in the spleen and a further squamous tumour in the right colon, both of which were successfully resected. No histological evidence of recurrent rectal tumour has been found. Two years following presentation, the patient remains disease-free although symptomatic from a radiotherapy-induced stricture of the rectum.
Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias do Colo/secundário , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Neoplasias Esplênicas/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias do Colo/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Esplênicas/cirurgia , Resultado do TratamentoRESUMO
OBJECTIVE: Faecal occult blood testing is being introduced for population screening in the United Kingdom. Flexible sigmoidoscopy may provide a viable alternative. The outcomes of the flexible sigmoidoscopy trial are awaited but the most obvious disadvantage is that only the lower third of the colon is examined and proximal pathology cannot be excluded. The relationship between proximal pathology and distal findings at flexible sigmoidoscopy is uncertain. The aim of this study was to determine the incidence of distal neoplasia in patients with confirmed proximal cancers of the colon. METHOD: All confirmed proximal colonic cancers (defined as those proximal to the splenic flexure) were identified from a database of pathology specimens at a single centre between January 1999 and August 2006. A retrospective analysis of preoperative and peri-operative mucosal imaging (contrast enema, colonoscopy and CT colonography) was conducted to identify any distal neoplasia in these patients. RESULTS: A total of 348 patients were identified. Pre- or peri-operative mucosal imaging was identified in 231 (66%) and 49 (21%) had distal neoplasia. Nineteen (8%) of these patients would have gone on to have a colonoscopy based on the UK flexible sigmoidoscopy trial protocol and 92% of the cohort would not have had a colonoscopy. CONCLUSION: Nearly 80% of confirmed proximal cancers in our series did not have any demonstrable distal neoplasia. Only 8% of our cohort would have proceeded to colonoscopy. A very significant number of proximal cancers would not have been detected.
Assuntos
Adenocarcinoma/diagnóstico , Neoplasias do Colo/diagnóstico , Programas de Rastreamento/métodos , Sigmoidoscopia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Neoplasias do Colo Sigmoide/diagnósticoRESUMO
Gangliocytic paragangliomas are rare tumors located in the gastrointestinal tract that are considered to be benign. They are composed of spindle-shaped cells, epithelioid cells, and ganglion-like cells. They usually present with abdominal pain, and/or gastrointestinal bleeding, and occasionally with obstructive jaundice. We report a case of obstruction in a 17-year-old female, which on histology was found to be a gangliocytic paraganglioma, with an extremely unusual presentation. Intraoperatively, the patient was found to have local tumor extension and regional lymph node invasion, and so she underwent a pylorus-preserving pancreaticoduodenectomy, with local lymph node clearance. We discuss the management of this unusual case and review the literature.
Assuntos
Neoplasias Duodenais/complicações , Obstrução Intestinal/etiologia , Paraganglioma/complicações , Adolescente , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Endoscopia do Sistema Digestório , Feminino , Humanos , Linfonodos/patologia , Invasividade Neoplásica , Pancreaticoduodenectomia , Paraganglioma/patologia , Paraganglioma/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Oesophageal adenocarcinoma, which arises from an acquired columnar lesion, Barrett's metaplasia, is rising in incidence more rapidly than any other cancer in the Western world. Elevated expression of c-MYC has been demonstrated in oesophageal adenocarcinoma; however, the expression of other members of the MYC/MAX/MAD network has not been addressed. The aims of this work were to characterise the expression of c-MYC, MAX and the MAD family in adenocarcinoma development and assess the effects of overexpression on cellular behaviour. mRNA expression in samples of Barrett's metaplasia and oesophageal adenocarcinoma were examined by qRT-PCR. Semi-quantitative immunohistochemistry and western blotting were used to examine cellular localisation and protein levels. Cellular proliferation and mRNA expression were determined in SEG1 cells overexpressing c-MYCER or MAD1 using a bromodeoxyuridine assay and qRT-PCR, respectively. Consistent with previous work expression of c-MYC was deregulated in oesophageal adenocarcinoma. Paradoxically, increased expression of putative c-MYC antagonists MAD1 and MXI1 was observed in tumour specimens. Overexpression of c-MYC and MAD proteins in SEG1 cells resulted in differential expression of MYC/MAX/MAD network members and reciprocal changes in proliferation. In conclusion, the expression patterns of c-MYC, MAX and the MAD family were shown to be deregulated in the oesophageal cancer model.
Assuntos
Adenocarcinoma/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Esofágicas/genética , Regulação Neoplásica da Expressão Gênica , Genes myc , Proteínas Repressoras/genética , Western Blotting , Linhagem Celular , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: The aim of the study was to determine the value of performing peritoneal lavage cytology during laparoscopy in the management of oesophagogastric adenocarcinoma. METHODS: Laparoscopy combined with peritoneal cytology was performed in patients with potentially resectable oesophagogastric adenocarcinoma. Macroscopic peritoneal findings at laparoscopy and the presence of free peritoneal tumour cells were recorded. All patients were followed to death or the census point. Patients with overt peritoneal disease or positive cytology were offered palliative chemotherapy, subject to performance status. RESULTS: Forty-eight (18.8 per cent) of 255 patients had overt peritoneal metastases at staging laparoscopy. Fifteen (7.2 per cent) of the remaining 207 patients had positive cytology; these patients had a median (95 per cent confidence interval) survival of 13 (3.1 to 22.9) months, versus 9 (7.4 to 10.6) months for those with overt peritoneal metastases (P = 0.517). Of patients receiving chemotherapy, those without overt metastases had a slight survival advantage over patients with metastases (median 15 (10.8 to 19.2) versus 9 (7.4 to 10.7) months; P = 0.045). CONCLUSION: Positive peritoneal cytology in the absence of overt peritoneal metastases is not uncommon in oesophagogastric adenocarcinoma. It is a marker of poor prognosis even in the absence of overt peritoneal metastases.
Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Lavagem Peritoneal/métodos , Neoplasias Gástricas/patologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Técnicas Citológicas/métodos , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Laparoscopia/métodos , Laparoscopia/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade , Análise de SobrevidaRESUMO
AIMS: Imatinib mesylate, a selective tyrosine kinase receptor inhibitor of KIT and PDGFRalpha, is currently licensed for the treatment of unresectable or metastatic gastrointestinal stromal tumours (GISTs), which are KIT positive. Partial response rates in 65% of patients and stable disease in 20% of patients are typically seen. The aim of this study was to assess the effectiveness and toxicity of an unselected cohort of patients treated with imatinib mesylate and to compare these results with published data. MATERIALS AND METHODS: A retrospective audit of the use of imatinib mesylate in GISTs within the Pan-Birmingham Cancer Network was carried out. In total, 39 patients were identified, the first commenced imatinib mesylate in September 2001. RESULTS: The most common primary tumour sites were small intestine (19 [49%]) and stomach (12 [31%]). Initial curative resection was carried out in 21 (54%), palliative resection in three (8%) and 15 (38%) were unresectable. Of those who had curative resection, the median time to recurrence was 13 months (range 2-276). Common sites of metastases were liver (19 [49%]) and peritoneum (12 [31%]). At 24 months 70% remained on imatinib. A partial response was reported in 23 (59%), stable disease in seven (18%) and disease progression in four (10%). Five patients (13%) have yet to be reassessed at 3 months. Imatinib was well tolerated with minor side-effects; peri-orbital oedema (nine [23%]), skin rash (four [10%]), minor gastrointestinal bleed (one [3%]). No significant toxicity was documented in 18 (46%). CONCLUSIONS: The response rates achieved in this unselected cohort of patients are consistent with published data. The duration of tumour control is good, with most patients responding to imatinib mesylate for more than 2 years. Side-effects are mild and acceptable.
Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Benzamidas , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Overexpression of cyclooxygenase-2 (Cox-2) is thought to exert antiapoptotic effects in cancer. Here we show that the tumor suppressor p53 upregulated Cox-2 in esophageal and colon cancer cell lines by inducing the binding of nuclear factor-kappaB (NF-kappaB) to its response element in the COX-2 promoter. Inhibition of NF-kappaB prevented p53 induction of Cox-2 expression. Cooperation between p53 and NF-kappaB was required for activation of COX-2 promoter in response to daunomycin, a DNA-damaging agent. Pharmacological inhibition of Cox-2 enhanced apoptosis in response to daunomycin, in particular in cells containing active p53. In esophageal cancer, there was a correlation between Cox-2 expression and wild-type TP53 in Barrett's esophagus (BE) and in adenocarcinoma, but not in squamous cell carcinoma (P<0.01). These results suggest that p53 and NF-kappaB cooperate in upregulating Cox-2 expression, promoting cell survival in inflammatory precursor lesions such as BE.
Assuntos
Ciclo-Oxigenase 2/metabolismo , Genes p53 , NF-kappa B/metabolismo , Ativação Transcricional , Caspases/metabolismo , Divisão Celular , Linhagem Celular Tumoral , Primers do DNA , Dinoprostona/metabolismo , Ativação Enzimática , Regulação Enzimológica da Expressão Gênica , Humanos , Cinética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Young patients with colorectal cancer are at increased risk of carrying a germline mutation in mismatch repair (MMR) genes. This study investigated the role of clinical criteria and immunohistochemistry for MMR proteins in selecting young patients for mutation testing. METHODS: A cohort of 56 consecutive patients with colorectal cancer aged less than 45 years were stratified into three groups based on clinical criteria: 'Amsterdam criteria', 'high risk' and 'young onset only'. Immunohistochemistry for four MMR proteins was carried out and the rate of compliance with clinical guidelines determined. RESULTS: Tumours from 11 patients (20 per cent) had abnormal MMR protein expression, of whom eight were referred for genetic assessment. Of 21 patients (38 per cent) in total referred to the genetics unit, six MMR gene mutations were identified, all associated with abnormal immunohistochemistry. CONCLUSION: MMR immunohistochemistry should be considered routine in young-onset colorectal cancer.
Assuntos
Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Mutação em Linhagem Germinativa/genética , Neoplasias Primárias Múltiplas/genética , Seleção de Pacientes , Adolescente , Adulto , Análise Mutacional de DNA/métodos , Feminino , Triagem de Portadores Genéticos/métodos , Heterozigoto , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Linhagem , Guias de Prática Clínica como Assunto , Fatores de RiscoRESUMO
AIMS: To report seven cases of epithelioid haemangioendothelioma (EHE) of the liver, a rare, low-grade malignant neoplasm of vascular origin that have been treated in our institution. MATERIALS AND METHODS: Patients with ages ranging from 25 to 60 years presenting mainly with non-specific symptoms, such as right upper quadrant abdominal pain or weight loss. The tumours presented as multiple, nodular lesions involving both lobes of the liver. This type of tumour is often difficult to diagnose, with the final diagnosis being established only by histological examination. The key to diagnosis was the demonstration of cells containing factor VIII-related antigen. RESULTS: Five patients underwent orthotopic liver transplantation (OLT), four of whom are alive at a median follow up 38 months (11-88 months). One patient died of recurrent of disease at 88 months. Two patients did not receive an OLT since they presented with extrahepatic metastatic disease; they died at 21 and 25 months from diagnosis. CONCLUSION: Orthotopic liver transplantation may be considered as a potentially curative treatment for this rare form of tumour when the disease is confined to the liver.
Assuntos
Hemangioendotelioma Epitelioide/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/métodos , Adulto , Biomarcadores Tumorais/metabolismo , Feminino , Seguimentos , Hemangioendotelioma Epitelioide/sangue , Hemangioendotelioma Epitelioide/diagnóstico , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Reino Unido/epidemiologia , Fator de von Willebrand/metabolismoRESUMO
Fas (APO-1/CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. In this study, we analyzed Fas and FasL expression in normal esophageal mucosa and esophageal squamous cell carcinomas. Reverse transcriptase-PCR revealed that Fas, soluble Fas, and FasL were expressed in all eight esophageal squamous carcinoma cell lines analyzed. Furthermore, it was demonstrated that FasL expressed in esophageal carcinoma cells is functional because coculture experiments using FasL-expressing TE-15 esophageal carcinoma cells resulted in apoptosis of Jurkat T leukemia cells, which are sensitive to Fas-mediated apoptosis. Immunohistochemistry of Fas and FasL showed that they are constitutively expressed in normal esophageal mucosa, FasL being predominantly in the basal and suprabasal layers, whereas Fas is in more differentiated layers, i.e., rows of polyhedral cells of the intermediate layers and squamous cells forming the outer layers. In 18 of 19 invasive esophageal squamous cell carcinomas, FasL expression was found in >50% of tumor cells. In contrast, most tumors (15 of 19, 79%) either showed no Fas expression or showed expression in <5% of tumor cells. These alterations were already detected in dysplasia and carcinoma in situ. These results suggest that up-regulation of FasL and down-regulation of Fas expression are early and frequent events associated with the evolution of esophageal squamous cell carcinomas.
Assuntos
Neoplasias Esofágicas/química , Glicoproteínas de Membrana/análise , Proteínas de Neoplasias/análise , Receptor fas/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Regulação para Baixo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Proteína Ligante Fas , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Extremely high rates of squamous cell carcinoma of the esophagus (SCCE) are observed in Iran, reflecting unknown, genetic and/or epidemiological risk factors. Among genetic alterations in SCCE, TP53 mutations are the most frequent, vary among populations, and may provide clues on etiological mechanisms. We have analysed mutations in TP53 (exons 5-8) in 98 SCCE from Iran by temporal temperature gel electrophoresis and direct sequencing. We found 58 mutations in 49 patients (50%), with a high prevalence of C to T transitions at CpG dinucleotides (29.3%). The TP53 mutation pattern in Iran was significantly different from that observed in SCCEs from high incidence areas of China and Western Europe (P=0.007). Moreover, the prevalence of mutations at A : T base pairs (transitions and transversions) was higher in men than in women (38.7% vs 11.1%, P=0.033). COX-2 overexpression was detected in 69% of the cases evaluated (24/35), without significant association with TP53 mutation. Accumulation of nitrotyrosine, a marker of protein damage by excess levels of nitric oxide, was observed in tumor cells in six of 18 [corrected] cases analysed. These results are consistent with the hypothesis that several factors are involved in TP53 mutagenesis in Iran. These factors include a baseline of chronic inflammatory stress, which may have a multiplicative impact on the sensitivity of esophageal cells to exogenous factors of risk.
Assuntos
Carcinoma de Células Escamosas/genética , DNA de Neoplasias/genética , Neoplasias Esofágicas/genética , Genes p53 , Mutação , Tirosina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/etiologia , China/epidemiologia , Doença Crônica , Códon/genética , Códon sem Sentido , Ilhas de CpG , Ciclo-Oxigenase 2 , Análise Mutacional de DNA , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/etiologia , Esofagite/complicações , Europa (Continente)/epidemiologia , Éxons/genética , Feminino , Mutação da Fase de Leitura , Humanos , Incidência , Irã (Geográfico)/epidemiologia , Isoenzimas/análise , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Óxido Nítrico/biossíntese , Mutação Puntual , Prostaglandina-Endoperóxido Sintases/análise , Fatores de Risco , Análise de Sequência de DNA , Tirosina/análiseRESUMO
Zygomycosis (mucormycosis) is a rare fungal infection seen most often in association with prolonged neutropenia. Intestinal zygomycosis is extremely rare and difficult to diagnose, but it is important not to miss, because early medical and surgical treatment can improve survival. This report describes a 56 year old woman who developed this infection while receiving chemotherapy for acute lymphoblastic leukaemia. Medical and surgical measures proved unsuccessful because there was a delay in diagnosis and institution of appropriate treatment.
Assuntos
Enteropatias/diagnóstico , Mucormicose/diagnóstico , Infecções Oportunistas/diagnóstico , Feminino , Humanos , Hospedeiro Imunocomprometido , Enteropatias/imunologia , Pessoa de Meia-Idade , Mucormicose/imunologia , Neutropenia/complicações , Infecções Oportunistas/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
The ataxia telangiectasia gene (ATM) has been implicated as a risk factor in the development of sporadic breast carcinomas. ATM protein expression was analyzed by immunohistochemistry in 17 breast carcinomas with two monoclonal antibodies whose immunohistochemical use was first validated by comparing the immunoreactivity observed in spleen samples from ataxia telangiectasia and trauma patients. In normal breast ducts, ATM showed nuclear expression in the epithelial but not in the myoepithelial cells. In contrast, this nuclear expression was absent or low in the epithelial cancer cells in 10 of 17 (59%) of the tumors studied. Allelic imbalance in the ATM gene was found in three of seven tumors examined. Two of these showed reduced ATM protein expression, but this did not correlate with the presence of ATM mutations in the tumor DNA detected by restriction endonuclease fingerprinting screening. These results suggest that the reduced ATM protein expression could be attributable, in certain tumors, to deletions or rearrangements within or close to the ATM gene. Positive p53 immunostaining was found in 10 tumors, with TP53 mutations detected in 8. Three tumors had both low ATM expression and mutated TP53. Our results indicate that in the majority (15 of 17) of the sporadic breast carcinomas examined, not only is the functionality of the ATM-p53-mediated DNA damage response compromised, but also other signaling pathways activated by these two multifunctional proteins are likely to be impaired, which could be a contributing factor to tumor development and progression.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Proteínas Serina-Treonina Quinases/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Desequilíbrio Alélico , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Genes p53 , Humanos , Imuno-Histoquímica , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas Serina-Treonina Quinases/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de TumorRESUMO
The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.