Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes.

PURPOSE: Breast cancer (BC) is considered a heterogeneous disease composed of distinct subtypes with diverse clinical outcomes. Luminal subtype tumors have the best prognosis, and patients benefit from endocrine therapy. However, resistance to endocrine therapies in BC is an obstacle to successful treatment, and novel biomarkers are needed to understand and overcome this mechanism. The RET, BCAR1, and BCAR3 genes may be associated with BC progression and endocrine resistance. METHODS: Aiming to evaluate the expression profile and prognostic value of RET, BCAR1, and BCAR3, we performed immunohistochemistry on tissue microarrays (TMAs) containing a cohort of 361 Luminal subtype BC. RESULTS: Low expression levels of these three proteins were predominantly observed. BCAR1 expression was correlated with nuclear grade (p = 0.057), and BCAR3 expression was correlated with lymph node status (p = 0.011) and response to hormonal therapy (p = 0.021). Further, low expression of either BCAR1 or BCAR3 was significantly associated with poor prognosis (p = 0.005; p = 0.042). Pairwise analysis showed that patients with tumors with low BCAR1/low BCAR3 expression had a poorer overall survival (p = 0.013), and the low BCAR3 expression had the worst prognosis with RET high expression stratifying these patients into two different groups. Regarding the response to hormonal therapy, non-responder patients presented lower expression of RET in comparison to the responder group (p = 0.035). Additionally, the low BCAR1 expression patients had poorer outcomes than BCAR1 high (p = 0.015). CONCLUSION: Our findings suggest RET, BCAR1, and BCAR3 as potential candidate markers for endocrine therapy resistance in Luminal BC.

Mutational Profile and New IASLC/ATS/ERS Classification Provide Additional Prognostic Information about Lung Adenocarcinoma: A Study of 125 Patients from Brazil.

AIM: To show additional prognostic information about the mutational profile and new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification of adenocarcinoma (ADC) in patients without epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor treatments. METHODS: In human lung ADC patients (n = 125), including 24 lepidic, 67 acinar, 23 papillary, and 11 solid predominant subtypes, EGFR and KRAS were sequenced, and anaplastic lymphoma kinase (ALK) rearrangements were screened using fluorescence in situ hybridization (FISH). RESULTS: EGFR was mutated in 21.6% of patients with 19.57% showing a mean expression. The most frequent EGFR mutation was a deletion in exon 19, followed by an L858R amino acid substitution in exon 21. KRAS was mutated in 26.4% of patients with 50% displaying mean expression. ALK rearrangement was detected in 6 patients (4.8%). Predominant acinar ADC was strongly associated with EGFR and KRAS mutation. Clinical stage, lymph node metastases, and EGFR mutation in exon 18 showed a significant difference in disease-free and overall survival, but only a trend significance for EGFR and KRAS mutations. Multivariate analysis revealed that men aged >71 years, with a history of smoking (<72 packs/year), clinical stage I/II, and acinar histologic subtype presented better survival than women aged ≤ 71 years, with a history of smoking (>72 packs/year), and having a predominant solid ADC and EGFR mutation in exon 18. CONCLUSIONS: These results indicate that the mutational profile and new IASLC/ATS/ERS classification provide additional prognostic information about lung ADC.

Intrahepatic lymphatic invasion but not vascular invasion is a major prognostic factor after resection of colorectal cancer liver metastases.

BACKGROUND: Despite advances in diagnosis and surgical strategies, up to 70% of patients will develop recurrence of the disease after resection of colorectal cancer liver metastases (CRCLM). The purpose of our study was to determine the frequency of four different mechanisms of intrahepatic dissemination, and to evaluate the impact of each mechanism on patient outcomes. METHODS: The medical records of 118 patients who underwent a first resection of CRCLM during the period between 2000 and 2010 were reviewed. Clinicopathologic variables and outcome parameters were examined. Resected specimens were submitted to routine histological evaluation, and immunohistochemical staining with D2-40 (lymphatic vessels), CD34 (blood vessels), CK-7 (biliary epithelium), and CK-20 (CRC cells). RESULTS: The mean follow-up after resection was 38 months. Tumor recurrence was observed in 76 patients, with a median interval of 13 months after resection. Overall survival and disease-free survival (DFS) rates after hepatectomy were 62 and 56%, and 26 and 24% at 3 and 5 years, respectively. Intrahepatic microscopic invasion included portal venous in 49 patients, sinusoidal in 43 patients, biliary in 20 patients, and lymphatic in 33 patients. Intra-hepatic lymphatic invasion was the only mechanism of dissemination independently associated with the risk of hepatic recurrence (odds ratio 2.75) and shorter DFS (p = 0.006). CONCLUSION: Intrahepatic lymphatic invasion is a significant prognostic factor. Other mechanisms of invasion, although frequently observed, are not related to recurrence or survival, suggesting that the lymphatic system is the main route for dissemination of CRCLM. Furthermore, immunohistochemical detection of intrahepatic lymphatic invasion might be of value in clinical practice.

The presence of bilobar tumor should be considered as a new limit for transplantation beyond the Milan criteria? / A presença de tumor bilobar deve ser considerado novo limite para exclusão de transplante em pacientes que excedem os critérios de Milão?

BACKGROUND: An imprecise estimate of the tumor's aggressiveness of the hepatocellular carcinoma especially in transplanted patients beyond the Milan criteria has a poor outcome, although a more reliable criteria including microscopic vascular invasion is difficult to be established before transplantation. AIM: To examine a cohort of patients with hepatocellular carcinoma undergoing liver transplantation to evaluate the preoperative predicting factors for microscopic vascular invasion. METHODS: A series of 46 consecutive cirrhotic patients with hepatocellular carcinoma undergoing transplantation based on Milan criteria or similar criteria in a single center were enrolled between 1993 and 2007. The survival was calculated using Kaplan-Meyer's method and a multivariate Cox regression was performed to evaluate survival and factors related to microscopic vascular invasion. RESULTS: Multifocal tumors were present in 39 percent. Microvascular invasion, tumor relapses and hepatocellular carcinoma beyond the Milan criteria were identified in 33 percent, 13 percent and 33 percent, respectively. Overall 1-, 3-, and 5-year actuarial patient survival rates were 64 percent, 59 percent and 45 percent respectively. Patients who exceeded the Milan criteria had a higher incidence of microscopic vascular invasion and bilobar tumor compared to those who met the Milan criteria (53 percent vs. 23 percent and 80 percent vs. 19 percent; p<0.05, respectively). After multivariate analysis, the variable identified as independent risk factor for microscopic vascular invasion was the presence of bilobar tumor (hazard ratio, 3.67; 95 percent confidence interval, 1.01 to 13.34; p<0.05). CONCLUSIONS: The presence of a bilobar tumor is more frequent in hepatocellular carcinoma beyond the Milan criteria and it is an independent predictive factor of a high risk of microscopic vascular invasion. The presence of bilobar tumor in hepatocellular carcinoma beyond the Milan ...

RACIONAL: A recidiva tumoral após o transplante de fígado para o carcinoma hepatocelular tem grande impacto desfavorável na mortalidade e a presença de invasão microvascular desempenha papel importante na recidiva tumoral. OBJETIVO: Avaliar a sobrevida, o risco de recidiva tumoral pós-transplante e os fatores relacionados à invasão microvascular de uma série de transplantados por carcinoma hepatocelular. MÉTODOS: No período entre 1993 e 2007 foi estudada uma série consecutiva de 46 cirróticos com carcinoma hepatocelular submetidos à transplante de fígado baseado nos critérios de Milão a partir de 1996 ou critérios semelhantes no período anterior a esta data. Inicialmente todas as variáveis foram analisadas descritivamente, e as quantitativas através da observação dos valores mínimos e máximos, e do cálculo de médias e desvios-padrão e medianas. Para as variáveis qualitativas calcularam-se frequências absolutas e relativas. Realizou-se a regressão logística com ajuste pelo modelo de Cox para avaliar a sobrevida e os fatores relacionados à recidiva tumoral e invasão microvascular. RESULTADOS: A sobrevida da amostra foi de 64 por cento, 59 por cento e 45 por cento para 1, 3 e 5 anos, respectivamente. Em 13 por cento dos casos, a recidiva tumoral foi verificada. A análise multivariada identificou a chance de um paciente com nódulo bilobar sofrer invasão microvascular é 3,67 vezes maior em relação a um paciente com nódulo unilobar e a presença de um tumor unilobar representar um significativo efeito protetor em relação à invasão microvascular (p = 0,048). CONCLUSÕES: A identificação de um tumor bilobar no estadiamento tumoral é fator preditivo independente de maior risco de invasão microvascular e é necessário ainda confirmar se a presença de tumor bilobar deve ser adicionada aos critérios de Milão para melhor indicação de transplante de fígado em pacientes cirróticos com carcinoma hepatocelular.

Intimal dissection of the hepatic artery after thrombectomy as a cause of graft loss in pediatric living-related liver transplantation.

HAT is the main cause of graft loss in pediatric living-related LTx. Revascularization of the graft by thrombectomy and re-anastomosis has been reported to be effective for graft salvage in cases of HAT and should be attempted when potential donors are not available for emergency re-transplantation. Immediate complications secondary to revascularization attempts in cases of HAT are not described. Late complications are mainly related to biliary tree ischemia. We report a case of child who experienced intimal hepatic artery dissection, which extended into intra-hepatic branches of the artery after a thrombectomy with a Fogarty balloon catheter in an attempt to restore arterial flow after HAT. This complication led to acute deterioration of the graft and the need for emergency re-transplantation.

Hepatic gene expression profile associated with non-alcoholic steatohepatitis protection by S-nitroso-N-acetylcysteine in ob/ob mice.

BACKGROUND/AIMS: To understand the molecular mechanisms underlying non-alcoholic steatohepatitis (NASH) prevention by S-nitroso-N-acetylcysteine (SNAC), an NO donor that inhibits lipid peroxidation, we examined hepatic differentially expressed genes between ob/ob mice receiving or not SNAC treatment concomitantly with a methionine-choline deficient (MCD) diet. METHODS: Ob/ob mice were assigned to receive oral SNAC fed solution (MCD+SNAC group) or vehicle (MCD group) by gavage. After four weeks, histopathological analysis and microarray hybridizations were conducted in liver tissues from groups. GeneSifter system was used to identify differentially expressed genes and pathways according to Gene Ontology. RESULTS: NASH was absent in the MCD+SNAC group and no significant changes in food intake or body weight were observed in comparison to MCD group. After SNAC treatment, several genes belonging to oxidative phosphorylation, fatty acid biosynthesis, fatty acid metabolism and glutathione metabolism pathways were down-regulated in comparison to the MCD group. CONCLUSIONS: SNAC treatment promotes down regulation of several genes from fatty acid (FA) metabolism related pathways, possibly through abrogation of the cytotoxic effects of reactive oxygen species and lipid peroxides with consequent prevention of mitochondrial overload. Further studies are required to investigate the clinical implications of these findings, in attempt to develop novel therapeutic strategies for NAFLD treatment.