Proliferações biliares intra-hepáticas: histopatologia e potenciais marcadores imuno-histoquímicos / Intrahepatic biliary proliferations: histopathology and potential immunohistochemical markers

ABSTRACT Intrahepatic biliary proliferations represent a spectrum from reactive (ductular reaction, some with atypical architecture), hamartomatous (von Meyenburg complex), benign (bile duct adenoma) and precursor/borderline entities (biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct) to fully malignant (cholangiocarcinoma) neoplasms. Clinical pictures and even imaging patterns may be similar, requiring refined studies aiming at histopathological and immunohistochemistry for more precise diagnosis, essential for correct patient management. This article discusses updated concepts and definitions of most relevant entities aiming more specifically at the differential diagnosis in practice, focusing on morphology and immunohistochemistry, with a discussion of potential markers to help distinguishing between benign and malignant lesions.

RESUMO As proliferações biliares intra-hepáticas representam um espectro que abrange desde entidades reativas (reação ductular, algumas com arquitetura atípica), hamartomatosas (complexo de von Meyenburg), benignas (adenoma de ductos biliares) e precursoras/limítrofes (neoplasia intraepitelial biliar, neoplasia papilar intraductal de ducto biliar) até neoplasias totalmente malignas (colangiocarcinoma). Os quadros clínicos e até mesmo os padrões de imagem podem ser semelhantes, exigindo estudos refinados visando critério histológicos e imuno-histoquímicos para diagnósticos mais precisos, essenciais para o correto manejo do paciente. Este artigo discute conceitos atualizados e definições das entidades mais relevantes visando mais especificamente ao diagnóstico diferencial na prática, com foco na morfologia e imuno-histoquímica, com discussão de potenciais marcadores para ajudar na distinção entre lesões benignas e malignas.

Implementation of an organized colorectal cancer screening program through quantitative fecal immunochemical test followed by colonoscopy in an urban low-income community: Guidance and strategies

Abstract Fecal Immunochemical Test (FIT) followed by a colonoscopy is an efficacious strategy to improve the adenoma detection rate and Colorectal Cancer (CRC). There is no organized national screening program for CRC in Brazil. The aim of this research was to describe the implementation of an organized screening program for CRC through FIT followed by colonoscopy, in an urban low-income community of São Paulo city. The endpoints of the study were: FIT participation rate, FIT positivity rate, colonoscopy compliance rate, Positive Predictive Values (PPV) for adenoma and CRC, and the rate of complications. From May 2016 to October 2019, asymptomatic individuals, 50-75 years old, received a free kit to perform the FIT. Positive FIT (≥ 50 ng/mL) individuals were referred to colonoscopy. 10,057 individuals returned the stool sample for analysis, of which (98.2%) 9,881 were valid. Women represented 64.8% of the participants. 55.3% of individuals did not complete elementary school. Positive FIT was 7.8% (776/9881). The colonoscopy compliance rate was 68.9% (535/776). There were no major colonoscopy complications. Adenoma were detected in 63.2% (332/525) of individuals. Advanced adenomatous lesions were found in 31.4% (165/525). CRC was diagnosed in 5.9% (31/525), characterized as adenocarcinoma: in situ in 3.2% (1/31), intramucosal in 29% (9/31), and invasive in 67.7% (21/31). Endoscopic treatment with curative intent for CRC was performed in 45.2% (14/31) of the cases. Therefore, in an urban low-income community, an organized CRC screening using FIT followed by colonoscopy ensued a high participation rate, and high predictive positive value for both, adenoma and CRC.

Avaliação imunohistoquímica dos vasos linfáticos em fígados humanos com hepatite crônica C - relação com variáveis histológicas / Immunohistochemical assessment of lymphatic vessels in human livers with chronic hepatitis c - relation to histological variables

ABSTRACT Background Viral hepatitis C is a significant public health challenge. The disease may remain clinically silent in both acute and chronic forms, and chronic infections may progress to advanced disease such as cirrhosis and hepatocellular carcinoma, requiring costly treatment, compromising the patient's quality of life and even leading to death. For this reason, it is one of the most frequent indications for liver transplantation. Although treatment with direct-acting antivirals represents remarkable progress, many patients are still infected and even those who cleared the viral infection must be followed due to their previous hepatic lesions, especially regarding the disturbances of lobular architecture and the sanguineal and lymphatic vessels. Objective To assess immunohistochemical aspects of lymphatic sprouts and mature lymphatic vascularity with histological variables of liver injury attributable to hepatitis C virus (HCV) and fatty disease. Methods The present study included 72 liver biopsies of cases with chronic hepatitis C. Morphologic changes reflecting "staging" and "activity" were analyzed. Immunohistochemical reactions were performed with monoclonal antibody D2-40 anti-podoplanin. Major histological variables were also semiquantified so as to enable the search for possible associations among histological and Immunohistochemical criteria, as well as with genotypes 1 and 3 of HCV. Results Histological findings showed that the different degrees of strutural changes were well represented in this casuistic. Intralobular/parenchymal necro-inflammatory activity was predominantly mild to moderate. Most cases did not show major evidences of fatty disease, which was found significantly higher in cases infected with HCV genotype 3. The amount of portal lymphatic sprouts increased along with the progression of structural changes, maximal at cirrhosis. Portal lymphatic sprouts as well as portal mature lymphatic vessels also showed an increase parallel to the increase in the degree of portal/septal inflammatory infiltrate. In the present study, no significant association was found between the proportion of portal lymphatic sprouts or portal mature lymphatic vessels and the degree of periportal/periseptal activity. No significant relations were detected between lymphatic sprouts/mature vessels and periportal or parenchymal inflammatory activity, nor with infections due to HCV genotype 1 or 3. Conclusion Visualization and semiquantitation of sprouts and mature lymphatic vessels were clearly yielded by Immunohistochemical staining with monoclonal antibody D2-40. The amount of lymphatics was increased along fibrogenic process, significantly related to progression of liver disease and maximal at cirrhosis. No significant relations were detected with necro-inflammatory activity at interface or in the parenchyma.

RESUMO Contexto A hepatite C é um relevante problema de saúde pública. A doença pode permanecer clinicamente silenciosa tanto na forma aguda como na crônica e as infecções crônicas podem progredir para doenças avançadas, tais como cirrose e carcinoma hepatocelular (CHC), requerendo tratamentos dispendiosos, comprometendo a qualidade de vida do paciente e até mesmo levando à morte. Por esta razão, é uma das indicações mais frequentes para o transplante hepático. Apesar da introdução do tratamento com antivirais de ação directa (AAD) representar um progresso notável, muitos pacientes não receberam o tratamento e continuam infectados, e mesmo aqueles que eliminaram a infecção viral devem ser seguidos devido às lesões hepáticas anteriores, especialmente no que diz respeito às alterações da arquitetura lobular e dos vasos sanguíneos e linfáticos. Objetivo Avaliar os aspectos imuno-histoquímicos dos brotos linfáticos e dos vasos linfáticos "maduros" com variáveis histológicas de lesão hepática atribuíveis ao vírus da hepatite C (VHC) e à doença gordurosa. Métodos O presente estudo incluiu 72 biópsias hepáticas em pacientes com hepatite C crônica. Foram analisadas alterações estruturais relativas a "estadiamento" e "atividade". Reações imuno-histoquímicas foram realizadas com anticorpo D2-40 anti-podoplanina. As principais variáveis histológicas também foram semiquantificadas, de modo a permitir a procura de possíveis associações entre os critérios histológicos e imunohistoquímicos, bem como com os genótipos 1 e 3 do VHC. Resultados Os achados histológicos mostraram que os diferentes graus de alterações estrutural estavam bem representados nesta casuística. A atividade necro-inflamatória lobular/parenquimatosa foi predominantemente leve à moderada. A maioria dos casos não apresentava grandes evidências de doença gordurosa, que foi encontrada significativamente mais elevada nos casos infectados com o genótipo 3 do VHC. A quantidade de brotos linfáticos portais aumentou com a progressão de alterações estruturais, sendo máxima na cirrose. Os brotos linfáticos portais, bem como os vasos linfáticos "maduros" portais também mostraram um aumento paralelo ao aumento do grau de infiltrado inflamatório portal/septal. No presente estudo, não foi encontrada qualquer associação significativa entre a proporção de brotos linfáticos portais ou vasos linfáticos maduros portais e o grau de atividade periportal/periseptal. Não foram detectadas relações significativas entre os brotos linfáticos/vasos maduros e a atividade inflamatória periportal ou atividade inflamatória parenquimatosa, nem com infecções devido ao genótipo 1 ou 3 do VHC. Conclusão A reação imunohistoquímica com anticorpo monoclonal D2-40 possibilitou a visualização e a semiquantitação de brotos e vasos linfáticos "maduros" nas amostras obtidas por biópsia hepática. A quantidade de linfáticos aumentou ao longo do processo fibrogênico, significativamente relacionada com a progressão da doença hepática e máxima na cirrose. Não foram detectadas relações significativas com a atividade necro-inflamatória periportal ou parenquimatosa.

Immunohistochemical assessment of lymphatic vessels in human livers with chronic hepatitis C ­ relation to histological variables

Background Viral hepatitis C is a significant public health challenge. The disease may remain clinically silent in both acute and chronic forms, and chronic infections may progress to advanced disease such as cirrhosis and hepatocellular carcinoma, requiring costly treatment, compromising the patient's quality of life and even leading to death. For this reason, it is one of the most frequent indications for liver transplantation. Although treatment with direct-acting antivirals represents remarkable progress, many patients are still infected and even those who cleared the viral infection must be followed due to their previous hepatic lesions, especially regarding the disturbances of lobular architecture and the sanguineal and lymphatic vessels. Objective To assess immunohistochemical aspects of lymphatic sprouts and mature lymphatic vascularity with histological variables of liver injury attributable to hepatitis C virus (HCV) and fatty disease. Methods The present study included 72 liver biopsies of cases with chronic hepatitis C. Morphologic changes reflecting "staging" and "activity" were analyzed. Immunohistochemical reactions were performed with monoclonal antibody D2-40 anti-podoplanin. Major histological variables were also semiquantified so as to enable the search for possible associations among histological and Immunohistochemical criteria, as well as with genotypes 1 and 3 of HCV. Results Histological findings showed that the different degrees of strutural changes were well represented in this casuistic. Intralobular/parenchymal necro-inflammatory activity was predominantly mild to moderate. Most cases did not show major evidences of fatty disease, which was found significantly higher in cases infected with HCV genotype 3. The amount of portal lymphatic sprouts increased along with the progression of structural changes, maximal at cirrhosis. Portal lymphatic sprouts as well as portal mature lymphatic vessels also showed an increase parallel to the increase in the degree of portal/septal inflammatory infiltrate. In the present study, no significant association was found between the proportion of portal lymphatic sprouts or portal mature lymphatic vessels and the degree of periportal/periseptal activity. No significant relations were detected between lymphatic sprouts/mature vessels and periportal or parenchymal inflammatory activity, nor with infections due to HCV genotype 1 or 3. Conclusion Visualization and semiquantitation of sprouts and mature lymphatic vessels were clearly yielded by Immunohistochemical staining with monoclonal antibody D2-40. The amount of lymphatics was increased along fibrogenic process, significantly related to progression of liver disease and maximal at cirrhosis. No significant relations were detected with necro-inflammatory activity at interface or in the parenchyma.

Hepatocellular carcinoma (HCC) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD): screening, treatment and survival analysis in a Brazilian series

Abstract Objective: The aim of the present study was to evaluate the clinical features, Hepatocellular Carcinoma (HCC) screening, treatment modalities, and Overall Survival (OS) in a series of Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma (NAFLD-HCC) Brazilian patients. Methods: This was a cross-sectional study at the Instituto do Cancer do Estado de São Paulo, at the Faculdade de Medicina da Universidade de São Paulo with the approval of the local research ethics committee. NAFLD patients with HCC diagnosed, from May 2010 to May 2019, were included. Results: A total of 131 patients were included. Risk factors for NAFLD were present in 94.7% of the patients. Only 29% of patients were in the HCC screening program before diagnosis. HCC treatment was performed in 84.7% of patients. Cumulative survival at the end of the first year was 72%, second-year 52%, and fifth-year 32%. HCC screening before diagnosis was not significantly associated with higher cumulative survival. The independent factors associated with shorter general survival were BCLC C-D, p < 0.001, and the size of the largest nodule > 42 mm, p = 0.039. Conclusions: Although the efficacy of screening in our population regarding overall survival was hampered due to the sample size (29% had screening), BCLC stages C‒D and the size of the largest nodule larger than 42 mm were identified as independent factors of worse prognosis.

Combined use of immunohistochemical markers of basal and luminal subtypes in urothelial carcinoma of the bladder: Association with clinicopathological features and outcomes

OBJECTIVES: Whole genome expression profiles allow the stratification of bladder urothelial carcinoma into basal and luminal subtypes which differ in histological patterns and clinical behavior. Morpho-molecular studies have resulted in the discovery of immunohistochemical markers that might enable discrimination between these two major phenotypes of urothelial carcinoma. METHODS: We used two combinations of immunohistochemical markers, i.e., cytokeratin (CK) 5 with CK20 and CK5 with GATA3, to distinguish subtypes, and investigated their association with clinicopathological features, presence of histological variants, and outcomes. Upon searching for tumor heterogeneity, we compared the findings of primary tumors with their matched lymph node metastases. We collected data from 183 patients who underwent cystectomy for high-grade muscle-invasive urothelial carcinoma, and representative areas from the tumors and from 76 lymph node metastasis were organized in tissue microarrays. RESULTS: Basal immunohistochemical subtype (CK5 positive and CK20 negative, or CK5 positive and GATA3 negative) was associated with the squamous variant. The luminal immunohistochemical subtype (CK5 negative and CK20 positive, or CK5 negative and GATA3 positive) was associated with micropapillary and plasmacytoid variants. Remarkably, only moderate agreement was found between the immunohistochemical subtypes identified in bladder tumors and their lymph node metastasis. No significant difference in survival was observed when using either combination of the markers. CONCLUSION: This study demonstrates that these three routinely used immunohistochemical markers could be used to stratify urothelial carcinomas of the bladder into basal and luminal subtypes, which are associated with several differences in clinicopathological features.

Hepatitis E virus infection increases the risk of diabetes and severity of liver disease in patients with chronic hepatitis C virus infection

OBJECTIVES: Co-infection with hepatitis A or B viruses may aggravate liver injury in patients infected with hepatitis C virus (HCV). However, few studies have assessed co-infection with hepatitis E virus (HEV) and HCV. Therefore, this study aimed to assess the prevalence and impact of HEV infection among Brazilian patients with chronic HCV infection. METHODS: This observational study included adult patients with chronic HCV infection who were naive to antiviral therapy from January 2013 to March 2016. A total of 181 patients were enrolled, and HEV serology and PCR were performed for all patients. RESULTS: Seropositivity for anti-HEV IgG was detected in 22 (12.0%) patients and anti-HEV immunoglobulin M in 3 (1.6%). HEV RNA showed inconclusive results in nine (4.9%) patients and was undetectable in the remaining patients. HEV serology positive patients had more severe liver disease, characterized by liver fibrosis ≥3 versus ≤2 (p<0.001), Aspartate Aminotransferase-to-Platelet Ratio Index of ≥1.45 (p=0.003), and Fibrosis-4 score of ≥3.25 (p=0.001). Additionally, the odds of HEV-positive patients developing diabetes mellitus were 3.65 (95% CI 1.40-9.52) times the corresponding odds of HEV-negative patients. A case-control-based histological analysis (n=11 HEV-HCV-positive patients and n=22 HCV-positive patients) showed no significant differences between the groups. CONCLUSIONS: This prevalence is higher than that reported in previous studies of the general population in Brazil. Thus, HEV infection may influence the severity of liver disease and may represent an additional risk of developing diabetes mellitus in patients with HCV infection.

Higher values in liver elastography and meld score are mortality predictors on liver transplant waiting list / Valores mais altos na elastografia do fígado e pontuação meld são preditores de mortalidade na lista de espera do transplante de fígado

ABSTRACT Background: Liver elastography have been reported in hepatocellular carcinoma (HCC) with higher values; however, it is unclear to identify morbimortality risk on liver transplantation waiting list. Aim: To assess liver stiffness, ultrasound and clinical findings in cirrhotic patients with and without HCC on screening for liver transplant and compare the morbimortality risk with elastography and MELD score. Method: Patients with cirrhosis and HCC on screening for liver transplant were enrolled with clinical, radiological and laboratory assessments, and transient elastography. Results: 103 patients were included (without HCC n=58 (66%); HCC n=45 (44%). The mean MELD score was 14.7±6.4, the portal hypertension present on 83.9% and the mean transient elastography value was 32.73±22.5 kPa. The median acoustic radiation force impulse value of liver parenchyma was 1.98 (0.65-3.2) m/s and 2.16 (0.59-2.8) m/s in HCC group. The HCC group was significantly associated with HCV infection (OR 26.84; p<0.0001), higher levels of serum alpha-fetoprotein (OR 5.51; p=0.015), clinical portal hypertension (OR 0.25; p=0.032) and similar MELD score (p=0.693). The area under the receiver operating characteristics (AUROC) showed sensitivity and specificity for serum alpha-fetoprotein (cutoff 9.1 ng/ml), transient elastography value (cutoff value 9 kPa), and acoustic radiation force impulse value (cutoff value 2.56 m/s) of 50% and 86%, 92% and 17% and 21% and 92%, respectively. The survival group had a mean transient elastography value of 31.65±22.2 kPa vs. 50.87±20.9 kPa (p=0.098) and higher MELD scores (p=0.035). Conclusion: Elastography, ultrasound and clinical findings are important non-invasive tools for cirrhosis and HCC on screening for liver transplant. Higher values in liver elastography and MELD scores predict mortality.

RESUMO Racional: A elastografia hepática tem sido relatada nos carcinomas hepatocelulares (CHC); porém, não é claro identificar o risco de morbimortalidade na lista de transplante hepático. Objetivo: Avaliar a morbimortalidade com elastografia transitória e escore MELD. Método: Pacientes adultos com cirrose na triagem para transplante de fígado foram incluídos no estudo. Resultados: Foram incluídos 103 pacientes (sem CHC n=58 (66%), CHC n=45 (44%). O escore MELD médio foi de 14,7±6,4, a hipertensão portal foi de 83,9% e o valor médio de elastografia transitória foi de 32,73±22,5 kPa. O valor médio de ARFI (Impulsão de Força de Radiação Acústica) do parênquima hepático foi de 1,98 (0,65-3,2) m/s e 2,16 (0,59-2,8) m/s no grupo CHC. O grupo CHC foi significativamente associado à infecção por vírus da hepatite C (OR 26,84, p<0,0001), níveis mais altos de alfa-feto proteína sérica (OR 5,51; p=0,015), hipertensão portal clínica (OR 0,25; p=0,032) e pontuação MELD semelhante (p=0,693). Os valores de AUROCs (Area Under the Receiver Operating Characteristics) mostraram sensibilidade e especificidade para a alfa-feto proteína sérica (limite de 9,1 ng/ml), valor elastografia transitória (valor de corte 9 kPa) e valor ARFI (valor de corte 2,56 m/s) de 50% e 86%, 92% e 17% e 21% e 92%, respectivamente. O grupo de sobrevivência apresentou valor elastografia transitória médio de 31,65±22,2 kPa vs. 50,87±20,9 kPa (p=0,098) e valores mais elevados de MELD (p=0,035). Conclusão: Valores mais elevados na elastografia do fígado e nos escores MELD predizem a mortalidade.

Accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI) imaging, the enhanced liver fibrosis (ELF) test, APRI, and the FIB-4 index compared with liver biopsy in patients with chronic hepatitis C

OBJECTIVES: Although liver biopsy is the gold standard for determining the degree of liver fibrosis, issues regarding its invasiveness and the small amount of liver tissue evaluated can limit its applicability and interpretation in clinical practice. Non-invasive evaluation methods for liver fibrosis can address some of these limitations. The aim of this study was to evaluate the accuracy of transient elastography-FibroScan®, acoustic radiation force impulse (ARFI), enhanced liver fibrosis (ELF), the aspartate aminotransferase-to-platelet ratio index (APRI), and the FIB-4 index compared with liver biopsy in hepatitis C. METHODS: We evaluated chronic hepatitis C patients who were followed at the Division of Clinical Gastroenterology and Hepatology, Hospital das Clínicas, Department of Gastroenterology of University of São Paulo School of Medicine, São Paulo, Brazil, and who underwent liver biopsy. The accuracy of each method was determined by a receiver operating characteristic (ROC) curve analysis, and fibrosis was classified as significant fibrosis (≥F2), advanced fibrosis (≥F3), or cirrhosis (F4). The Obuchowski method was also used to determine the diagnostic accuracy of each method at the various stages of fibrosis. In total, 107 FibroScan®, 51 ARFI, 68 ELF, 106 APRI, and 106 FIB-4 analyses were performed. RESULTS: A total of 107 patients were included in the study. The areas under the ROC curve (AUROCs) according to fibrosis degree were as follows: significant fibrosis (≥F2): FibroScan®: 0.83, FIB-4: 0.76, ELF: 0.70, APRI: 0.69, and ARFI: 0.67; advanced fibrosis (≥F3): FibroScan®: 0.85, ELF: 0.82, FIB-4: 0.77, ARFI: 0.74, and APRI: 0.71; and cirrhosis (F4): APRI: 1, FIB-4: 1, FibroScan®: 0.99, ARFI: 0.96, and ELF: 0.94. The accuracies of transient elastography, ARFI, ELF, APRI and FIB-4 determined by the Obuchowski method were F0-F1: 0.81, 0.78, 0.44, 0.72 and 0.67, respectively; F1-F2: 0.73, 0.53, 0.62, 0.60, and 0.68, respectively; F2-F3: 0.70, 0.64, 0.77, 0.60, and 0.67, respectively; and F3-F4: 0.98, 0.96, 0.82, 1, and 1, respectively. CONCLUSION: Transient elastography remained the most effective method for evaluating all degrees of fibrosis. The accuracy of all methodologies was best at F4.

Quantitative analysis of lymph nodes in neck dissection specimens. Morphologic study

ABSTRACT PURPOSE: To quantify the amount of lymph nodes harvested in modified radical neck dissection. METHODS: Cross-sectional anatomical study conducted in 28 non-preserved cadavers. RESULTS: The mean number of lymph nodes found in each nodal level of the 56 modified radical neck dissections performed were: level IA - 1.5 (95% CI: 1.1 - 1.8), level IB - 2.5 (95% CI: 2.1 - 2.9), level IIA - 7.2 (95% CI: 6.0 - 8.5), IIB level - 6.5 (95% CI: 5.5 - 7.4), level III - 6.6 (95% CI: 5.7 - 7.4), level IV - 8.6 (95% CI: 7.1 - 10.1), level V - 11 (95% CI: 9.2 - 12.7), totalizing 43.8 lymph nodes (95% CI: 40.3 - 47.4). CONCLUSION: The results defined a parameter in relation to the minimum recommended nodal yield in a modified radical neck dissection, as well as the number of lymph nodes in each level of this dissection, performed in clinical practice.

Quantification of C4d deposition and hepatitis C virus RNA in tissue in cases of graft rejection and hepatitis C recurrence after liver transplantation

Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection.

Avaliação do processo de dispensação de medicamentos aos portadores de hepatite C crônica em farmácias de componentes especializados da Secretaria de Estado da Saúde de São Paulo, em 2010 / Evaluation of medication dispensation to patients with chronic hepatitis C in São Paulo State Health Department specialized unit pharmacies, Brazil, in 2010 / Evaluación del proceso de dispensación de medicamentos a los portadores de hepatitis C crónica en farmacias de componentes especializados de la Secretaría de Estado de la Salud de São Paulo, en 2010

Objetivo: avaliar a dispensação dos medicamentos para o tratamento da hepatite viral C crônica verificando sua adequação às recomendações do Ministério da Saúde e estimar gastos com a dispensação inadequada dos medicamentos. Métodos: estudo transversal descritivo sobre 643 prontuários de pacientes portadores de hepatite viral C crônica cadastrados em 2010, em quatro farmácias do Sistema de Dispensação de Medicamentos Excepcionais da Secretaria de Estado da Saúde de São Paulo (SES/SP). Resultados: foram identificadas diferenças expressivas entre as farmácias, em relação ao processo de dispensação dos medicamentos; com base nos laudos das biópsias, estimou-se que 64,5 por cento dos pacientes teriam indicação de tratamento e que R$1.096.132,32 foram despendidos com o tratamento de pacientes em não conformidade com as diretrizes terapêuticas. Conclusão: faz-se necessária uma padronização mais rigorosa nos procedimentos de dispensação de medicamentos para o tratamento da hepatite C crônica na rede pública da SES/SP...

Objective: to assess whether the medication dispensing procedures for chronic viral hepatitis C treatment follow Ministry of Health guidelines and to estimate possible costs of inadequate procedures. Methods: this was a descriptive cross-sectional study of 643 medical records of patients with chronic viral hepatitis C registered in 2010 with four São Paulo State Health Department (SES/SP) Exceptional Drug Dispensing System pharmacies. Results: relevant discrepancies regarding medication dispensing procedures were detected. Based on the histopathology reports it was estimated that only 64.5 per cent of assessed patients actually met the guideline criteria for treatment and therefore R$ 1,096,132.32 was spent in nonconformity with the guidelines. Conclusion: a more rigorous standardization of procedures for dispensing medication for the treatment of chronic hepatitis C in SES/SP Public Health Services must be implemented...

OBJETIVO: evaluar la dispensación de los medicamentos para el tratamiento de la hepatitis viral C crónica, verificando su adecuación a las recomendaciones del Ministerio de Salud y estimar gastos con la dispensación inadecuada de los medicamentos.MÉTODOS: estudio transversal descriptivo sobre 643 prontuarios de pacientes portadores de hepatitis viral C crónica registrados en 2010, en cuatro farmacias del Sistema de Dispensación de Medicamentos Excepcionales de la Secretaría de Estado de la Salud de São Paulo (SES/SP).RESULTADOS: se identificaron diferencias expresivas entre las farmacias, en relación al proceso de dispensación de los medicamentos; con base en los laudos de las biopsias, se estimó que 64,5% de los pacientes tendría indicación de tratamiento y que se gastaron R$ 1.096.132,32 con el tratamiento de pacientes en no-conformidad con las directrices terapéuticas.CONCLUSIÓN: es necesaria una estandarización más rigurosa en los procedimientos de dispensación de medicamentos para el tratamiento de la hepatitis C crónica en la red pública de la SES/SP...

Espessura tumoral como fator de risco independente para a recorrência precoce em portadores de carcinomas espinocelulares da cavidade oral / Tumor thickness as an independent risk factor of early recurrence in oral cavity squamous cell carcinoma

Introdução: A espessura tumoral é reconhecidamente um fator de risco para a presença de metástases ocultas e para menor sobrevivência em carcinoma espinocelular da cavidade oral, porém o tratamento adjuvante desses pacientes não foi alterado. O intervalo livre de doença é outro fator associado a pior prognóstico, e é sabido que as recorrências precoces também diminuem a sobrevivência desses pacientes. Objetivo: Determinar se a espessura tumoral é um fator de risco para recorrências precoces em portadores de carcinomas espinocelulars de cavidade oral operados. Pacientes e Métodos: Estudo de coorte retrospectivo conduzido no Instituto do Câncer do Estado de São Paulo (ICESP) com 57 pacientes portadores de carcinomas espinocelulars de boca, exceto lábios, e virgens de tratamento prévio. Analisou-se o desenvolvimento de recorrência de doença (locorregional ou a distância) nos primeiros 12 meses após o tratamento inicial. Os aspectos histopatológicos dos espécimes foram analisados. Resultados: Espessura tumoral maior do que 10 mm (p=0,034), invasão angiolinfática (p=0,001), invasão perineural (p=0,041) e metástases linfonodais cervicais (p=0,021) apresentaram associação com menor sobrevivência livre de doença no primeiro ano após o tratamento (teste de LogRank). À análise multivariada, a espessura tumoral maior que 10 mm foi identificada como um fator de risco independente de progressão inicial da doença. A radioterapia pós-operatória pareceu representar um fator protetor contra a progressão inicial dos tumores com espessura superior a 10 mm. Conclusão: A espessura tumoral superiores a 10 mm representa um fator de risco independente para a progressão precoce do carcinoma espinocelular de cavidade oral cirurgicamente tratado. Terapias adjuvantes, especialmente a radioterapia, devem ser consideradas, a despeito da coexistência de outros fatores histológicos de risco bem estabelecidos.

Introduction: Tumor thickness has been recognized as a risky factor for occult regional metastasis and survival in oral squamous cell carcinoma. Nevertheless, the adjuvant treatment of these neoplasms did not change regarding the thickness of the tumor. Disease-free interval is another factor associated with prognosis in head and neck cancer, and, it is known that early recurrences adversely affect survival. Objective: To determine if tumor thickness is a risk factor related to the development of early recurrences in surgically treated oral cavity squamous cell carcinoma. Methods: Retrospective cohort study conducted at Instituto do Câncer do Estado de São Paulo (ICESP). Results: Fifty-seven patients with oral cavity squamous cell carcinoma (excluding lip tumors and patients previously submitted to any treatment) were analyzed regarding the occurrence of an early disease progression (locoregional or distant metastasis) within the first 12 months after initial treatment. Tumor thickness and other histological characteristics related to the development of recurrence up to one year after treatment were tested. Results demonstrated that tumor thickness greater than 10 mm (P=0.034), as well as angiolymphatic invasion (P=0.001), perineural invasion (P=0.041) and lymph node metastasis (P=0.021) were associated with a worse 12-month disease-free survival (Log-Rank test). In multivariate analysis, tumor thickness greater than 10 mm emerged as an independent risk factor for early recurrence in oral cavity tumors (HR=3.4, CI95%: 1.005-11.690; P=0.049 - Cox regression). Post-operative radiotherapy seems to be a protective factor for early recurrences in patients with tumor thickness greater than 10 mm (P=0.017 - Log-Rank test; HR=0.32, CI95%: 0.12-0.87, P=0.026 - Cox regression). Conclusion: The results of the present research suggest that tumor thickness greater than 10 mm may be an independent adverse factor for early progression of surgically treated oral cavity squamous cell carcinoma. Adjuvant therapies, in particular post-operative radiotherapy, should be advocated in this group of patients, regardless of the co-existence of other well described histological risk factors.

Effects of the administration of pentoxifylline and prednisolone on the evolution of portal fibrogenesis secondary to biliary obstruction in growing animals: immunohistochemical analysis of the expression of TGF-β and VEGF

OBJECTIVE: During the neonatal and infancy periods, some chronic liver diseases may lead to progressive hepatic fibrosis, which is a condition that can ultimately result in the loss of organ function and severe portal hypertension necessitating hepatic transplantation. In a previous report, pharmacological interventions were demonstrated to modulate hepatic fibrosis induced by bile duct ligation in young rats. The administration of pentoxifylline or prednisolone, or the combination of both, resulted in reduced fibrogenesis in portal spaces. The objectives of the present study were to evaluate the expression of transforming growth factor β and vascular endothelial growth factor after bile duct ligation in young rats and to assess the effect of those same drugs on cytokine expression. METHODS: In this experimental study, 80 young rats (21 or 22 days old) were submitted either to laparotomy and common bile duct ligation or to sham surgery. The animals were allocated into four groups according to surgical procedure, and the following treatments were administered: (1) common bile duct ligation + distilled water, (2) sham surgery + distilled water, (3) common bile duct ligation + pentoxifylline, or (4) common bile duct ligation + prednisolone. After 30 days, a hepatic fragment was collected from each animal for immunohistochemical analysis using monoclonal antibodies against transforming growth factor β and vascular endothelial growth factor. Digital morphometric and statistical analyses were performed. RESULTS: The administration of pentoxifylline reduced the transforming growth factor β-marked area and the amount of transforming growth factor β expressed in liver tissue. This effect was not observed after the administration of prednisolone. There was a significant reduction in vascular endothelial growth factor expression after the administration of either drug compared with the non-treatment group. CONCLUSIONS: The administration of pentoxifylline to cholestatic young rats resulted in the diminished expression of transforming growth factor β and vascular endothelial growth factor in liver tissue. The administration of steroids resulted in the diminished expression of vascular endothelial growth factor only. These pathways may be involved in hepatic fibrogenesis in young rats submitted to bile duct ligation and exposed to pentoxifylline or prednisolone.

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.

Hiperparatireoidismo secundário: fatores prognósticos de recidiva atribuída ao implante após paratireoidectomia total e auto-implante / Secondary hyperparathyroidism: prognostic factors of graft-dependent recurrence after total parathyroidectomy adn parathyroid autotransplantation

Introdução: Quando o tratamento clínico do hiperparatireoidismo secundário falha, é recomendada a paratireoidectomia. Na DCCP HCFMUSP, a cirurgia de escolha é a paratireoidectomia total com auto-implante imediato de fragmentos de paratireoide em membro superior. Nestes casos, caso haja recidiva do hiperparatireoidismo, pode ser causada pelo tecido implantado e, em alguns casos, há necessidade de ressecção dos implantes. Objetivo: O estudo atual tem como objetivo avaliar os pacientes submetidos a este tratamento e identificar fatores clínicos que podem prever recidiva atribuída ao implante. Método: Analisamos retrospectivamente dados de 57 doentes e identificamos nove recidivas do hiperparatireoidismo atribuídas ao implante, que foram submetidos a 14 procedimentos de retirada. Escolhemos um grupo controle (pareado por sexo e idade) de pacientes submetidos a paratireoidectomia total com auto-implante, sem recidiva por pelo menos dois anos. Resultados: Analisamos dados clínicos e laboratoriais, assim como pesos e padrões histológicos das paratireoides operadas. Houve diferença estatisticamente significante entre a dosagem pré-operatória de PTH (p=0,0091), tamanho da paratireoide ressecada durante a primeira cirurgia (p=0,0052) e padrão nodular na paratireoide selecionada para implante (p=0,0152) e recidiva no implante. Oito dos nove pacientes diagnosticados com recidiva tiveram controle da doença após os procedimentos. Todos os dados estatisticamente significativos foram pré ou peri-operatórios, e podem ajudar em decisões intra-operatórias. Conclusões: Baseado no estudo, sugerimos que a quantidade de tecido paratireoideo necessário a ser implantado pode variar conforme a dosagem sérica de PTH, o tamanho das glândulas e a presença de hiperplasia nodular no intra-operatório. As glândulas maiores e com hiperplasia nodular devem ser evitadas para implante.

Introduction: When clinical treatment of secondary hyperparathyroidism fails, parathyroidectomy is mandatory. Total parathyroidectomy and immediate parathyroid autotransplantation in the forearm is the standard treatment at the DCCP HCFMUSP. In these cases, if hyperparathyroidism reccurs, it may be caused by hyperplastic graft tissue and, sometimes, reintervention is needed to resect hyperplasic implants. Objective: The present study seeks to evaluate patients submitted to this treatment and try to clarify clinical factors that could predict hyperparathyroidism recurrence due to graft hyperplasia. Method: We could retrospectively analyse data from 57 patients, and identify nine recurrences of hyperparathyroidism caused by graft hyperplasia, submitted to 14 implant resections. We choose a control group: autotransplantation without recurrence for at least two years (matched by age and sex). Results: We analyzed pre-operative clinical and laboratorial data, parathyroid weight and histological patterns. There were statistically significant differences among preoperative serum PTH (p=0,0091), parathyroid gland size resected during first surgery (p=0,0052) and nodular pattern at parathyroid chosen for transplantation (p=0,0152) and recurrence caused by graft tissue. In all patients, but one, the disease is controlled. All statistically significant identified risk factors were pre or perioperative and may help intra operative decisions. Conclusion: Based on this study, we suggest that the amount of graft tissue may be influenced by pre-op PTH levels, size of glands and presence of nodular hyperplasia. A large and/or nodular glands should be avoided for implants.

Adenocarcinoma of the esophagogastric junction: relationship between clinicopathological data and p53, cyclin D1 and Bcl-2 immunoexpressions / Adenocarcinoma da junção esôfago-gástrica: relação entre os dados cllnipatológicos e a imunoexpressão de p53, ciclina D1 e Bcl-2

Context: Esophagogastric junction adenocarcinoma has an aggressive behavior, and TNM (UICC) staging is not always accurate enough to categorize patient's outcome. Objectives: To evaluated p53, cyclin D1 and Bcl-2 immunoexpressions in esophagogastric junction adenocarcinoma patients, without Barrett's esophagus, and to compared to clinicopathological characteristics and survival rate. Methods: Tissue sections from 75 esophagogastric junction adenocarcinomas resected from 1991 to 2003 were analyzed by immunohistochemistry for p53, cyclin D1 and Bcl-2 using streptavidin-biotin-peroxidase method. The mean follow-up time was 60 months SD = 61.5 (varying from 4 to 273 months). Results: Fifty (66.7 percent) of the tumors were intestinal type and 25 (33.3 percent) were diffuse. Vascular, lymph node and perineural infiltration were verified in 16 percent, 80 percent and 68 percent of the patients, respectively. The patients were distributed according to the TNM staging in IA in 4 (5.3 percent), IB in 10 (13.3 percent), II in 15 (20 percent), IIA in 15 (20 percent), IIIB in 15 (20 percent) and IV in 16 (21.3 percent). Immunohistochemical analysis was positive for p53, cyclin D1 and bcl-2 in 68 percent, 18.7 percent and 100 percent, respectively. There was no association between immunoexpression and vascular and/or perineural invasions, clinicopathological characteristics and patients' survival rate. Conclusion: In this selected population, there was no association between the immunomarkers, p53, cyclin D1 and bcl-2 and clinicopathological data and/or overall survival.

Contexto: O adenocarcinoma da junção esôfago-gástrica tem um comportamento agressivo e o estádio TNM não é sempre suficiente para categorizar o paciente de acordo com a evolução do mesmo. Objetivo: Avaliar a imunoexpressão do p53, ciclina D1 e Bcl-2 em pacientes com adenocarcinoma da junção esôfago-gástrica sem esôfago de Barrett e comparar com as características clínicas e sobrevida. Métodos: Cortes histológicos de 75 adenocarcinomas da esôfago-gástrica ressecados de 1991 a 2003 foram analisados por imunoistoquímica para o p53, ciclina D1 e Bcl-2, usando-se o método da estreptavidina-biotina-peroxidase. O tempo médio de seguimento foi de 60 meses, DP=61,5 (variando de 4 a 273 meses). Resultados: Cinquenta (66,7 por cento) dos tumores eram do tipo intestinal e 25 (33,3 por cento) eram difusos. Verificou-se infiltração vascular, linfonodal e perineural em 16 por cento, 80 por cento e 68 por cento dos pacientes, respectivamente. O estádio TNM foi IA em 4 (5,3 por cento), II em 15 (20 por cento), IIIA em 15 (20 por cento), IIIB em 15 (20 por cento) e IV em 16 (21,3 por cento). A análise imunoistoquímica foi positiva para p53, ciclina D1 e Bcl-2 em 68 por cento, 18,7 por cento e 100, respectivamente. Não houve associação entre a imunoexpressão e invasão vascular ou perineural, características clinicopatológicas e sobrevida geral. Conclusão: Nesta população selecionada, não houve associação entre os imunomarcadores, p53, ciclina D1 e Bcl-2 e os dados clinicopatológicos e a sobrevida geral dos pacientes.

Clínica médica / Medical clinic

A obra faz parte de um projeto da Faculdade de Medicina da Universidade de São Paulo (FMUSP) e do Hospital das Clínicas da FMUSP de editar livros que reúnam o conhecimento e a experiência dos médicos, pesquisadores e professores dessas instituições. Tem por objetivo ser um livro de Clínica Médica dedicado a estudantes de Medicina, médicos residentes e médicos que atuam nas áreas gerais de atendimento a adultos. Pode servir, também, de consulta para especialistas que necessitam aprofundar conhecimentos em áreas da Clínica Médica fora de sua especialidade. Nos últimos anos, houve um extraordinário avanço em várias áreas da Medicina, tanto no entendimento da fisiopatologia como nos métodos de diagnóstico e no tratamento de diversas doenças. A Medicina continua a ser, e provavelmente sempre será, uma profissão em que o conhecimento científico e a competência técnica do médico devem estar associados a uma profunda visão humanista, ética e de compromisso com o paciente. Neste livro, procuramos continuar a abordagem geral do paciente com o conhecimento profundo de Epidemiologia, Fisiopatologia, diagnóstico, tratamento e prognóstico de cada doença ou síndrome relevante para a prática do clínico. Para facilitar a leitura, dividimos o livro em sete volumes, todos coerentes com o mesmo projeto editorial.