Epstein-Barr Virus Positive Gastric Cancer: A Distinct Subtype Candidate for Immunotherapy.

BACKGROUND: Epstein-Barr virus (EBV) positive gastric cancer (GC) has been described as a distinct molecular subtype of the disease, especially associated with gastric carcinoma with lymphoid stroma (GCLS). The possibility that EBV associated GC (EBVaGC) had better prognosis and may be susceptible to immunotherapy has increased the interest in this subtype. However, immune checkpoint and survival of EBVaGC are still controversial, especially with regard to GCLS and conventional gastric adenocarcinoma (CGA). This study aimed to evaluate the clinicopathological characteristics, immunohistochemical profiles and prognosis of EBVaGC according to the histological type GCLS and CGA. METHODS: we retrospectively evaluated a series of EBVaGC who underwent gastrectomy with D2-lymphadenectomy. Biomarkers and tumor-infiltrating cells were evaluated by immunohistochemistry. PD-L1 was evaluated using a combined positive score (CPS). RESULTS: From a total of 30 EBVaGC, 14 (46.7%) were identified as GCLS and 16 (53.3%) as CGA (9 Intestinal, 6 diffuse, 1 undetermined). There were no significant differences in age, sex, and pTNM between GCLS and CGA. CPS-positivity and high-CD8+ was significantly higher in GCLS compared with CGA (P = 0.007 and P = 0.005, respectively). Diffuse EBVaGC had worse survival than intestinal type (P = 0.020). There was no difference in survival between GCLS and intestinal CGA (P = 0.260). In multivariate analysis, CPS and pN status were related with survival in EBVaGC. CONCLUSIONS: CGLS was associated with a predominance of CD8+ cell infiltration and PD-L1 expression. CPS and lymph node metastasis were independent factors associated with prognosis in EBVaGC. These results suggest that specifically EBV-positive GCLS may be prime candidates for PD-1 directed therapy.

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.

INTRAHEPATIC BILIARY PROLIFERATIONS: HISTOPATHOLOGY AND POTENTIAL IMMUNOHISTOCHEMICAL MARKERS.

•Intrahepatic biliary proliferations represent a spectrum varying from reactive to malignant entities. •Clinical and imaging patterns may be similar, requiring histopathological and immunohistochemistry for precise diagnosis. 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.

INTRAPERITONEAL CHEMOTHERAPY FOR GASTRIC CANCER WITH PERITONEAL CARCINOMATOSIS: STUDY PROTOCOL OF A PHASE II TRIAL.

BACKGROUND: Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS: The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS: This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18-75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy. RESULTS: The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled. CONCLUSIONS: Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.

GASTRIC CANCER WITH POSITIVE EXPRESSION OF ESTROGEN RECEPTOR ALPHA: A CASE SERIES FROM A SINGLE WESTERN CENTER. / CÂNCER GÁSTRICO COM EXPRESSÃO POSITIVA DO RECEPTOR DE ESTROGÊNIO ALFA: UMA SÉRIE DE CASOS DE UM ÚNICO CENTRO OCIDENTAL.

AIM: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.

OBJETIVO: Apesar do avanço nas terapias, o prognóstico de pacientes com câncer gástrico (CG) avançado permanece ruim. Vários estudos demonstraram a expressão do receptor de estrogênio alfa (REa), porém seu significado no CG permanece controverso. relatar uma série de casos de CG com expressão de REa-positivo, e descrever suas características clínicopatológicas e prognóstico. MÉTODOS: Avaliamos retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa entre 2009 e 2019. A expressão do REa foi avaliada por imuno-histoquímica por meio da construção de microarranjos de tecido (TMA). Pacientes com adenocarcinoma gástrico ERa-negativos serviram como grupo comparação. RESULTADOS: No período selecionado, foram identificados 6 (1,8%) CG REa-positivos entre os 345 CG analisados. Todos os ERa-positivos eram homens, com idades entre 34-78 anos, tinham CG do tipo difuso de Lauren e pN+. Comparado aos REa-negativos, os CG REa-positivos associaram-se a maior diâmetro (p=0,031), gastrectomia total (p=0,012), tipo de Lauren difuso/misto (p=0,012), presença de invasão perineural (p=0,030) e metástase linfonodal (p=0,215). O estágio final foi o IIA em um caso; IIIA em três e IIIB em dois casos. Entre os 6 pacientes REa -positivos, 3 tiveram recorrência da doença (peritoneal) e morreram. Não houve diferença significativa na sobrevida entre os grupos REa-positivo e negativo. CONCLUSÃO: A expressão do REa é menos comum no CG, estando associada à histologia difusa e presença de metástases linfonodal, podendo servir como um marcador relacionado à progressão tumoral e pior prognóstico. Além disso, uma alta taxa de recorrência peritoneal foi observada em pacientes ERa-positivos.

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.

Intraperitoneal chemotherapy for gastric cancer with peritoneal carcinomatosis: study protocol of a phase ii trial / Quimioterapia intraperitoneal para o câncer gástrico com carcinomatose peritoneal: protocolo de estudo de um ensaio de fase ii

ABSTRACT BACKGROUND: Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS: The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS: This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18-75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy. RESULTS: The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled. CONCLUSIONS: Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.

RESUMO RACIONAL: A carcinomatose peritoneal no câncer gástrico é considerada uma doença fatal, sem expectativa de cura definitiva. Como a quimioterapia sistêmica não é suficiente para conter a doença, uma abordagem multimodal associando a quimioterapia intraperitoneal à cirurgia pode representar uma alternativa para esses casos. OBJETIVOS: Investigar o papel da quimioterapia intraperitoneal em pacientes com câncer gástrico estágio IV com metástases peritoneais. MÉTODOS: Trata-se de um ensaio clínico prospectivo unicêntrico, braço único, fase II (NCT05541146). Pacientes com os seguintes critérios de inclusão serão submetidos à implantação de cateter peritoneal para quimioterapia intraperitoneal: adenocarcinoma gástrico estágio IV; idade 18-75 anos; carcinomatose peritoneal com índice de câncer peritoneal<12; ECOG 0/1; bom estado clínico e exames laboratoriais dentro da normalidade. O protocolo do estudo consiste em 4 ciclos de quimioterapia intraperitoneal com Paclitaxel associado à quimioterapia sistêmica. Após o tratamento, os pacientes com resposta peritoneal avaliada por laparoscopia serão submetidos à gastrectomia de conversão. RESULTADOS: O desfecho primário é a taxa de resposta peritoneal completa. A sobrevida livre de progressão e global são outros desfechos avaliados. O estudo foi iniciado em julho de 2022 e os pacientes serão selecionados para inclusão até que 30 sejam inscritos. CONCLUSIONS: Terapias para pacientes com câncer gástrico avançado foram avaliadas em ensaios clínicos, mas sem sucesso em pacientes com metástase peritoneal. O tratamento proposto neste estudo pode ser promissor, com fácil implantação do cateter e regime de quimioterapia intraperitoneal ambulatorial. Verificar a eficácia e segurança do Paclitaxel associado à quimioterapia sistêmica é um progresso importante que o presente estudo pretende investigar.

Experimental models of hepatectomy and liver regeneration using newborn and weaning rats.

OBJECTIVES: Liver regeneration is a complex process that has not been completely elucidated. The model most frequently used to study this phenomenon is 70% hepatectomy in adult rats; however, no papers have examined this effect in developing animals. The aims of the present study were: 1) to standardize two models of partial hepatectomy and liver regeneration in newborn suckling and weaning rats, and 2) to study the evolution of remnant liver weight and histological changes of hepatic parenchyma on the days that follow partial hepatectomy. METHODS: Fifty newborn and forty-four weaning rats underwent 70% hepatectomy. After a midline incision, compression on both sides of the upper abdomen was performed to exteriorize the right medial, left medial and left lateral hepatic lobes, which were tied inferiorly and resected en bloc. The animals were sacrificed on days 0 (just after hepatectomy), 1, 2, 3, 4 and 7 after the operation. Body and liver weight were determined, and hepatic parenchyma was submitted to histological analysis. RESULTS: Mortality rates of the newborn and weaning groups were 30% and 0%, respectively. There was a significant decrease in liver mass soon after partial hepatectomy, which completely recovered on the seventh day in both groups. Newborn rat regenerating liver showed marked steatosis on the second day. In the weaning rat liver, mitotic figures were observed earlier, and their amount was greater than in the newborn. CONCLUSIONS: Suckling and weaning rat models of partial hepatectomy are feasible and can be used for studies of liver regeneration. Although similar, the process of hepatic regeneration in developing animals is different from adults.

DETECTION OF OCCULT LYMPH NODE TUMOR CELLS IN NODE-NEGATIVE GASTRIC CANCER PATIENTS.

Background: The presence of lymph nodes metastasis is one of the most important prognostic indicators in gastric cancer. The micrometastases have been studied as prognostic factor in gastric cancer, which are related to decrease overall survival and increased risk of recurrence. However, their identification is limited by conventional methodology, since they can be overlooked after routine staining. Aim: To investigate the presence of occult tumor cells using cytokeratin (CK) AE1/AE3 immunostaining in gastric cancer patients histologically lymph node negative (pN0) by H&E. Methods: Forty patients (T1-T4N0) submitted to a potentially curative gastrectomy with D2 lymphadenectomy were evaluated. The results for metastases, micrometastases and isolated tumor cells were also associated to clinicopathological characteristics and their impact on stage grouping. Tumor deposits within lymph nodes were defined according to the tumor-node-metastases guidelines (7th TNM). Results: A total of 1439 lymph nodes were obtained (~36 per patient). Tumor cells were detected by immunohistochemistry in 24 lymph nodes from 12 patients (30%). Neoplasic cells were detected as a single or cluster tumor cells. Tumor (p=0.002), venous (p=0.016), lymphatic (p=0.006) and perineural invasions (p=0.04), as well as peritumoral lymphocytic response (p=0.012) were correlated to CK-positive immunostaining tumor cells in originally negative lymph nodes by H&E. The histologic stage of two patients was upstaged from stage IB to stage IIA. Four of the 28 CK-negative patients (14.3%) and three among 12 CK-positive patients (25%) had disease recurrence (p=0.65). Conclusion: The CK-immunostaining is an effective method for detecting occult tumor cells in lymph nodes and may be recommended to precisely determine tumor stage. It may be useful as supplement to H&E routine to provide better pathological staging.

Racional: A presença de metástase em linfonodos é um dos indicadores prognósticos mais importantes no câncer gástrico. As micrometástases têm sido estudadas como fator prognóstico no câncer gástrico, sendo relacionadas à diminuição da sobrevida global e aumento do risco de recidiva da doença. Entretanto, sua identificação é limitada pela metodologia convencional, uma vez que podem não ser identificadas pela rotina histopatológica por meio da coloração de H&E. Objetivos: Investigar a presença de células tumorais ocultas através de imunoistoquimica utilizando as citoqueratinas (CK) AE1/AE3 em pacientes com câncer gástrico com linfonodos histologicamente classificados como negativos por H&E. Métodos: Quarenta pacientes (T1-T4N0) submetidos à gastrectomia potencialmente curativa com linfadenectomia D2 foram avaliados. A presença de metástases, micrometástases e células tumorais isoladas foram correlacionadas com características clínicopatológicas e impacto no estadiamento. Os depósitos tumorais nos linfonodos foram classificados de acordo com o sistema TNM (7º TNM). Resultados: Um total de 1439 linfonodos foi obtido (~36 por paciente). Células tumorais foram detectadas por imunoistoquimica em 24 linfonodos de 12 pacientes (30%). As células neoplásicas estavam presentes na forma isolada ou em cluster. Invasão tumoral (p=0,002), venosa (p=0,016), linfática (p=0,006) e perineural (p=0,04), assim como resposta linfocítica peritumoral (p=0,012) foram correlacionadas com linfonodos CK-positivos que originalmente eram negativos à H&E. Dois pacientes tiveram o estadiamento alterado, migrando do estádio IB para IIA. Quatro dos 28 CK-negativos (14,3%) e três dos 12 CK-positivos (25%) tiveram recorrência da doença (p=0,65). Conclusão: A imunoistoquimica é meio eficaz para a detecção de células tumorais ocultas em linfonodos, podendo ser recomendada para melhor determinar o estágio do tumor. Ela pode ser útil como técnica complementar à rotina de H&E, de modo a fornecer melhor estadiamento patológico.

Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation.

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Câncer gástrico com expressão positiva do receptor de estrogênio alfa: uma série de casos de um único centro ocidental / Gastric cancer with positive expression of estrogen receptor alpha: a case series from a single western center

RESUMO - RACIONAL: Apesar do avanço nas terapias, o prognóstico de pacientes com câncer gástrico (CG) avançado permanece ruim. Vários estudos demonstraram a expressão do receptor de estrogênio alfa (REa), porém seu significado no CG permanece controverso. OBJETIVO: relatar uma série de casos de CG com expressão de REa-positivo, e descrever suas características clínicopatológicas e prognóstico. MÉTODOS: Avaliamos retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa entre 2009 e 2019. A expressão do REa foi avaliada por imuno-histoquímica por meio da construção de microarranjos de tecido (TMA). Pacientes com adenocarcinoma gástrico ERa-negativos serviram como grupo comparação. RESULTADOS: No período selecionado, foram identificados 6 (1,8%) CG REa-positivos entre os 345 CG analisados. Todos os ERa-positivos eram homens, com idades entre 34-78 anos, tinham CG do tipo difuso de Lauren e pN+. Comparado aos REa-negativos, os CG REa-positivos associaram-se a maior diâmetro (p=0,031), gastrectomia total (p=0,012), tipo de Lauren difuso/misto (p=0,012), presença de invasão perineural (p=0,030) e metástase linfonodal (p=0,215). O estágio final foi o IIA em um caso; IIIA em três e IIIB em dois casos. Entre os 6 pacientes REa -positivos, 3 tiveram recorrência da doença (peritoneal) e morreram. Não houve diferença significativa na sobrevida entre os grupos REa-positivo e negativo. CONCLUSÃO: A expressão do REa é menos comum no CG, estando associada à histologia difusa e presença de metástases linfonodal, podendo servir como um marcador relacionado à progressão tumoral e pior prognóstico. Além disso, uma alta taxa de recorrência peritoneal foi observada em pacientes ERa-positivos.

ABSTRACT - BACKGROUND: Despite advances in therapies, the prognosis of patients with advanced gastric cancer (GC) remains poor. Several studies have demonstrated the expression of estrogen receptor alpha (ERa); however, its significance in GC remains controversial. AIM: The present study aims to report a case series of GC with ERa-positive expression and describe their clinicopathological characteristics and prognosis. METHODS: We retrospectively evaluated patients with GC who underwent gastrectomy with curative intent between 2009 and 2019. ERa expression was assessed by immunohistochemistry through tissue microarray construction. Patients with ERa-negative gastric adenocarcinoma served as a comparison group. RESULTS: During the selected period, 6 (1.8%) ERa-positive GC were identified among the 345 GC patients analyzed. All ERa-positive patients were men, aged 34-78 years, and had Lauren diffuse GC and pN+ status. Compared with ERa-negative patients, ERa-positive patients had larger tumor size (p=0.031), total gastrectomy (p=0.012), diffuse/mixed Lauren type (p=0.012), presence of perineural invasion (p=0.030), and lymph node metastasis (p=0.215). The final stage was IIA in one case, IIIA in three cases, and IIIB in two cases. Among the six ERa-positive patients, three had disease recurrence (peritoneal) and died. There was no significant difference in survival between ERa-positive and ERa-negative groups. CONCLUSIONS: ERa expression is less common in GC, is associated with diffuse histology and presence of lymph node metastasis, and may be a marker related to tumor progression and worse prognosis. Also, a high rate of peritoneal recurrence was observed in ERa-positive patients.

Patients with chronic hepatitis C and normal transaminases.

Hepatitis C virus infection evolves progressively persisting in the majority of patients (85%). Most patients have high ALT (alanine aminotransferase) levels and approximately 25% normal ALT. The latter are usually female and there is no association between genotype and severity of hepatic lesion. Histologic analysis usually shows small lesion and absence or low amount of fibrosis, despite cirrhosis having been reported. Aiming at assessing prevalence, demographic, genotypical and anatomopathological characteristics in patients with normal ALT levels, we have carried out a study of 68 chronic hepatitis C patients between January 1997 and April 2000. There was a prevalence of 13.8% chronic hepatitis C patients with normal ALT levels, 45.6% of which were male and 54.4% female, the mean age being 38 +/- 13 years. We found a predominance of genotype 1 in 84.7% of the patients, genotype 2 in 6.8% and genotype 3 in 10.7%. In 52.9% of the cases liver biopsies revealed liver reaction, periportal activity score 0-1 was observed in 85.3% of the patients and score 2-4 was seen in 14.7%. Structural activity score 0-1 was seen in 73.5% of the patients and score 2-4 in 26.5% of them. Periportal activity > or = 2 and structural activity > 1 was seen in 29%, but steatosis was not seen in 73.5%. Our results suggest the need to revisit for liver biopsy practice in patients with chronic hepatitis C and normal transaminases.

Chloroquine for the maintenance of remission of autoimmune hepatitis: results of a pilot study.

BACKGROUND: Due to the risks related to long-term treatment with prednisone and azathioprine, most clinicians try to withdraw these drugs when patients with autoimmune hepatitis are in remission. However, there is a high probability of relapse, and most patients end up receiving maintenance treatment. AIM: To evaluate the safety and efficacy of maintenance treatment with chloroquine in the prevention of autoimmune hepatitis relapses. METHODS: Classical treatment was stopped after achievement of biochemical and histological remission of autoimmune hepatitis. Chloroquine diphosphate, 250 mg daily, was given for at least 12 months or until the occurrence of relapses defined by levels of aminotransferases at least twice the upper normal values. RESULTS: Fourteen patients were consecutively treated and compared with 18 historical controls. There was a 6.49 (1.38-30.30) greater chance of relapse in the historical controls when compared with patients treated with chloroquine (72.2% x 23.5%; 0.031). CONCLUSIONS: The group treated with chloroquine had a lower frequency of relapses. Chloroquine was safe in patients with autoimmune hepatitis and hepatic cirrhosis without decompensation, on 250 mg daily up to 2 years. These preliminary results provide a basis for upcoming controlled studies comparing chloroquine with placebo or for maintenance treatment with prednisone and/or azathioprine for the prevention of autoimmune hepatitis relapses.

Different methods of cell quantification can lead to different results: a comparison of digital methods using a pilot study of dendritic cells in HIV-positive patients

BACKGROUND: Although new digital pathology tools have improved the positive cell quantification, there is a heterogeneity of the quantification methods in the literature. The aim of this study was to evaluate and propose a novel dendritic cells quantification method in squamous cell carcinoma comparing it with a conventional quantification method. MATERIAL AND METHODS: Twenty-six squamous cell carcinomas HIV-positive cases affecting the oropharynx, lips and oral cavity were selected. Immunohistochemistry for CD1a, CD83, and CD207 was performed. The immunohistochemical stains were evaluated by automated examination using a positive pixel count algorithm. A conventional quantification method (unspecific area method; UA) and a novel method (specific area method; SA) were performed obtaining the corresponding density of positive dendritic cells for the intratumoral and peritumoral regions. The Mann-Whitney U test was used to verify the influence of the quantification methods on the positive cell counting according to the evaluated regions. Data were subjected to the ANOVA and Student's t-test to verify the influence of the tumour location, stage, histological grade, and amount of inflammation on the dendritic cells density counting. RESULTS: The cell quantification method affected the dendritic cells counting independently of the evaluated region (P-value < 0.05). Significant differences between methods were also observed according to the tumour features evaluations. CONCLUSIONS: The positive cell quantification method influences the dendritic cells density results. Unlike the conventional method (UA method), the novel SA method avoids non-target areas included in the hotspots improving the reliability and reproducibility of the density cell quantification

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Molecular aspects of hepatic carcinogenesis.

Exogenous agents correlated with hepatocellular carcinoma (HCC) have been identified and well characterized. These agents, including the different viruses that cause chronic hepatitis and cirrhosis, can lead to regenerative nodules and dysplastic nodules/adenomatous hyperplasia. These conditions associated with several molecular alterations of hepatocyte ultimately culminate in hepatocellular carcinoma. Recently, there has been a great progress in the identification of somatic and germinative mutations that may be correlated with the development of HCC, justifying a review on the subject. Hence, the factors involved in the process of hepatic carcinogenesis, such as infection by the hepatitis B and C viruses, with a special focus in the molecular alterations described in recent years are discussed herein, pointing out areas potentially relevant for clinical development.

Tumor thickness as a predictive factor of lymph node metastasis and disease recurrence in T1N0 and T2N0 squamous cell carcinoma of the oral tongue.

OBJECTIVE: The aim of the study was to compare the thickness of primary tumors with the frequency of nodal metastases and survival in patients surgically treated for T1/T2N0 oral tongue squamous cell carcinoma. STUDY DESIGN: This is a retrospective longitudinal study with 74 patients. RESULTS: None of the patients with a tumor thickness (TT) ≤ 7 mm presented with nodal metastasis, whereas 25 of the patients with a TT > 7 mm (51.0%) developed metastases (P < .0001). Multivariate analysis showed that TT > 7 mm was a risk factor for occult nodal metastasis (odds ratio = 8.7; P = .002) with 81.9% accuracy. TT > 10 mm was also a predictive factor of worse disease-free survival in these patients (hazard ratio = 12.2; P = .003). CONCLUSIONS: Tumor thickness of greater than 7 mm is predictive of a higher incidence of lymph node metastasis, and a TT > 10 mm is predictive of worse disease-free survival in squamous cell carcinoma of the oral tongue.

Histological remission of autoimmune hepatitis after the addition of allopurinol and azathioprine dose reduction

The standard therapy for some autoimmune diseases consists of a combination of corticosteroids and thiopurines. In non-responders to thiopurine drugs, the measurement of the metabolites of azathioprine, 6-thioguanine, and 6-methylmercaptopurine, can be a useful tool. The measurement has been used during the treatment of inflammatory bowel diseases and, less commonly, in autoimmune hepatitis. Many patients preferentially metabolize thiopurines to 6-methylmercaptopurine (6-MMP), which is potentially hepatotoxic, instead of 6-thioguanine, the active immunosuppressive metabolite. The addition of allopurinol shifts the metabolism of thiopurine towards 6-thioguanine, improving the immunosuppressive effect. We present the case of a 51-year-old female with autoimmune hepatitis who had a biochemical response after azathioprine and prednisone treatment without histological remission, and who preferentially shunted to 6-MMP. After the addition of allopurinol, the patient's 6-thioguanine levels increased, and she reached histological remission with a reduction of 67% of the original dose of azathioprine. The patient did not develop clinical manifestations as a consequence of her increased immunosuppressive state. We also review the relevant literature related to this issue. In conclusion, the addition of allopurinol to thiopurine seems to be an option for those patients who do not reach histological remission and who have a skewed thiopurine metabolite profile.

Detection of occult lymph node tumor cells in node-negative gastric cancer patients / Identificação de células tumorais ocultas em linfonodos de pacientes com câncer gástrico classificados como pn0

ABSTRACT Background: The presence of lymph nodes metastasis is one of the most important prognostic indicators in gastric cancer. The micrometastases have been studied as prognostic factor in gastric cancer, which are related to decrease overall survival and increased risk of recurrence. However, their identification is limited by conventional methodology, since they can be overlooked after routine staining. Aim: To investigate the presence of occult tumor cells using cytokeratin (CK) AE1/AE3 immunostaining in gastric cancer patients histologically lymph node negative (pN0) by H&E. Methods: Forty patients (T1-T4N0) submitted to a potentially curative gastrectomy with D2 lymphadenectomy were evaluated. The results for metastases, micrometastases and isolated tumor cells were also associated to clinicopathological characteristics and their impact on stage grouping. Tumor deposits within lymph nodes were defined according to the tumor-node-metastases guidelines (7th TNM). Results: A total of 1439 lymph nodes were obtained (~36 per patient). Tumor cells were detected by immunohistochemistry in 24 lymph nodes from 12 patients (30%). Neoplasic cells were detected as a single or cluster tumor cells. Tumor (p=0.002), venous (p=0.016), lymphatic (p=0.006) and perineural invasions (p=0.04), as well as peritumoral lymphocytic response (p=0.012) were correlated to CK-positive immunostaining tumor cells in originally negative lymph nodes by H&E. The histologic stage of two patients was upstaged from stage IB to stage IIA. Four of the 28 CK-negative patients (14.3%) and three among 12 CK-positive patients (25%) had disease recurrence (p=0.65). Conclusion: The CK-immunostaining is an effective method for detecting occult tumor cells in lymph nodes and may be recommended to precisely determine tumor stage. It may be useful as supplement to H&E routine to provide better pathological staging.

RESUMO Racional: A presença de metástase em linfonodos é um dos indicadores prognósticos mais importantes no câncer gástrico. As micrometástases têm sido estudadas como fator prognóstico no câncer gástrico, sendo relacionadas à diminuição da sobrevida global e aumento do risco de recidiva da doença. Entretanto, sua identificação é limitada pela metodologia convencional, uma vez que podem não ser identificadas pela rotina histopatológica por meio da coloração de H&E. Objetivo: Investigar a presença de células tumorais ocultas através de imunoistoquimica utilizando as citoqueratinas (CK) AE1/AE3 em pacientes com câncer gástrico com linfonodos histologicamente classificados como negativos por H&E. Métodos: Quarenta pacientes (T1-T4N0) submetidos à gastrectomia potencialmente curativa com linfadenectomia D2 foram avaliados. A presença de metástases, micrometástases e células tumorais isoladas foram correlacionadas com características clínicopatológicas e impacto no estadiamento. Os depósitos tumorais nos linfonodos foram classificados de acordo com o sistema TNM (7º TNM). Resultados: Um total de 1439 linfonodos foi obtido (~36 por paciente). Células tumorais foram detectadas por imunoistoquimica em 24 linfonodos de 12 pacientes (30%). As células neoplásicas estavam presentes na forma isolada ou em cluster. Invasão tumoral (p=0,002), venosa (p=0,016), linfática (p=0,006) e perineural (p=0,04), assim como resposta linfocítica peritumoral (p=0,012) foram correlacionadas com linfonodos CK-positivos que originalmente eram negativos à H&E. Dois pacientes tiveram o estadiamento alterado, migrando do estádio IB para IIA. Quatro dos 28 CK-negativos (14,3%) e três dos 12 CK-positivos (25%) tiveram recorrência da doença (p=0,65). Conclusão: A imunoistoquimica é meio eficaz para a detecção de células tumorais ocultas em linfonodos, podendo ser recomendada para melhor determinar o estágio do tumor. Ela pode ser útil como técnica complementar à rotina de H&E, de modo a fornecer melhor estadiamento patológico.

Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.