Prevalence of Hepatocellular Carcinoma and Its Characteristics in 10 Years of Transplantation in a University Hospital in Brazil.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, accounting for up to 90% of all primary liver neoplasms. HCC treatment options depend on tumor burden, the degree of liver dysfunction, and performance status. Orthotopic liver transplant offers the best chance for cure. The selection criteria adopted for transplant are based on the Milan Criteria (MC), which depend on tumor size and number (1 lesion ≤5 cm or up to 3 lesions of ≤3 cm, without vascular invasion or extrahepatic spread). In Brazil, an expanded version of the original MC, named the Brazilian Criteria (BC), takes into consideration only tumors larger or equal to 2 cm. This retrospective cohort aims to describe the prevalence of primary liver tumors and analyze the macro and microscopic characteristics of HCC on explant pathology in a university hospital over 10 years. Of 485 transplants, 243 (50.1%) had HCC. Most patients were men (77.4%) with a mean age of 58.4 years, and the most common primary etiology of liver disease was hepatitis C infection (64.2%). The total number of tumors was 628, generally multicentric (55.6%); segment VIII was the most affected, and alpha-fetoprotein was altered in 70.7% of the cases. Most patients had tumors meeting MC at pretransplant and on explant evaluation, along with higher overall survival when compared to those exceeding MC and BC, and especially with those outside both criteria. In addition, tumors outside MC represent an independent risk factor associated with death.

Impact of Brazilian expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a multicenter study.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the main indications for orthotopic liver transplantation (OLT). In Brazil, selection criteria for HCC is an expanded version of the Milan Criteria (MC), the so-called "Brazilian Milan Criteria" (BMC). Our aims were to evaluate post-OLT outcomes in patients with HCC and analyze the BMC performance. MATERIALS AND METHODS: We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,059 liver transplant recipients with HCC. Tumor was staged according to MC and BMC and correlated with overall survival (OS) and disease-free survival (DFS). We compared the ability of MC and BMC to predict OS and DFS using Delta C-statistic. RESULTS: Post-OLT OS were 63% in five years and HCC recurrence was observed in 8% of patients. At diagnosis, 85% of patients were within MC. Patients within MC at diagnosis and in the explant showed a higher OS and DFS than patients outside MC and within BMC and patients outside both criteria (p < 0.001). Patients outside MC in the explant had an increased risk of tumor recurrence (HR: 3.78; p < 0.001) and poor survival (HR:1.77; p = 0.003). The BMC presented a lower performance than MC in properly classifying patients regarding recurrence risk. CONCLUSIONS: In a large Brazilian cohort of HCC patients submitted to liver transplantation, we observed satisfactory overall survival and recurrence rates. However, patients transplanted within the Brazilian expanded criteria had lower OS and DFS when compared to patients within MC, which may generate future discussions regarding the criteria currently used.

Hepatocellular carcinoma recurrence after liver transplantation in a Brazilian multicenter study: clinical profile and prognostic factors of survival.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with unresectable early hepatocellular carcinoma (HCC). Post-LT HCC recurrence rates range from 8 to 20% and still impact on overall survival (OS). The aim of our study was to evaluate the impact of HCC recurrence on post-LT survival and analyze prognostic factors among those patients with recurrence. PATIENTS AND METHODS: We carried out a national, multicenter, retrospective cohort study in Brazil. Medical records of 1119 LT recipients with HCC were collected. Data from patients with post-LT HCC recurrence were analyzed and correlated with post-relapse survival. RESULTS: OS of the 1119 patients included in the study was 63% over 5 years. Post-LT HCC recurrence occurred in 86 (8%) patients. The mean time to recurrence was 12 months. Sites of recurrence were extrahepatic in 55%, hepatic in 27%, and both hepatic and extrahepatic in 18%. Recurrence treatment was performed in 50 (64%) cases, mostly with sorafenib. Post-relapse survival rates were 34% at 1 year and 13% at 5 years. Univariable analysis identified α-fetoprotein more than 1000 ng/ml at relapse, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years as prognostic factors. In multivariable analysis, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years were independent predictors of better survival. CONCLUSION: In a large Brazilian cohort of LT recipients with HCC, post-LT HCC recurrence occurred in 8% and impacted significantly on the OS. Patients with early recurrence presented a worse prognosis. However, treatment of recurrence improved outcomes, highlighting the importance of early diagnosis.

Probable transfusion-transmitted Zika virus in Brazil.

BACKGROUND: Zika virus (ZIKV) is an emerging arthropod-borne flavivirus transmitted by Aedes mosquitoes. Recent commentaries regarding ZIKV routes of transmission describe a potential transmission by transfusion. Herein, we report a probable case of transfusion-transmitted ZIKV infection through a platelet transfusion that was detected from postdonation information. CASE REPORT: A blood donor made a voluntary telephone report to the blood donor facility 3 days after donation and informed the facility of a febrile illness (fever, malaise, and headaches). Due to the ongoing dengue epidemic, the initial clinical investigation included dengue among other possible diagnoses. The serology and molecular laboratory results excluded dengue infection. However, stored samples from the donation were positive for ZIKV on reverse transcription-polymerase chain reaction (RT-PCR) analysis. A retrospective investigation demonstrated that the platelet concentrate, which was part of a pool, had been transfused after a liver transplantation. A physician had evaluated the patient 4 days after surgery. Laboratory investigation showed enzyme-linked immunosorbent assay results that were negative for dengue immunoglobulin M antibodies; however, the results were positive for hemagglutination inhibition antibodies against flavivirus. ZIKV RT-PCR and virus isolation analyses in cell cultures from recipient serum were both positive. The sequencing confirmed ZIKV in the donor and patient samples. Ten partial nucleotide sequences from the ZIKV strain that were detected in the donor were aligned and compared with the ZIKV genome detected in the recipient, revealing a 99.8% homology between the two strains. CONCLUSIONS: This is a case of probable transmission of ZIKV through blood transfusion. The patient had been transfused with the blood product from an infected donor, most likely in the incubation period after ZIKV infection but prior to clinical disease onset. This report emphasizes the importance of postdonation information and recipient investigations during outbreaks of potentially blood-borne infections.

Low-power laser irradiation fails to improve liver regeneration in elderly rats at 48 h after 70 % resection.

The liver regeneration is an important clinical issue after major hepatectomies. Unfortunately, many organs (including the liver) exhibit age-related impairments regarding their regenerative capacity. Recent studies found that low-power laser irradiation (LPLI) has a stimulatory effect on the liver regeneration process. However, its effects in elderly remain unknown. Thus, this study aimed to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized elderly rats exposed to LPLI. The effects of 15 min of LPLI (wavelength of 632.8 nm; fluence of 0.97 J/cm(2); total energy delivered of 3.6 J) were evaluated in hepatectomized elderly Wistar male rats. Afterwards, through immunoblotting approaches, the protein expression and phosphorylation levels of hepatocyte growth factor (HGF), Met, Akt and Erk 1/2 signaling pathways as well as the proliferating cell nuclear antigen (PCNA) were investigated. It was observed that LPLI was not able to improve liver regeneration in elderly rats as evidenced by the lack of improvement of HGF and PCNA protein expression or phosphorylation levels of Met, Akt and Erk 1/2 in the remnant livers. In sum, this study demonstrated that the main molecular pathway, i.e. HGF/Met → Akt and Erk 1/2 → PCNA, involved in the hepatic regeneration process was not improved by LPLI in elderly hepatectomized rats, which in turn rules out LPLI as an adjuvant therapy, as observed in this protocol of liver regeneration evaluation (i.e. at 48 h after 70 % resection), in elderly.

Evaluation and comparison of microvessel density using the markers CD34 and CD105 in regenerative nodules, dysplastic nodules and hepatocellular carcinoma.

PURPOSE: The progression of hepatocellular carcinoma (HCC) is multifactorial and angiogenesis plays a fundamental role, mainly because HCC is a highly vascularized tumor. METHODS: In this study, we determined microvessel density (MVD) using the immunohistochemical markers, CD34 and CD105 (Endoglin), in 44 hepatectomy specimens, encompassing 44 malignant nodules (HCC), 44 regenerative nodules (RN), and 15 dysplastic nodules (DN). The evaluation included the determination of MVD in all nodules. For statistical analysis, a descriptive analysis was carried out using measurements of position and dispersion for continuous variables; ANOVA was used to compare between groups, considering p < 0.05 as statistically significant. RESULTS: We observed a significant difference when comparing CD34 and CD105 immunoexpression in HCC, DN, and RN. CD105 was predominantly expressed in the peripheral regions in HCC, with mean MVD scores of 6.2 ± 4.1 and 10.7 ± 4.4 at the center and periphery of the nodules, respectively, with significant differences between groups (p < 0.0001). CD34 had higher mean MVD scores than CD105 in HCC, with a more uniform positivity pattern. CD105 immunoexpression in DN exhibited a pattern similar to HCC. However, in RN, CD105 exhibited a higher MVD score in the central portion of the nodules. CD105 was expressed in a subset of newly formed microvessels in HCC and demonstrated an elevated mean MVD in cirrhotic or regenerative nodules. CONCLUSIONS: MVD determined by CD34 and CD105 expression may be used as an additional parameter to distinguish benign from malignant liver nodules.

Liver regeneration following partial hepatectomy is improved by enhancing the HGF/Met axis and Akt and Erk pathways after low-power laser irradiation in rats.

A simple, easy, and safe procedure aiming to improve liver regeneration could be of great clinical benefit in critical situations such as major hepatectomy, trauma, or hemorrhage. Low-power laser irradiation (LPLI) has come into a wide range of use in clinical practice by inducing regeneration in healthy and injured tissues. However, the effect of LPLI on the process of liver regeneration, especially those related to the molecular mechanisms, is not fully understood. Thus, the aim of the present study was to investigate the main molecular mechanisms involved in liver regeneration of partially hepatectomized rats exposed to LPLI. We used Wistar male rats, which had their remaining liver irradiated or not with LPLI (wavelength of 632.8 nm and fluence of 65 mW/cm(2)) for 15 min after a 70% hepatectomy. We subsequently investigated hepatocyte growth factor (HGF), Met, Akt, and Erk 1/2 signaling pathways through protein expression and phosphorylation analyses along with cell proliferation (proliferating cell nuclear antigen (PCNA) and Ki-67) using immunoblotting and histological studies. Our results show that LPLI can improve liver regeneration as shown by increased HGF protein expression and the phosphorylation levels of Met, Akt, and Erk 1/2 accompanied by higher levels of the PCNA and Ki-67 protein in the remnant livers. In summary, our results suggest that LPLI may play a clinical role as a simple, fast, and easy-to-perform strategy in order to enhance the liver regenerative capacity of a small liver remnant after hepatectomy.

Possible influence of glutathione S-transferase GSTT1 null genotype on age of onset of sporadic colorectal adenocarcinoma.

INTRODUCTION: Glutathione S-transferase enzymes mediate exposure to cytotoxic and genotoxic agents and may be involved in cancer susceptibility. Both glutathione S-transferase mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null variant allele in which the entire gene is absent. The association of glutathione S-transferase null genotype and risk of developing colorectal cancer is not yet fully clarified. METHODS: We tested whether the null genotypes for GSTM1 and GSTT1 genes altered the risk for sporadic colorectal adenocarcinoma in Brazilian patients. Genomic DNA from 102 sporadic colorectal adenocarcinoma patients and 300 controls was analyzed by polymerase chain reaction. RESULTS: Frequencies of GSTM1, GSTT1, and null combined genotypes were similar in patients and controls (49.9 vs. 44.6 percent, 16.6 vs. 17.3 percent, and 8.8 vs. 8 percent, respectively). We found a 1.03-fold (95 percent confidence interval, 0.96-1.10) and 1.08-fold (95 percent confidence interval, 0.99-1.18) increased risk associated with GSTM1 and GSTT1 null genotypes, respectively (P = 0.45 and P = 0.08) and a 1.18-fold (95 percent confidence interval, 0.47-2.90) increased risk associated with the combined null genotype (P = 0.74). The GSTT1 null genotype was more common in patients who were diagnosed before the age of 60 years than in those who were diagnosed at an older age (28.8 vs. 4 percent, respectively; P = 0.0008). CONCLUSIONS: The results suggest that inherited absence of this carcinogen detoxification pathway may not be associated with sporadic colorectal adenocarcinoma in the present cases. However, a higher frequency of GSTT1 null genotype in patients diagnosed before the age of 60 years suggests that this genotype could influence the age of disease onset in Brazil.

Icterícia obstrutiva: conceito, classificaçäo, etiologia e fisiopatologia / Extrahepatic obstruction: definition, classification, ethiology, pathophysiology

A icterícia é um sinal clínico comum a várias condiçöes patológicas. As icterícias obstrutivas ocorrem quando há algum obstáculo ao livre fluxo de bile entre o sítio produtor (hepatócito) e o duodeno e säo causadas por drogas, doenças imunológicas, afecçöes congênitas, parasitas, cálculos ou tumores. Para o cirurgiäo, as icterícias obstrutivas extra-hepáticas säo as mais importantes e podem näo cursar com as clássicas elevaçöes enzimáticas. O aumento da pressäo ductal e a contaminaçäo da bile têm efeitos deletérios näo só para a célula hepática como para todo o sistema imunológico. O benefício da descompressäo pré-operatória ainda é objeto de discussäo e a completa avaliaçäo pré-operatória pode diminuir as taxas de morbidade cirúrgica.

Icterícia obstrutiva: diagnóstico laboratorial e de imagem / Extrahepatic cholestasis: laboratory and image diagnosis

A investigaçäo das icterícias obstrutivas inicia-se pela história, exame físico e testes laboratoriais. Os métodos de imagens (ultra-sonografia, tomografia computadorizada, ressonância magnética) atualmente säo indispensáveis para uma correta avaliaçäo. Outros métodos intervencionistas, como a colangiografia percutânea e endoscópica também desempenham importante papel e possuem indicaçöes precisas. A cintilografia hepatobiliar tem limitado papel na propedêutica desses doentes, mas métodos modernos como a colangio-ressonância podem ocupar mais espaço na medida em que apresentam boa resoluçäo e baixo risco. O sucesso do tratamento cirúrgico das icterícias obstrutivas depende de uma completa avaliaçäo pré-operatória que é possível apenas com a cooperaçäo entre cirurgiöes, clínicos e radiologistas. Centros especializados têm sido criados com este objetivo.