RESUMO
BACKGROUND: Patients undergoing liver transplantation for hepatocellular carcinoma within the Milan criteria (single tumour =5 cm in size or =3 tumours each =3 cm in size, and no macrovascular invasion) have an excellent outcome. However, survival for patients with cancers that exceed these criteria remains unpredictable and access to transplantation is a balance of maximising patients' chances of cure and organ availability. The aim of this study was to explore the survival of patients with tumours that exceed the Milan criteria, to assess whether the criteria could be less restrictive, enabling more patients to qualify as transplant candidates, and to derive a prognostic model based on objective tumour characteristics, to see whether the Milan criteria could be expanded. METHODS: Data on patients who underwent transplantation for hepatocellular carcinoma despite exceeding Milan criteria at different centres were recorded via a web-based survey completed by specialists from each centre. The survival of these patients was correlated retrospectively with the size of the largest tumour nodule, number of nodules, and presence or absence of microvascular invasion detected at pathology. Contoured multivariable regression Cox models produced survival estimates by means of different combinations of the covariates. The primary aim of this study was to derive a prognostic model of overall survival based on tumour characteristics, according to the main parameters used in the Tumour Node Metastasis classification. The secondary aim was the identification of a subgroup of patients with hepatocellular carcinoma exceeding the Milan criteria, who achieved a 5-year overall survival of at least 70%-ie, similar to the outcome expected for patients who meet the Milan criteria. FINDINGS: Over a 10-month period, between June 25, 2006, and April 3, 2007, data for 1556 patients who underwent transplantation for hepatocellular carcinoma were entered on the database by 36 centres. 1112 patients had hepatocellular carcinoma exceeding Milan criteria and 444 patients had hepatocellular carcinoma shown not to exceed Milan criteria at post-transplant pathology review. In the group of patients with hepatocellular carcinomas exceeding the criteria, the median size of the largest nodule was 40 mm (range 4-200) and the median number of nodules was four (1-20). 454 of 1112 patients (41%) had microvascular invasion and, for those transplanted outside the Milan criteria, 5-year overall survival was 53.6% (95% CI 50.1-57.0), compared with 73.3% (68.2-77.7) for those that met the criteria. Hazard ratios (HR) associated with increasing values of size and number were 1.34 (1.25-1.44) and 1.51 (1.21-1.88), respectively. The effect was linear for size, whereas for number of tumours, the effect tended to plateau above three tumours. The effect of tumour size and number on survival was mediated by recurrence (b=0.08, SE=0.12, p=0.476). The presence of microvascular invasion doubled HRs in all scenarios. The 283 patients without microvascular invasion, but who fell within the Up-to-seven criteria (hepatocellular carcinomas with seven as the sum of the size of the largest tumour [in cm] and the number of tumours) achieved a 5-year overall survival of 71.2% (64.3-77.0). INTERPRETATION: More patients with hepatocellular carcinoma could be candidates for transplantation if the current dual (yes/no) approach to candidacy, based on the strict Milan criteria, were replaced with a more precise estimation of survival contouring individual tumour characteristics and use of the up-to-seven criteria.
Assuntos
Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado , Adolescente , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Criança , Humanos , Neoplasias Hepáticas/mortalidade , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
PURPOSE: Heat shock proteins (HSP) from tumor cells contain the gp96 polypeptide associated with cancer-specific antigenic peptides. Mice that are immunized with HSP/peptide-complex (HSPPC) derived from cancer tissue reject tumor from which HSPs are purified. We tested in humans whether vaccination with HSPPC-gp96 (Oncophage) from autologous liver metastases of colorectal carcinoma induces cancer-specific T-cell responses in patients rendered disease free by surgery. EXPERIMENTAL DESIGN: Twenty-nine consecutive patients underwent radical resection of liver metastases [Memorial Sloan-Kettering Cancer Center (MSKCC) score 1-3 (good prognosis), 18 patients; score 4-5 (bad prognosis), 11 patients] and received autologous tumor-derived HSPPC-96. Two vaccine cycles were administered (four weekly injections followed by four biweekly injections after 8 weeks). Class-I HLA-restricted, anti-colon cancer lines T-cell response was measured by ELISPOT assay on peripheral blood mononuclear cells (PBMCs) obtained before and after vaccination. Feasibility, safety, and possible clinical benefits were also evaluated. RESULTS: Either a de novo induced or a significant increase of preexisting class I HLA-restricted T-cell-mediated anti-colon cancer response was observed in 15 (52%) of 29 patients. Frequency of CD3+, CD45RA+, and CCR7- T lymphocytes increased in immune responders. No relevant toxicity was observed. As expected, patients with good prognosis had a significantly better clinical outcome than those with poor prognosis [2-year overall survival (OS), 89 versus 64%, P = 0.001; disease-free survival (DFS), 46 versus 18%, P = 0.001]. Patients with immune response had a statistically significant clinical advantage over nonresponding subjects (2-year OS, 100% versus 50%, P = 0.001; DFS, 51% versus 8%, P = 0.0001). Occurrence of immune response led to better tumor-free survival, whatever the predicted prognosis was (hazard ratio, 0.11-0.12 with/without stratification; P = 0.0012-0.0003). CONCLUSIONS: HSPPC-96 vaccination after resection of colorectal liver metastases is safe and elicits a significant increase in CD8+ T-cell response against colon cancer. In this limited number of patients, two-year OS and DFS were significantly improved in subjects with postvaccination antitumor immune response, independently from other clinical prognostic factors.
Assuntos
Antígenos de Neoplasias/química , Antígenos de Neoplasias/genética , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Complexo CD3/biossíntese , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/química , Estudos de Coortes , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Teste de Histocompatibilidade , Humanos , Imunofenotipagem , Antígenos Comuns de Leucócito/biossíntese , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Peptídeos/química , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores CCR7 , Receptores de Quimiocinas/biossíntese , Análise de Regressão , Linfócitos T/metabolismo , Resultado do TratamentoRESUMO
Fibroblastic reticulum cells (FBRCs) are stromal support cells located in the parafollicular area and deep cortex of lymph nodes and in the extrafollicular areas of the spleen and tonsils. We report a case of malignant FBRC tumor of the spleen occurring in a 61-year-old woman. Two years after splenectomy, multiple hepatic lesions were found, which were resected. Histologically, the tumor showed similar morphological features in the spleen as in the liver metastases. There was a whorled pattern of oval and spindle cells in a collagenized background admixed with an inflammatory cell infiltrate composed of lymphocytes and plasma cells. The tumor cells were positive for common muscle actin, smooth muscle actin, and focally for CD68. In situ hybridization for Epstein Barr virus was negative. To the best of our knowledge, this is the first report of malignant FBRC tumor arising in the spleen. The differential diagnosis of splenic tumors with inflammatory pseudotumor-like features is discussed.
Assuntos
Fibroblastos/patologia , Sarcoma/secundário , Neoplasias Esplênicas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Sarcoma/cirurgia , Baço/diagnóstico por imagem , Neoplasias Esplênicas/cirurgia , Células Estromais/patologia , Tomografia Computadorizada por Raios XAssuntos
Tumores do Estroma Gastrointestinal/patologia , Neoplasias do Jejuno/patologia , Neoplasias Primárias Múltiplas/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/patologia , Idoso , Análise Mutacional de DNA , DNA de Neoplasias/análise , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Neoplasias do Jejuno/genética , Neoplasias do Jejuno/metabolismo , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/metabolismo , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
OBJECTIVE: To assess the reliability of computed tomography (CT) cholangiography in evaluating the anatomy of the intrahepatic biliary ducts. MATERIALS AND METHODS: Twenty-eight patients underwent CT cholangiography at the National Cancer Institute of Milan, Italy. Twenty-one patients were candidates for liver surgery and seven had suspected postoperative biliary complications. The patients had not dilatation of the intrahepatic biliary ducts at US examination and bilirubin levels were not higher than 2 mg/dl. To define the reability of the CT cholangiography, a scoring system (from 0 to 3) was used for each order of biliary branches. RESULTS: In all cases, it was technically possible to carry out the CT cholangiography according to the protocol. There were no adverse reactions to the contrast agent. Two radiologists gave the maximum score of 3 for visualisation of the first- and second-order biliary branches in all cases. For visualisation of third- and fourth-order biliary branches the maximum score of 3 was given in 18 patients, a score of 2 in 8 patients and a score of 1 in 2 patients. Three anatomical variants of biliary ducts were detected. CT cholangiography was diagnostic in all seven cases of suspected postoperative biliary complications. CONCLUSION: Our work confirms the high spatial resolution and reability of CT cholangiography in evaluating the intrahepatic biliary anatomy of patients who are candidates for liver surgery, with non-dilated biliary ducts and with bilirubin levels no higher than 2 mg/dl.
Assuntos
Doenças dos Ductos Biliares/diagnóstico por imagem , Doenças dos Ductos Biliares/etiologia , Hepatectomia/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Colangiografia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Hepatic epitheloid hemangioendothelioma (HEHE) is a rare low-grade vascular tumor. Its treatment algorithm is still unclear mainly due to a lack of larger clinical experiences with detailed long-term follow-up. MATERIAL AND METHODS: Fifty-nine patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation (LT) in the treatment of this disease. Eleven (19%) patients were asymptomatic. Eighteen (30.5%) patients had pre-LT surgical [hepatic (7 patients) and extrahepatic (3 patients)] and/or systemic or locoregional (10 patients) medical therapy. Ten (16.9%) patients had extrahepatic disease localization before or at the time of LT. Follow-up was complete for all patients with a median of 92.5 (range, 7-369) from moment of diagnosis and a median of 78.5 (range, 1-245) from the moment of LT. RESULTS: HEHE was bilobar in 96% of patients; 86% of patients had more than 15 nodules in the liver specimen. Early (<3 months) and late (>3 months) post-LT mortality was 1.7% (1 patient) and 22% (14 patients). Fourteen (23.7%) patients developed disease recurrence after a median time of 49 months (range, 6-98). Nine (15.3%) patients died of recurrent disease and 5 are surviving with recurrent disease. One-, 5-, and 10- year patient survival rates from moment of transplantation for the whole series are 93%, 83%, 72%. Pre-LT tumor treatment (n = 18) (89%, 89%, and 68% 1-, 5-, and 10-year survival rates from moment of LT vs. 95%, 80%, and 73% in case of absence of pre-LT treatment), lymph node (LN) invasion (n = 18) (96%, 81%, and 71% 1-, 5-, and 10-year survival rates vs. 83%, 78%, and 67% in node negative patients) and extrahepatic disease localization (n = 10) (90%, 80%, and 80% 1-, 5-, and 10-year survival rates vs. 94%, 83%, and 70% in case of absence of extrahepatic disease) did not significantly influence patient survival whereas microvascular (n = 24) (96%, 75%, 52% 1-, 5-, and 10-year survival vs. 96%, 92%, 85% in case of absence of microvascular invasion) and combined micro- and macrovascular invasion (n = 28) (90%, 72%, and 54% 1-,5-, and 10-year survival vs. 96%, 92%, and 85% in case of absence of vascular invasion, P = 0.03) did. Disease-free survival rates at 1, 5, and 10 years post-LT are 90%, 82%, and 64%. Disease-free survival is not significantly influenced by pre-LT treatment, LN status, extrahepatic disease localization, and vascular invasion. CONCLUSIONS: The results of the largest reported transplant series in the treatment of HEHE are excellent. Preexisting extrahepatic disease localization as well as LN involvement are not contraindications to LT. Microvascular or combined macro-microvascular invasion significantly influence survival after LT. LT therefore should be offered as a valid therapy earlier in the disease course of these, frequently young, patients. Recurrent (allograft) disease should be treated aggressively as good long-term survivals can be obtained. Long-term prospective follow-up multicenter studies as well as the evaluation of antiangiogenic drugs are necessary to further optimize the treatment of this rare vascular hepatic disorder.
Assuntos
Hemangioendotelioma Epitelioide/cirurgia , Neoplasias Hepáticas/cirurgia , Transplante de Fígado/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Europa (Continente) , Feminino , Seguimentos , Hemangioendotelioma Epitelioide/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Tumor recurrence after resection of hepatocellular carcinoma (HCC) can occur early (<2 years) or late (>2 years) as metastases or de novo tumors. Interferon (IFN) has the potential for chemoprevention against hepatitis C virus (HCV)-related cirrhosis. A predetermined group of 150 HCV RNA-positive patients undergoing resection of early- to intermediate-stage HCC was stratified into 80 HCV-pure (hepatitis B anticore antibody [anti-HBc]-negative) and 70 mixed HCV+hepatitis B virus (HBV) (anti-HBc-positive) groups, then randomized to IFN-alpha (3 million units 3 times every week for 48 weeks [n = 76]) versus control (n = 74). The primary end point was recurrence-free survival (RFS); secondary end points were disease-specific and overall survival. Intention-to-treat and subgroup analysis on adherent patients were conducted. Treatment effects on early/late recurrences were assessed using multiple Cox regression analysis. No patient experienced life-threatening adverse events. There were 28 adherent patients (37%). After 45 months of median follow-up, overall survival was 58.5%, and no significant difference in RFS was detectable between the two study arms (24.3% vs. 5.8%; P = .49). HCC recurred in 100 patients (48 IFN-treated, 52 controls), with a 50% reduction in late recurrence rate in the treatment arm. HCC multiplicity and vascular invasion were significantly related to recurrence (P = .01 and .0003). After viral status stratification, while no treatment effect was apparent in the mixed HCV+HBV population and on early recurrences (72 events), there was a significant benefit on late recurrences (28 events) in HCV-pure patients adherent to treatment (HR: 0.3; 95% CI: 0.09-0.9; P = .04). In conclusion, IFN does not affect overall prevention of HCC recurrence after resection, but it may reduce late recurrence in HCV-pure patients receiving effective treatment.
Assuntos
Carcinoma Hepatocelular/prevenção & controle , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Idoso , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/secundário , Comorbidade , Feminino , Hepatectomia , Antígenos do Núcleo do Vírus da Hepatite B/análise , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Hepatite C Crônica/cirurgia , Humanos , Interferon alfa-2 , Cirrose Hepática/cirurgia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Proteínas Recombinantes , Risco , alfa-Fetoproteínas/análiseRESUMO
OBJECTIVE: Determine the histologic response-rate (complete versus partial tumor extinction) after single radiofrequency ablation (RFA) of small hepatocellular carcinoma (HCC) arising in cirrhosis. Investigate possible predictors of response and assess efficacy and safety of RFA as a bridge to liver transplantation (OLT). BACKGROUND: RFA has become the elective treatment of local control of HCC, although histologic data supporting radiologic assessment of response are rare and prospective studies are lacking. Prognostic impact of repeated RFA for HCC persistence is also undetermined. METHODS: Percentage of RFA-induced necrosis and tumor persistence-rate at various intervals from treatment was studied in 60 HCC (median: 3 cm; Milan-Criteria IN: 80%) isolated in 50 consecutive cirrhotic patients undergoing OLT. Single-session RFA was the only treatment planned before OLT. Histologic response determined on explanted livers was related to 28 variables and to pre-OLT CT scan. RESULTS: Mean interval RFA-->OLT was 9.5 months. Post-RFA complete response rate was 55%, rising to 63% for HCC =3 cm. Tumor size was the only prognostic factor significantly related to response (P = 0.007). Tumor satellites and/or new HCC foci (56 nodules) were unaffected by RFA and significantly correlated with HCC >3 cm (P = 0.05). Post-RFA tumor persistence probability increased with time (12 months: 59%; 18 months: 70%). Radiologic response rate was 70%, not significantly different from histology. Major post-RFA morbidity was 8%. No mortality, Child deterioration, patient withdrawal because of tumor progression was observed. Post-OLT 3-year patient/graft survival was 83%. CONCLUSIONS: RFA is a safe and effective treatment of small HCC in cirrhotics awaiting OLT, although tumor size (>3 cm) and time from treatment (>1 year) predict a high risk of tumor persistence in the targeted nodule. RFA should not be considered an independent therapy for HCC.