Computational study of a novel catheter for liver radioembolization.

Radioembolization (RE) is a medical treatment for primary and secondary liver cancer that involves the transcatheter intraarterial delivery of micron-sized and radiation-emitting microspheres, with the goal of improving microsphere deposition in the tumoral bed while sparing healthy tissue. An increasing number of in vitro and in silico studies on RE in the literature suggest that the particle injection velocity, spatial location of the catheter tip and catheter type are important parameters in particle distribution. The present in silico study assesses the performance of a novel catheter design that promotes particle dispersion near the injection point, with the goal of generating a particle distribution that mimics the flow split to facilitate tumour targeting. The design is based on two factors: the direction and the velocity at which particles are released from the catheter. A series of simulations was performed with the catheter inserted at an idealised hepatic artery tree with physiologically realistic boundary conditions. Two longitudinal microcatheter positions in the first generation of the tree were studied by analysing the performance of the catheter in terms of the outlet-to-outlet particle distribution and split flow matching. The results show that the catheter with the best performance is one with side holes on the catheter wall and a closed frontal tip. This catheter promotes a flow-split-matching particle distribution, which improves as the injection crossflow increases.

The tumor diameter cut-off for predicting microscopic intrahepatic metastasis of hepatocellular carcinoma patients without treatment history differs from that of hepatocellular carcinoma patients with a treatment history.

BACKGROUND AND AIM: Intrahepatic metastasis (IM) of hepatocellular carcinoma (HCC) occurs via vascular invasion; the tumor diameter that affects the risk of micro intra-hepatic metastasis (MIM) should be larger than that which affects the risk of micro vessel invasion (MVI). The aim of the present study was to determine the optimum tumor diameter cut-off value for predicting the presence of MIM in HCC patients without treatment history and HCC patients with a treatment history and to compare these diameters between cases of MVI and MIM. METHODS: This retrospective study included 621 patients without macroscopic vessel invasion or intrahepatic metastasis on preoperative imaging who underwent hepatectomy. The cut-off tumor diameter for predicting the presence of MIM was determined by a receiver operating characteristic curves analysis. RESULTS: The optimum cut-off value for predicting the presence of MIM in HCC patients without treatment history was 43 mm. In contrast, the optimum cut-off value for predicting the presence of MIM in HCC patients with a treatment history was 20 mm. Among 46 HCC patients with MIM without treatment history, there were 20 patients with MIM without MVI who were considered to have potential multi-centric (MC) tumors rather than IM. The cumulative overall survival rates in patients with MIM without MVI (potential MC) was significantly better than that in patients with both MIM and MVI (P = 0.022). CONCLUSIONS: The tumor diameter cut-off value for predicting MIM differed between HCC patients without treatment history and with a treatment history and slightly smaller than those for predicting MVI beyond our expectation.

Associating Liver Partition and Portal vein ligation for Staged hepatectomy procedure using ischemic bipartition: Two case reports.

RATIONALE: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure is a recently introduced treatment strategy for patients with advanced primary or metastatic liver tumors and small future liver remnants. ALPPS procedure using ischemic bipartition of the liver is a modified technique that may reduce complications compared to classical ALPPS. PATIENT CONCERNS: Two patients with multiple colorectal liver metastasis with extensive involvement of the liver were considered unresectable before treatment because of small future liver remnant (FLR). DIAGNOSES: Two patients were diagnosed by imaging examination with volumetry of the liver. INTERVENTIONS: In the first stage, ischemic bipartition of the liver is achieved using radiofrequency ablation. The Glissonian pedicles from Segment 4 are identified and ablated, the FLR is cleared, and the right portal vein is ligated. In the second stage, the typical procedure is performed, and an extended liver resection is performed. OUTCOMES: The procedure was feasible with acceptable hypertrophy of FLRs. Blood transfusions were unnecessary, and severe postoperative complications were avoided. LESSONS: The ALPPS procedure with ischemic bipartition is safe and feasible and can produce results that are the same as those of the classical ALPPS procedure while reducing invasiveness during the first stage.

[Hepatocholangiocarcinoma in young patient with a giant liver tumour]. / Hepatocolangiocarcinoma en paciente joven con tumoración hepática gigante.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma is a rare primary hepatic tumour, showing both hepatocellular as well as biliary epithelium differentiation. Its diagnosis is often delayed, as it occurs in young patients without comorbidities and with non-specific symptoms. Most cases are confused with other types of cancer, especially fibrolamellar liver cancer, which is more frequent and has similar clinical and radiological features. CLINICAL CASE: The case is presented of a 26 year old woman with a giant combined hepatocellular-cholangiocarcinoma with difficulties in its diagnosis and a complicated surgical approach. DISCUSSION: The definitive diagnosis of this disease is defined by the histological demonstration of cholangiolar and hepatocellular differentiation, with surgical treatment always being the best choice, but with lower survival than classic hepatocellular carcinoma and cholangiocarcinoma. In some patients with unfavourable prognostic factors, adjuvant chemotherapy mainly directed cholangiolar component can be given. CONCLUSION: The current incidence of combined hepatocellular-cholangiocarcinoma varies from 2 to 5% of cases, and is one of the rarest histological types in the world. The large size and hypervascularisation of the tumour makes a surgical approach difficult in these patients, while the rare histological features require a more detailed study of the piece and the application of immunohistochemical techniques to confirm the diagnosis.

Immunohistochemical angiogenic biomarkers in hepatocellular carcinoma and cirrhosis: correlation with pathological features.

OBJECTIVE: To investigate immunohistochemical markers of angiogenesis and their association with pathological prognostic features in hepatocellular carcinoma and cirrhotic liver. METHODS: Vascular endothelial growth factor, CD105, and cyclooxygenase-2 were immunohistochemically detected in 52 hepatocellular carcinoma tissue samples and 48 cirrhotic liver tissue samples. Semiquantitative measurements of vascular endothelial growth factor and cyclooxygenase-2 were evaluated considering the degree and intensity of immunostaining based on a 7-point final scoring scale. CD105 microvascular density (MVD-CD105) was measured using automated analysis. Morphological aspects evaluated in the hepatocellular carcinoma samples included size (≤2 and >2 cm), differentiation grade, and microvascular invasion. RESULTS: The mean vascular endothelial growth factor immunoreactivity score was slightly higher in the hepatocellular carcinoma samples (4.83±1.35) than the cirrhotic liver (4.38±1.28) samples. There was a significant and direct correlation between these mean scores (rs=0.645, p=0.0001). Cyclooxygenase-2 was expressed in all the cirrhotic liver samples but was only found in 78% of the hepatocellular carcinoma samples. The mean cyclooxygenase-2 score was higher in the cirrhotic liver samples (4.85±1.38) than the hepatocellular carcinoma samples (2.58±1.68), but there was no correlation between the scores (rs=0.177, p=0.23). The mean CD105 percentage in the hepatocellular carcinoma samples (11.2%) was lower than that in the cirrhotic samples (16.9%). There was an inverse relationship in MVD-CD105 expression between the hepatocellular carcinoma and cirrhotic samples (rs=-0.78, p=0.67). There were no significant associations between vascular endothelial growth factor expression and morphological characteristics. Cyclooxygenase-2 and CD105 were associated with hepatocellular carcinoma differentiation grade (p=0.003 and p=0.05, respectively). CONCLUSION: Vascular endothelial growth factor, cyclooxygenase-2, and MVD-CD105 were highly expressed in cirrhotic liver compared to hepatocellular carcinoma and might be involved in liver carcinogenesis. Additionally, cyclooxygenase-2 and CD105 might be involved in hepatocellular carcinoma differentiation grade.

Immunohistochemical angiogenic biomarkers in hepatocellular carcinoma and cirrhosis: correlation with pathological features

OBJECTIVE To investigate immunohistochemical markers of angiogenesis and their association with pathological prognostic features in hepatocellular carcinoma and cirrhotic liver. METHODS Vascular endothelial growth factor, CD105, and cyclooxygenase-2 were immunohistochemically detected in 52 hepatocellular carcinoma tissue samples and 48 cirrhotic liver tissue samples. Semiquantitative measurements of vascular endothelial growth factor and cyclooxygenase-2 were evaluated considering the degree and intensity of immunostaining based on a 7-point final scoring scale. CD105 microvascular density (MVD-CD105) was measured using automated analysis. Morphological aspects evaluated in the hepatocellular carcinoma samples included size (≤2 and >2 cm), differentiation grade, and microvascular invasion. RESULTS The mean vascular endothelial growth factor immunoreactivity score was slightly higher in the hepatocellular carcinoma samples (4.83±1.35) than the cirrhotic liver (4.38±1.28) samples. There was a significant and direct correlation between these mean scores (rs=0.645, p=0.0001). Cyclooxygenase-2 was expressed in all the cirrhotic liver samples but was only found in 78% of the hepatocellular carcinoma samples. The mean cyclooxygenase-2 score was higher in the cirrhotic liver samples (4.85±1.38) than the hepatocellular carcinoma samples (2.58±1.68), but there was no correlation between the scores (rs=0.177, p=0.23). The mean CD105 percentage in the hepatocellular carcinoma samples (11.2%) was lower than that in the cirrhotic samples (16.9%). There was an inverse relationship in MVD-CD105 expression between the hepatocellular carcinoma and cirrhotic samples (rs=-0.78, p=0.67). There were no significant associations between vascular endothelial growth factor expression and morphological characteristics. Cyclooxygenase-2 and CD105 were associated with hepatocellular carcinoma differentiation grade (p=0.003 and p=0.05, respectively). CONCLUSION Vascular endothelial growth factor, cyclooxygenase-2, and MVD-CD105 were highly expressed in cirrhotic liver compared to hepatocellular carcinoma and might be involved in liver carcinogenesis. Additionally, cyclooxygenase-2 and CD105 might be involved in hepatocellular carcinoma differentiation grade.

Lesão renal aguda como complicação da ingestão excessiva de suco do fruto biri biri (Averrhoa bilimbi)

O fruto biri-biri pertence à família das Oxalidacae, espécie Averrhoa bilimbi. Este fruto tem um alto conteúdo de oxalato solúvel e é utilizado na culinária, na produção de picles, geleias, e como tratamento para algumas doenças como hipertensão, diabetes e hiperlipidemia. Assim como outros frutos ricos em oxalato, pode provocar lesão renal aguda. Relatamos o caso de um paciente de 50 anos, hipertenso, com função renal normal, que ingeriu uma grande quantidade de suco em jejum para tratamento de hipertensão. O paciente desenvolveu quadro de lesão renal aguda associado a dores lombares, soluços e diarreia. A lesão renal aguda era não oligúrica e teve uma evolução favorável em 10 dias sem necessidade de tratamento dialítico. A função renal retornou ao normal após esses 10 dias de seguimento.

Study of DNA synthesis and mitotic activity of hepatocytes and its relation to angiogenesis in hepatectomised tumour bearing mice.

Partial hepatectomy (PH) alters serum concentrations of substances involved in cellular proliferation, leading to the compensatory liver hyperplasia. Furthermore, angiogenesis is mainly stimulated by vascular endothelial growth factor (VEGF) and is a fundamental requirement either in liver regeneration or in tumours growth. This study looks at the expression of VEGF, DNA synthesis (DNAs) and mitotic activity (MA) in hepatectomised (H) and hepatectomised-tumour bearing (HTB) mice throughout a 24 h period. Adult male mice were sacrificed every 4 h from 26 to 50 h post-hepatectomy. H mice show a circadian rhythm in VEGF expression with a maximum value of 2.6 ± 0.1 at 08/46 h of day/hours posthepatectomy (HD/HPH); in DNAs, the maximum value was 3.4 ± 0.3 at 16/30 (HD/HPH) and in MA it was 2.3 ± 0.01 at 12/50 (HD/HPH). In HTB animals the peak of VEGF expression appears at 16/30 (HD/HPH) with a maximum value of 3.7 ± 0.1, the peak of DNAs was at 00/38 (HD/HPH) with a value of 4.6 ± 0.3 and the maximum value of MA of 08/46 (HD/HPH) with a value of 3.01 ± 0.3. We can conclude that the presence of the tumour induces modifications in the intensity and the temporal distribution of the circadian curves of VEGF expression, DNAs and MA of hepatectomised animals.

Novel antiangiogenic therapies against advanced hepatocellular carcinoma (HCC).

Angiogenesis is a cornerstone in the process of hepatocarcinogenesis. In the sorafenib era, other antiangiogenic targeted drugs, such as monoclonal antibodies and a new generation of tyrosine kinase inhibitors, have been shown in phase II trials to be safe and effective in the treatment of advanced hepatocellular carcinoma. Several currently active phase III trials are testing these drugs, both in first- and second-line settings. Strategies to overcome primary and acquired resistance to antiangiogenic therapy are urgently needed. Novel biomarkers may help in improving the efficacy of drugs targeting angiogenesis.

Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up.

Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies.

Spontaneous rupture of a giant hepatic hemangioma. Sequential treatment with preoperative transcatheter arterial embolization and conservative hepatectomy.

Hemangioma is the most common benign tumor of the liver and it is often asymptomatic. Spontaneous rupture of liver hemangiomas is a rare but potentially lethal complication. Emergent hepatic resection has been the treatment of choice but carries high operative morbidity and mortality. Recently, preoperative transcatheter arterial embolization (TAE) has been used successfully for the management of bleeding ruptured liver tumors and non-operative treatment of symptomatic giant liver hemangiomas. We report a case of spontaneous rupture of a giant hepatic hemangioma that presented with thoracic and abdominal pain and shock due to hemoperitoneum. Once proper diagnosis was made the patient was successfully managed by TAE, followed by conservative hepatic resection.

Metastatic renal cell carcinoma management.

PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC) patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Metastatic renal cell carcinoma management: [review]

PURPOSE: To assess the current treatment of metastatic renal cell carcinoma, focusing on medical treatment options. MATERIAL AND METHODS: The most important recent publications have been selected after a literature search employing PubMed using the search terms: advanced and metastatic renal cell carcinoma, anti-angiogenesis drugs and systemic therapy; also significant meeting abstracts were consulted. RESULTS: Progress in understanding the molecular basis of renal cell carcinoma, especially related to genetics and angiogenesis, has been achieved mainly through of the study of von Hippel-Lindau disease. A great variety of active agents have been developed and tested in metastatic renal cell carcinoma (mRCC) patients. New specific molecular therapies in metastatic disease are discussed. Sunitinib, Sorafenib and Bevacizumab increase the progression-free survival when compared to therapy with cytokines. Temsirolimus increases overall survival in high-risk patients. Growth factors and regulatory enzymes, such as carbonic anhydrase IX may be targets for future therapies. CONCLUSIONS: A broader knowledge of clear cell carcinoma molecular biology has permitted the beginning of a new era in mRCC therapy. Benefits of these novel agents in terms of progression-free and overall survival have been observed in patients with mRCC, and, in many cases, have become the standard of care. Sunitinib is now considered the new reference first-line treatment for mRCC. Despite all the progress in recent years, complete responses are still very rare. Currently, many important issues regarding the use of these agents in the management of metastatic renal cancer still need to be properly addressed.

Mechanisms of angiogenesis in chronic inflammatory liver disease.

Intrahepatic hypoxia may occur during the inflammatory and fibrotic processes that characterize several chronic liver diseases of viral and autoimmune origin. As a consequence, new vascular structures are formed to provide oxygen and nutrients. Angiogenesis involves a tightly regulated network of cellular and molecular mechanisms that result in the formation of functional vessels. Of particular importance are growth factors and molecules involved in matrix remodeling and cell migration, as weel as vessel maturation-related factors. In recent years a number of studies have investigated the expression and function of many pro- and antiangiogenic molecules in chronic liver diseases and liver regeneration. This review examines the potential pathogenic role of angiogenesis in the context of viral hepatitis, autoinmmune hepatitis, primary biliary cirrhosis and hepatocellular carcinoma.

[Helical computed tomography of the liver: evaluation of the different circulatory phases]. / Tomografia computada helicoidal de higado: evaluación de las diferentes fases circulatorias.

With Helical CT development it is possible to examine the entire liver during one breath hold, marking difficult to miss any piece of parenchyma, and besides the speed of this method makes it capable to evaluated the different phases of the hepatic circulation after i.v. administration of contrast material. Both sensitivity and specificity of CT have improved since the use of this new device. Another advantage of the technique is the factibility of multidirectional and tridimensional reconstruction. We present in this paper our records of patients having hepatic lesions examined with this new methodology.

Tomografia computada helicoidal de higado: evaluacion de las diferentes fases circulatorias / Helical computed tomography of the liver: evaluation of the different circulatory phases

Con el desarrollo de los nuevos Tomógrafos Computados Helicoidales es posible explorar todo el hígado en una sola apnea por lo cual no existen áreas sin evaluar, siendo posible además la valoración de las diferentes fases de circulación luego de la inyección de la sustancia de contraste endovenoso, obteniendo imágenes durante las tres fases circulatorias hepáticas, la arterial, la portal y la de equilibrio. Con esta nueva modalidad la sensibilidad y especificidad del método han aumentado considerablemente. Otra ventaja es la posibilidad de estudiar en forma multidireccional o tridimensional las imágenes obtenidas. Presentamos nuestra casuística en pacientes portadores de lesiones hepáticas o posibles portadores de las mismas.

Tomografia computada helicoidal de higado: evaluacion de las diferentes fases circulatorias / Helical computed tomography of the liver: evaluation of the different circulatory phases

Con el desarrollo de los nuevos Tomógrafos Computados Helicoidales es posible explorar todo el hígado en una sola apnea por lo cual no existen áreas sin evaluar, siendo posible además la valoración de las diferentes fases de circulación luego de la inyección de la sustancia de contraste endovenoso, obteniendo imágenes durante las tres fases circulatorias hepáticas, la arterial, la portal y la de equilibrio. Con esta nueva modalidad la sensibilidad y especificidad del método han aumentado considerablemente. Otra ventaja es la posibilidad de estudiar en forma multidireccional o tridimensional las imágenes obtenidas. Presentamos nuestra casuística en pacientes portadores de lesiones hepáticas o posibles portadores de las mismas. (AU)

Is there a role for pericytic cells in the vascular bed of infantile hemangioendothelioma of the liver?

Electron microscopic examination of an infantile hemangioendothelioma (IHE) type I of the liver, appearing in a five month old child, showed a high density of pericytes in the walls of the neoplastic vessels. These vessels, in part of the IHE patients, establish an important arteriovenous shunt leading to high output, congestive cardiac failure. It is unclear whether functions ascribed to pericytes, such as participation in microvascular contractility or as suppressors of endothelial cell proliferation are involved in two noteworthy aspects of the present case. The child exhibited no congestive heart failure and the multiple nodular lesions underwent spontaneous regression.

Resecciones hepáticas asociadas a una desarterialización completa del hígado: estudio experimental para una posibilidad terapéutica / Hepatic resections associated with complete desarterialización of the liver: experimental study for one therapeutic posibility

Se estudiaron comparativamente 7 grupos de ratas a las que se les practicaron hepatectomías parciales del 30% o del 60%, asociadas o no a una desarterialización hepática completa. Se evaluó la mortalidad, los estudios morfológicos de regeneración, el peso relativo del hígado a los 2 y a los 7 días del postoperatorio y los "test" serológico enzimáticos de la función hepática. De los resultados obtenidos los autores afirman que cuando se realiza simultáneamente una hepatectomía no mayor del 30% de la masa hepática y una desarterialización hepática completa, la función se altera considerablemente en el postoperatorio inmediato, pero no se observa una mayor mortalidad, y la regeneración hepática se lleva a cabo de igual forma que cuando se practica solamente una hepatectomía parcial. La desarterialización hepática asociada a una hepatectomía del 60% da una muy alta mortalidad (83%)

Resecciones hepáticas asociadas a una desarterialización completa del hígado: estudio experimental para una posibilidad terapéutica / Hepatic resections associated with complete desarterialización of the liver: experimental study for one therapeutic posibility

Se estudiaron comparativamente 7 grupos de ratas a las que se les practicaron hepatectomías parciales del 30% o del 60%, asociadas o no a una desarterialización hepática completa. Se evaluó la mortalidad, los estudios morfológicos de regeneración, el peso relativo del hígado a los 2 y a los 7 días del postoperatorio y los "test" serológico enzimáticos de la función hepática. De los resultados obtenidos los autores afirman que cuando se realiza simultáneamente una hepatectomía no mayor del 30% de la masa hepática y una desarterialización hepática completa, la función se altera considerablemente en el postoperatorio inmediato, pero no se observa una mayor mortalidad, y la regeneración hepática se lleva a cabo de igual forma que cuando se practica solamente una hepatectomía parcial. La desarterialización hepática asociada a una hepatectomía del 60% da una muy alta mortalidad (83%) (AU)