The incidence of hepatocellular carcinoma (HCC) is high in Taiwan, because Taiwan is one of HBV-endemic areas. Moreover, HCCs are the 2nd most common cause of death caused by malignancies in Taiwan. Early detection of HCC can improve the survival rate because the stage is one of important prognostic factors. Alpha-fetoprotein (AFP) is the most important tumor marker for diagnosis of HCC and surveillance of treatment. However, the sensitivity, the specificity and positive predictive value of AFP are not very satisfactory. The cell cycle inhibitor p27kip1 is known as a potential prognostic marker for HCC. Decreased expression of cell cycle inhibitor p27kip1 is associated with poor prognosis in HCC. The decreased expression of p27kip1 results from increased ubiquitin-proteosome degradation. S-phase kinase associated protein (Skp2) and cyclin-dependent kinase subunit 1 (Cks1) are the subunits of the ubiquitin ligases responsible for the ubiquitin-proteosome degradation of p27kip1. The increased expression of Skp2 and Cks1 were found in many kinds of human cancers. However, there is no report about the relationship between Cks1, Skp2 and p27kip1 expression in hepatocellular carcinoma. In the present study, we investigated the expression of Cks1, Skp2 and p27kip1 and their prognostic roles in hepatocellular carcinoma. We used highly specific antibodies in immunohistochemistry to examine the expressions of Cks1, Skp2, and p27kip1 on paraffin-embedded tissue section from 75 patients with hepatocellular carcinoma. Meanwhile, we also analyzed the clinical significance of these three proteins with the various clinicopathological factors and follow-up data. Well-differentiated HCCs tended to express higher level of p27kip1 (55.6%), and lower levels of Skp2 (66.7%) and Cks1 (77.8%). Poorly differentiated HCCs tended to express lower level of p27kip1 (64.3%). The expression of Cks1 was significantly associated with the expression of Skp2 (P=0.000). In contrast, there were no inverse relationships between the expression of p27kip1 and the expressions of Skp2 and Cks1 in the present study. The expressions of p27kip1, Skp2, and Cks1 were significantly associated with disease stage (AJCC TNM stage system and CLIP scoring system). Moreover, there were significant associations between overall survival rates and the expressions of Skp2 and Cks1 (P = 0.036 and 0.015, respectively). Patients with higher expression of Skp2 and Cks1 had worse survival rates. This is the first report of the expression and prognostic role of Cks1 in HCC. Higher expression of Skp2 and Cks1 were significantly associated with advanced stage and poor prognosis. Thus, both Skp2 and Cks1 may be considered as potential novel prognostic markers providing more accurate prediction of prognosis combined with AFP and therapeutic targets in HCCs.

The aim of the present study was to characterize the phenomenon of resistance in putative preneoplastic hepatocyte nodules. These hyperplastic nodules are generated during the development of liver cancer in response to chemical carcinogens, and comprise a population of cells from which hepatocellular carcinoma can develop. As hepatocyte nodules grow in an environment that is otherwise toxic they possess a resistant phenotype. To understand this resistance phenomenon at the biochemical level, several phase I and II drug-metabolizing enzymes in the nodules were examined. Initial experiments were carried out in rats with nodules produced by initiation with diethylnitrosamine, followed by selection with 2-acetylaminofluorene and carbon tetrachloride. These nodules showed a large decrease in phase I enzymes and enzymic activities, such as the cytochromes P-450, cytochrome b[5], total microsomal haem, aminopyrine N-demethylase and ethoxyresorufin 0-deethylase, but glutathione and the phase II enzymes, namely, glutathione S-transferase, UDP-glucuronyl transferase, DT-diaphorase and gamma-glutamyltransferase were significantly increased. The pattern of changes of these drug-metabolizing enzymes of the nodules was similar when the nodules were produced by different initiation-promotion treatments, including diethylnitrosamine plus a choline/methionine-deficient diet, 2-acetamidofluorene plus phenobarbi-tone, or diethylnitrosamine plus orotic acid. In addition, the resistance phenotype was maintained when these nodules were transferred into the spleen of a rat not exposed to chemical carcinogens, and allowed to grow for several months, thus indicating that the newly acquired biochemical pattern in the nodules had become constitutive. Unlike the hepatic nodules generated by previous initiation-pro-motion treatments, nodules generated by the hypolipidemic agent, ciprofibrate, exhibited only a decrease in phase I components of the drug-metabolizing enzymes, with no increase in the phase II components. Similarly, hyperplastic nodules in liver mouse showed a decrease in phase I components, but no increase in phase II components. In addition to cytochrome P-450 and cytochrome b5, the total haem and two other haem containing proteins, namely, catalase and tryptophan 2,3-dioxygenase were also decreased in the nodules. A deficiency in hepatic iron, and a decrease in the activity of delta-ALA-synthetase, the first rate limiting enzyme in haem synthesis, were also apparent. Characterization of the phase II components revealed the presence of a new glutathione-S-transferase polypeptide, which has been shown to be identical to a placental form of the transferase. This polypeptide, although present to a minimal extent, or absent, in normal rat liver, is present in normal male mouse liver. Administration of lead nitrate to rats induces a biochemical pattern in the liver similar to that seen in the hepatocyte nodules, including a decrease of phase I components and an increase in phase II components of the drug-metabolizing enzymes, and the induction of the novel glutathione S-transferase. Further studies with lead nitrate may yield new insights into the mechanisms of production of the biochemical changes induced in the nodules, as this agent generates the same changes within 30 hours. Furthermore, the lead nitrate-induced changes in phase I and phase II enzymes are reversible, while the changes seen in the hyperplastic nodules are not. Thus this study has characterized one pattern of biochemical changes exhibited by the resistant phenotype of hyperplastic hepatic nodules, and a model system has been developed which induces the same changes, more rapidly and in a reversible fashion. One of the important questions yet to be answered however is the biological significance of the resistant phenotype in cancer development. Is the acquisition of resistance only important in expanding the initiated cell population to generate nodules or does it also have a more direct role in the progression of nodules to cancer? This is highly relevant to the clarification of the carcinogenic process in the liver and perhaps in other organs as well.

archives@tulane.edu / Hepatocellular carcinoma is an intractable cancer with a high mortality rate. Transarterial chemoembolization, a non-curative method, is the first line therapy for intermediate stage patients. This effectively extends patient survival but requires a complicated intraarterial catheterization procedure and is poorly suited to repeated administration. Gas embolization has been proposed as a fast, easily administered, more spatially selective, and less invasive alternative. This process involves generating emboli in situ using acoustic droplet vaporization, the noninvasive focused ultrasound-mediated conversion of intravenously administered perfluorocarbon microdroplets into microbubbles. The work presented in this dissertation provides the first evidence of the feasibility and efficacy of gas embolization in vivo. Following confirmation of the cessation of tumor growth after treatment in a preliminary study, two additional preclinical studies were conducted. Varying treatment parameters and the use of systemic chemotherapy alongside gas embolization resulted in consistent, substantial tumor regression and a suppression of tumor recurrence following the cessation of treatment. Subsequent steps toward optimizing the treatment method, primarily intended to mitigate off-target tissue damage and to maximize the uniformity of treatment coverage across a lesion, involved the implementation of two specialized imaging modes for tumor detection and treatment planning and the development of an ultrasound-guided treatment method. Finally, retention of the lipid droplet shell upon vaporization was investigated in the context of selective targeting for localized drug delivery. The dissertation closes with a discussion of the implications of the presented work and proposed future studies. / 1 / Jonah Harmon

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Hepatocellular carcinoma (HCC) is one of deadliest cancers worldwide and ranking the third among all cancer-related mortalities. Current effective therapeutic approaches for HCC include surgical resection and trans-arterial embolization (TAE). Chemotherapy remains largely ineffective, and most popular used agents are epirubicin, doxorubicin, cisplatin and 5-FU. Besides, these chemotherapic drugs had potential serious side-effects such as low blood count, hair loss, vomiting, and they rarely present good anti-HCC effect in clinical practice. Our previous studies found that epirubicin injection attenuated the tumor burden of orthotopic Novikoff hepatoma, but caused serious side effects to hosts including reduction in spleen weight, white count, and body weight and high GOT level. Therefore, we aimed to evaluate possible alternative treatment such as COX-2 inhibitor for HCC. Celecoxib is a highly selective COX-2 inhibitor and less toxic than the traditional non-selective NSAIDs. Celecoxib showed relatively low cytotoxicity in Novikoff N1-S1 hepatoma cells and Clone 9 normal hepatocytes with an IC50 of up to 100 microM. Expression analysis revealed that COX-2 expression is very low in N1-S1 cells at protein and mRNA levels. Thus, N1-S1 is a kind of hepatoma cell line with low COX-II level. Interestingly, celecoxib upregulated PTEN expression and decreased AKT phosphorylation in vitro by COX-2 independent pathway, and then oral administration of celecoxib (30 mg/kg) for 7 days showed tendency of tumor suppression of Novikoff hepatoma in rats revealed by ultrasound and computed tomography (CT) scan. Histological analysis revealed that CD31-positive neo-vascularization¡BKi-67-positive cell-proliferation and FOXP3-positive regulatory T cells were found to reduce in celecoxib-treated rats, and then TUNEL-positive apoptotic cells were found to increase in celecoxib-treated rats. Besides, celecoxib-treated rats exhibited no significant side effect. Therefore, oral celecoxib may be a suitable chose of adjuvant therapy in combination with epirubicin or other chemotherapeutic agents for the treatment of HCC.

Hepatitis C virus (HCV) infects an estimated 200,000 people in Canada, and is the leading cause of liver transplants in North America. Viral infection usually leads to chronic infection, and complications include liver fibrosis, steatosis and hepatocellular carcinoma (HCC). The HCV non-structural proteins 3 and 4A (NS3/4A), is a multifunctional protein complex with roles in RNA replication and polyprotein processing. Additionally, the NS3 protease has been shown to induce advanced cellular transformation in vivo and tumour formation in nude mice. However, the mechanism by which transformation occurs remains unknown. The objective of this study was to determine if the naturally occurring NS3/4A protein complex, rather than the NS3 protease domain on its own, could also induce cellular transformation and to determine the changes that NS3/4A expression had on the host cell proteome.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / A 24-year-old pregnant woman arrived at the emergency service at 34 weeks of gestational age with intermittent right upper abdominal pain. An abdominal ultrasound was performed showing signs of hepatopathy with multiple neo-formative nodules with mild ascites and fetal biometry confirmed at 34 weeks gestation. During her hospitalization, an emergency caesarean was induced with favorable result in the survival of the mother and the baby. / Revisión por pares

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Für Lebertransplantationen bei Patienten mit hepatozellulärem Karzinom stellt sich angesichts der defizitären Organspendesituation die berechtigte Frage, unter welchen Bedingungen diese Form der Therapie ein gutes Outcome für die Patienten verspricht und somit keine Verschwendung der ohnehin knappen Ressourcen darstellt. Ziel dieser Arbeit war es, ein Kollektiv aus 98 Patienten, die an einem hepatozellulären Karzinom erkrankten und im Zeitraum von 1994 bis einschließlich 2010 am Universitätsklinikum Leipzig eine Lebertransplantation erhielten, retrospektiv zu charakterisieren und den Einfluss mehrerer Faktoren auf das Outcome der Patienten zu untersuchen. Bei den Faktoren handelte es sich um die Wartezeit, den präoperativen Einsatz der TACE, den präoperativen AFP-Serumspiegel, sowie die Tumorzahl und -größe. Der Nachbeobachtungszeitraum lag bei 3 Jahren. Die Charakterisierung des Kollektivs erbrachte folgende Ergebnisse: Das Kollektiv bestand zu rund 80% aus Männern. Das mediane Alter zum Zeitpunkt der Transplantation lag bei 59 Jahren. Die Transplantationszahlen bei HCC-Patienten sind am UKL seit Einführung des MELD-Scores 2006 deutlich angestiegen. Die mediane Wartezeit hat sich seit Einführung des MELD-Scores nicht wesentlich verändert. Sie betrug 7,3 Monate in der Prä-MELD-Ära und 6,9 Monate in der MELD-Ära. Mit über 60% war der Alkoholabusus die häufigste Ursache für die Entstehung des hepatozellulären Karzinoms. An zweiter Stelle stand die Hepatitis-C-Infektion. In der Diagnostik des HCC spielte die Computertomographie die größte Rolle. Die Sensitivität des AFP zur Erfassung des HCC (>400 ng/ml) war mit Werten unter 30% sehr niedrig. Die TACE war die mit Abstand am häufigsten durchgeführte, neoadjuvante Maßnahme. Zum Zeitpunkt der Transplantation befanden sich rund 75% der Patienten in einem Stadium bis maximal T2. Das Auftreten von solitären und multifokalen HCCs war in etwa gleich häufig (46,9% vs. 53,1%). Die Milan-Kriterien waren bei knapp 39% der Patienten im postoperativen Explantat-Befund überschritten. Nach Transplantation traten bei 26 Patienten Abstoßungsreaktionen auf. 8 Patienten mussten aufgrund eines Transplantatversagens retransplantiert werden. Das postoperative Überleben (intention-to-treat) betrug 75,5% (6 Monate), 71,4% (1 Jahr) und 63,3% (3 Jahre). Die entsprechenden Rezidivraten lagen bei 11,2%, 14,3% und 22,4%. Rezidiven traten am häufigsten in der Spenderleber auf, gefolgt von einem Befall der Lymphknoten und Knochen. Ein signifikanter Einfluss auf das Outcome der Patienten konnte für das AFP, die Tumorzahl und die Milan-Kriterien nachgewiesen werden: Präoperative AFP-Spiegel unter 100 ng/ml zeigten eine signifikant niedrigere Rezidivrate. Multifokale Tumoren waren mit einem signifikant schlechteren 3-Jahres-Überleben verknüpft. Bei Erfüllung der Milan-Kriterien (im postoperativen Explantat-Befund) war die Rezidivrate signifikant und die Überlebensrate deutlich besser. Für die Wartezeit konnte seit Einführung des MELD-Scores eine positive Entwicklung festgestellt werden. Das 3-Jahresüberleben hat sich bei Wartezeiten unter 12 Monaten um 22,5% verbessert. Die Rezidivrate ist bei Wartezeiten über 12 Monate um 15,3% gesunken. Für den Einfluss der TACE auf das Outcome der Patienten konnten keine signifikanten Unterschiede festgestellt werden. Auch andere Studien belegten bisher lediglich einen Vorteil für das erfolgreiche Downstaging gegenüber Patienten, bei denen die TACE erfolglos blieb. Für die Untersuchung des tatsächlichen Nutzens einer TACE vor Transplantation werden daher Studien mit höherem Evidenzgrad benötigt.

There are unmet needs in evaluating treatment response of hepatocellular carcinoma in research protocols. Early predictors, such as imaging biomarkers, could allow for earlier judgment of treatment effect. Currently RECIST is the most widely accepted criterion in clinical trials. A modified RECIST (mRECIST) criterion was developed to take into account the unique imaging characteristics of HCC lesions. Much discussion has occurred regarding linear measurements and their appropriateness for evaluating change in tumor burden over time. The simplicity of currently accepted criteria differs with the increasing sophistication of imaging techniques. Tumor volume change on 3D imaging can provide insight into actual action of treatment rather than an estimate of action as shown by linear and bi-dimensional measurements. It was the aim of this study to determine whether linear, bi-dimensional, and volumetric percent changes of HCC lesions, in both the arterial and portal venous phases, are significantly comparable. 27 HCC lesions (identified on 25 subjects) were measured at two timepoints by each method on 3D GRE MRI scans in both phases. Percent change was calculated per lesion for each measurement type in both the arterial and portal venous phases. Signed rank tests, paired t tests, and comparison of change tests were run to evaluate the data. Significant differences between the percent changes of linear measurements versus volumetric measurements were observed using a Wilcoxon signed-rank test which showed p = 0.0000. A simple correlation assessment showed positive correlations for all measurements, with the lowest being correlations 0.8679 for the arterial linear percent change versus the arterial volumetric percent change and 0.8434 for the portal venous linear percent change versus the portal venous volumetric percent change. Differences between percent changes of linear versus bi-dimensional measurements and bi-dimensional versus volumetric measurements were significant as well (Linear versus bi-dimensional p = 0.0001, bi-dimensional versus volumetric p = 0.0004). To conclude, the differences in the percent changes when comparing the measurement types are statistically significant, particularly when comparing linear and volumetric measurements. Establishing a reproducible volumetric criterion could lead to improvements in the implementation of clinical trials.