Pierce K. H. Chow

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

IntroductionThe Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations.MethodsThe working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.ResultsParticipants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

Management of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009

Asia has a disproportionately large share of the worlds hepatocellular carcinoma (HCC), mainly because of the endemic status of chronic hepatitis B and C viruses, which leads to liver cirrhosis and an increased risk of HCC. This etiological factor presents important opportunities for prevention, early detection, diagnosis, and treatment of HCC. This consensus statement reviews the available medical evidence for management of HCC in Asia, and gives treatment recommendations that are adapted to resource availability in this diverse region with disparate health-care delivery systems.

Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma

Although metastasis is the leading cause of cancer-related death, it is not clear why some patients with localized cancer develop metastatic disease after complete resection of their primary tumor. Such relapses have been attributed to tumor cells that disseminate early and remain dormant for prolonged periods of time; however, little is known about the control of these disseminated tumor cells. Here, we have used a spontaneous mouse model of melanoma to investigate tumor cell dissemination and immune control of metastatic outgrowth. Tumor cells were found to disseminate throughout the body early in development of the primary tumor, even before it became clinically detectable. The disseminated tumor cells remained dormant for varying periods of time depending on the tissue, resulting in staggered metastatic outgrowth. Dormancy in the lung was associated with reduced proliferation of the disseminated tumor cells relative to the primary tumor. This was mediated, at least in part, by cytostatic CD8+ T cells, since depletion of these cells resulted in faster outgrowth of visceral metastases. Our findings predict that immune responses favoring dormancy of disseminated tumor cells, which we propose to be the seed of subsequent macroscopic metastases, are essential for prolonging the survival of early stage cancer patients and suggest that therapeutic strategies designed to reinforce such immune responses may produce marked benefits in these patients.

Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma

Purpose: Hepatocellular carcinoma (HCC) is the fifth most common primary neoplasm; surgery is the only curative option but 5-year survival rates are only 25% to 50%. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. The aim of this study was to determine the antineoplastic activity of brivanib alaninate, a dual inhibitor of VEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Experimental Design: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. The effects of brivanib on apoptosis and cell proliferation were evaluated by immunohistochemistry. The SK-HEP1 and HepG2 cells were used to investigate the effects of brivanib on the VEGFR-2 and FGFR-1 signaling pathways in vitro. Western blotting was used to determine changes in proteins in these xenografts and cell lines. Results: Brivanib significantly suppressed tumor growth in five of six xenograft lines. Furthermore, brivanib–induced growth inhibition was associated with a decrease in phosphorylated VEGFR-2 at Tyr1054/1059, increased apoptosis, reduced microvessel density, inhibition of cell proliferation, and down-regulation of cell cycle regulators. The levels of FGFR-1 and FGFR-2 expression in these xenograft lines were positively correlated with its sensitivity to brivanib-induced growth inhibition. In VEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation. Conclusion: This study provides a strong rationale for clinical investigation of brivanib in patients with HCC.

Perforation of the Gastrointestinal Tract Secondary to Ingestion of Foreign Bodies

Ingesting a foreign body (FB) is not an uncommon occurrence. Most pass through the gastrointestinal (GI) tract uneventfully, and perforation is rare. The aim of this study was to report our experience with ingested FB perforations of the GI tract treated surgically at our institution. A total of 62 consecutive patients who underwent surgery for an ingested FB perforation of the GI tract between 1990 and 2005 were retrospectively reviewed. Three patients with no definite FB demonstrated intraoperatively were included. The patients had a median age of 58 years, and 37 (60%) were male. Of the 59 FBs recovered, 55 (93%) were toothpicks and dietary FBs such as fish bones or bone fragments. A definitive preoperative history of FB ingestion was obtained for only two patients, and 36 of 52 patients (69%) wore dentures. Altogether, 18 (29%) perforations occurred in the anus or distal rectum, and 44 perforations were intraabdominal, with the most common abdominal site being the distal ileum (39%). Patients with FB perforations in the stomach, duodenum, and large intestine were significantly more likely to be afebrile (P = 0.043), to have chronic symptoms (> 3 days) (P < 0.001), to have a normal total white blood cell count (P < 0.001), and to be asymptomatic or present with an abdominal mass or abscess (P < 0.001) compared to those with FB perforations in the jejunum and ileum. Ingested FB perforation in the adult population is most commonly secondary to unconscious accidental ingestion and is frequently caused by dietary FBs especially fish bones. A preoperative history of FB ingestion is thus rarely obtained, although wearing dentures is a common risk factor. FB perforations of the stomach, duodenum, and large intestine tend to present with a longer, more innocuous clinical picture than perforations in the jejunum or ileum.

Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers

The impact of different carcinogenic exposures on the specific patterns of somatic mutation in human tumors remains unclear. To address this issue, we profiled 209 cholangiocarcinomas (CCAs) from Asia and Europe, including 108 cases caused by infection with the liver fluke Opisthorchis viverrini and 101 cases caused by non–O. viverrini–related etiologies. Whole-exome sequencing (n = 15) and prevalence screening (n = 194) identified recurrent somatic mutations in BAP1 and ARID1A, neither of which, to our knowledge, has previously been reported to be mutated in CCA. Comparisons between intrahepatic O. viverrini–related and non–O. viverrini–related CCAs demonstrated statistically significant differences in mutation patterns: BAP1, IDH1 and IDH2 were more frequently mutated in non–O. viverrini CCAs, whereas TP53 mutations showed the reciprocal pattern. Functional studies demonstrated tumor suppressive functions for BAP1 and ARID1A, establishing the role of chromatin modulators in CCA pathogenesis. These findings indicate that different causative etiologies may induce distinct somatic alterations, even within the same tumor type.

Critical Appraisal of 232 Consecutive Distal Pancreatectomies With Emphasis on Risk Factors, Outcome, and Management of the Postoperative Pancreatic Fistula : A 21-Year Experience at a Single Institution

OBJECTIVE To critically analyze a large single-institution experience with distal pancreatectomy (DP), with particular attention to the risk factors, outcome, and management of the postoperative pancreatic fistula (PF). DESIGN Retrospective study. SETTING Tertiary referral center. PATIENTS A total of 232 consecutive patients with pancreatic or extrapancreatic disease necessitating DP over 21 years. INTERVENTIONS Twenty-one patients underwent spleen-preserving DP, 117 underwent DP with splenectomy, and 94 underwent DP with multiorgan resection. MAIN OUTCOME MEASURES The perioperative and postoperative data of patients who underwent DP were analyzed. This included factors associated with postoperative morbidity with particular attention to the PF (defined by the International Study Group of Pancreatic Fistula) and changing trends in operative and perioperative data during the study period. RESULTS The overall operative morbidity and mortality were 47% (107 patients) and 3% (7 patients), respectively. During the study period, the rates of resection increased from 3 cases to 23 per year, and increasingly these were performed for smaller and incidental lesions. The morbidity rate remained unchanged, but there was a decline in postoperative stay and the need for care in the intensive care unit. Pancreatic fistulas occurred in 72 patients (31%); 41 (18%) were grade A, 13 (6%) grade B, and 18 (8%) grade C. Increased weight, higher American Society of Anesthesiologists score, blood loss greater than 1 L, increased operation time, decreased albumin level, and sutured closure of the stump without main duct ligation were associated with a postoperative PF on univariate analysis. A DP with splenectomy was associated with a higher incidence of grade B or C PF and non-PF-related complications. Ninety-two percent of PFs were successfully managed nonoperatively. Clinical outcomes correlated well with PF grading, as evidenced by the progressive increase in outcome measures such as postoperative stay, readmissions, reoperations, radiologic interventions, and non-PF-related complications from grade A to C PFs. CONCLUSIONS Pancreatic fistula is the most common complication after DP and its incidence varies depending on the definition applied. Several risk factors for developing a PF were identified. Splenic preservation after DP is safe. The grade of a PF correlates well with clinical outcomes, and most PFs may be managed nonoperatively.

Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment.

The effective treatment of malignant brain glioma is hindered by the poor transport across the blood-brain barrier (BBB) and the low penetration across the blood-tumor barrier (BTB). In this study, transferrin-conjugated magnetic silica PLGA nanoparticles (MNP-MSN-PLGA-Tf NPs) were formulated to overcome these barriers. These NPs were loaded with doxorubicin (DOX) and paclitaxel (PTX), and their anti-proliferative effect was evaluated in vitro and in vivo. The in vitro cytotoxicity of drug-loaded NPs was evaluated in U-87 cells. The delivery and the subsequent cellular uptake of drug-loaded NPs could be enhanced by the presence of magnetic field and the usage of Tf as targeting ligand, respectively. In particular, cells treated with DOX-PTX-NPs-Tf with magnetic field showed the highest cytotoxicity as compared to those treated with DOX-PTX-NPs-Tf, DOX-PTX-NPs, DOX-PTX-NPs-Tf with free Tf. The in vivo therapeutic efficacy of drug-loaded NPs was evaluated in intracranial U-87 MG-luc2 xenograft of BALB/c nude mice. In particular, the DOX-PTX-NPs-Tf treatment exhibited the strongest anti-glioma activity as compared to the PTX-NPs-Tf, DOX-NPs-Tf or DOX-PTX-NPs treatment. Mice did not show acute toxicity after administrating with blank MNP-MSN-PLGA-Tf NPs. Overall, MNP-MSN-PLGA-Tf NPs are promising carriers for the delivery of dual drugs for effective treatment of brain glioma.

A review of mucinous cystic neoplasms of the pancreas defined by ovarian-type stroma: clinicopathological features of 344 patients.

Despite formal definitions of mucinous cystic neoplasms (MCNs) and intraductal papillary neoplasms (IPMNs) by the World Health Organization (WHO) and Armed Forces Institute of Pathology (AFIP), several controversies with regard to MCNs remain. The aim of this review was to determine the clinicopathological features of MCNs defined by ovarian-type stroma (OS) as proposed by the WHO and AFIP and to compare them with MCNs defined by less stringent criteria. A MEDLINE search was conducted to identify English-language articles on pancreatic MCNs from 1996 to 2005. Twenty-five studies were identified. The studies were divided into 2 groups: group A included 10 studies with 344 patients whereby the presence of OS was a criteria for the diagnosis of MCNs, and group B, included 15 studies comprising 761 patients whereby the presence of OS was not mandatory for the diagnosis of MCNs. Patients in group A (MCNs as defined by OS) were almost always female (99.7%), with a mean age of 47 (range, 18–95) years. MCNs were located predominantly in the body or tail of the pancreas (94.6%) and had a mean size of 8.7 cm (range, 0.6–35 cm); 76% were symptomatic, 6.8% demonstrated ductal communication, and 27% were malignant. At a mean follow-up of 57.5 (range, 1–264) months and 43 (range, 2–257) months after surgery, 97.9% of benign and 61.9% of malignant neoplasms were disease free, respectively. Patients in group B were older and had a higher proportion of males. Neoplasms were more evenly distributed in the pancreas, were smaller, communicated more frequently with the pancreatic duct, and were composed of a higher proportion of malignant tumors compared with group A. Their clinicopathological features were intermediate between those of group A and patients with IPMN. Pancreatic MCNs with OS have unique and distinct clinicopathological features. MCNs should be defined by the presence of OS, as it is the most reliable way of distinguishing MCNs from IPMN. Adoption of “looser” criteria will result in misclassification of some IPMNs as MCNs.

Thermoresponsive core–shell magnetic nanoparticles for combined modalities of cancer therapy

Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.