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AimsLiver allograft biopsy is important in the management of liver transplant (LT) recipients. Cholestasis is an indicator of liver dysfunction, and histological evidence of cholestasis can be observed in a wide range of pathological entities in the post-LT setting. In this study, we describe the clinicopathological features and significance of liver allograft biopsies with histological cholestasis over 11 years in our centre.MethodsLiver allograft biopsies performed in Queen Mary Hospital, Hong Kong from 2004 to 2014 showing histological cholestasis were retrieved from the pathology archive. Clinical and pathological data were retrospectively reviewed and analyzed.ResultsAmong the 254 biopsies from 167 patients, large duct obstruction (LDO) and acute cellular rejection (ACR) were the two main aetiologies associated with cholestasis. There was a decrease in sepsis as a cause over the study duration. In cases showing cholestasis at 6 months or more after LT, LDO was more common than ACR. Over half (61%) of the 254 biopsies showed mild cholestasis. Severe panacinar cholestasis was more often observed in LDO. Mild cholestasis was most commonly observed regardless of the severity of ACR. Severe cholestasis was associated with poorer 1-year and 3-year graft survival and patient survival, as well as higher 3-month and 6-month post-biopsy mortality.ConclusionHistological cholestasis and its severity in liver allograft biopsies has clinical and prognostic significance. Our study summarizes our previous experience and provides further insights into the management of post-LT patients.

BACKGROUND To explore the prevalence and clinicians' awareness of psychiatric comorbidities, and to identify factors associated with current psychiatric comorbidities in first-episode schizophrenia (FES) patients. METHOD In this cross-sectional study, 128 patients with FES, who were in symptomatic remission, were consecutively recruited from a local early intervention clinic. All patients were interviewed using the Chinese bilingual version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Axis I Disorders, Positive and Negative Syndrome Scales, Scale to Assess Unawareness of Mental Disorder, Social and Occupational Functioning Assessment Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale and Abnormal Involuntary Movement Scale. Bivariate and multivariate analyses were performed to investigate factors associated with psychiatric comorbidities in FES patients. RESULTS The lifetime and point prevalence of psychiatric comorbidities among FES patients were 47.7% and 27.3%, respectively. Current psychiatric comorbidities were documented on the medical records of 39.3% of the patients. The FES patients with current psychiatric comorbidities had a lower level of functioning. Depression in FES was also associated with akathisia. CONCLUSION Psychiatric comorbidities are prevalent among community FES patients. In addition to achieving symptomatic remission in schizophrenia, both treating psychiatric comorbidities and minimizing the side-effects of treatment, particularly akathisia, are fundamental for supporting FES patients in their journey to recovery.

This chapter provides a comprehensive review of some of the key issues in early intervention for psychosis using the example of a population-based service in Hong Kong, for which a full range of data is available. The authors review a number of studies addressing: (i) the DUP and its associated factors in Hong Kong; (ii) whether DUP can be changed by public awareness programmes; (iii) the immediate outcome of a two-year early intervention programme; (iv) whether the improved outcome can be sustained after the programme, over ten years; and (v) whether receiving one more year of intervention could further improve the outcome. The results show that even in a low-resource setting in Hong Kong, significant improvements in functioning can be achieved, with reduced hospitalization and reduced suicide. A long-term follow-up study observed that these effects are sustainable over ten years. Further improvements can be attained by providing longer intervention to a group that responded less favourably. However, these enhancements proved more difficult to sustain. Together, these suggest a possible dose effect on the impact and sustainability of early intervention for psychosis. Future work should aim to clarify the role of increased intervention resources such as manpower and a more defined specific programme (e.g. coaching, exercise, cognitive interventions). More work is also required to investigate the culture of early psychosis services (such as a hope-centred culture), as well as how more personalized needs of individual patients can be met.

In some individuals with undetectable serum levels of hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA can still be detected in serum or hepatocytes and HBV replicates at low levels-this is called occult HBV infection (OBI). OBI has been associated with increased risk of hepatocellular carcinoma (HCC). We investigated the incidence of OBI in patients with HCC and other liver diseases. We also investigated whether, in patients with OBI and HCC, HBV DNA has integrated into the DNA of hepatocytes.We collected clinical information and liver tissues from 110 HBsAg-negative patients (90 with HCC and 20 without HCC; median ages at surgical resection and biopsy collection, 64.1 and 48.6 years, respectively) who underwent liver resection or liver biopsy from November 2002 through July 2017 in Hong Kong. HBV DNA and covalently closed circular DNA (cccDNA) were analyzed and quantified by PCR in liver tissues. Integration of HBV DNA into the DNA of liver cells was detected by Alu-PCR.Of the 90 HBsAg-negative patients with HCC, 18 had alcoholic liver disease (20%), 14 had non-alcoholic fatty liver disease or steatohepatitis (16%), 2 had primary biliary cholangitis, 2 had recurrent pyogenic cholangitis, 1 had autoimmune hepatitis, and 53 had none of these (59%). Among the 20 patients without HCC, 7 had non-alcoholic fatty liver disease or steatohepatitis, 7 had primary biliary cholangitis, and 6 had autoimmune hepatitis. OBI was detected in 62/90 patients with HCC (69%) and 3/20 patients without HCC (15%) (P.0001). cccDNA was detectable in liver cells of 29 patients with HCC and OBI (47%) and HBV DNA had integrated into DNA of liver cells of 43 patients with HCC and OBI (69%); cccDNA and integrated HBV DNA were not detected in the 3 patients who had OBI without HCC. There were 29 patients with integration of HBV DNA among 33 patients with undetectable cccDNA in liver tissues (88%) and 14 patients with integration of HBV DNA among the 29 patients with cccDNA in liver tissues (48%) (P = .001). HBV DNA was found to integrate near genes associated with hepatocarcinogenesis, such as those encoding telomerase reverse transcriptase, lysine methyltransferase 2B, and cyclin A2. Among the 43 patients with integration of HBV DNA, 39 (91%) did not have cirrhosis.In an analysis of clinical data and liver tissues from 90 HBsAg-negative patients with HCC, we found that almost 70% had OBI, of whom 70% had integration of HBV DNA into liver cell DNA; 90% of these patients did not have cirrhosis. HBV DNA integrated near hepatic oncogenes; these integrations might promote development of liver cancer.

Supplemental material, Supplementary_online_appendix_JAG_1.20.19 for Older Chinese Americans’ Perspectives on Physical Activity: A Mixed Methods Study by Carina Katigbak, Dale Dagar Maglalang, Tam Nguyen, Minna Wang and Cheuk-Lam Lo in Journal of Applied Gerontology

Increased congestion at hub airports affects on-time airline performance to the detriment of customer satisfaction and may have substantially negative repercussions for airlines in a hypercompetitive environment. This paper concentrates on the on-time performance of British Airways (BA) at London Heathrow Airport (LHR) to identify BA's delays/disruption management; measure the passengers' expectations in case of a delay; and investigate the passenger satisfaction levels. A survey of 160 BA passengers based on a close-ended questionnaire was conducted, complemented by semi-structured interviews with four members of staff at BA's network operations department. The survey results show that BA has been able to satisfy its customers by matching or exceeding their expectations and that those customers will travel with BA again.Interestingly, the results contradict the widespread belief that BA passengers are annoyed by a service failure/delay at LHR; this is because they expect to experience such a delay anyway.

Background: Effective treatment against non-alcoholic fatty liver disease (NAFLD) is lacking. Song Zhi Wan (SZW), a Chinese formulation medicine comprising eight herbal ingredients, has been demonstrated to confer a liver protective effect in chronic hepatitis C patients. We aimed to investigate the effect of SZW on NAFLD using a high-fat diet (HFD; 60% fat) induced obese mouse model. Methods: C57BL/6J mice were fed with HFD for 10 weeks, followed by daily oral administration of various dosages of SZW (low [n=6], normal [n=10], high [n=10]) or water (n=10) for 8 weeks. Another formulation of SZW (modified SZW), in which two ingredients were replaced by radish seed and barley, was tested. Serum total cholesterol and triglyceride levels, liver transaminases, and histologic steatosis were assessed. Results: At the end of experiment, the HFD-fed placebo mice had a mean increase in serum total cholesterol and triglyceride by 57.7% and 35.0%, respectively. HFD-fed mice receiving either SZW formulation had a smaller increase in serum total cholesterol (mean increase 7.9% – 39.4%) and a significant reduction in triglyceride (mean reduction 4.2% – 27.4%; P < 0.05). A dosage dependent effect on serum total cholesterol and triglyceride was observed with modified SZW (=0.043 and 0.006, respectively). 90% of placebo mice and 59% of SZW-treated mice had severe steatosis (P=0.079). With an escalating dosage of original SZW, there was a decreasing proportion of mice with severe steatosis (P=0.013). Conclusion: SZW administration can attenuate hypercholesterolemia, reduce dyslipidemia and alleviate steatosis in HFD-induced obese mice.

Aim To explore the changes of functioning in people suffering from first-episode psychosis throughout their first year into an early intervention service, and the baseline predictors of their functioning levels at baseline, 6 and 12 months Method Consecutive subjects presenting to an early intervention service were recruited from 1 February 2013 to 31 May 2015. Information on their socio-demographic status was collected. Structured instruments were used to assess their premorbid functioning, duration of untreated psychosis, psychopathology and insight at baseline. Psychosocial functioning was assessed by Social Occupational Functioning Assessment Scale (SOFAS) and Role Functioning Scale at baseline, 6 and 12 months. Results A total of 269 subjects were recruited. The mean baseline scores for SOFAS were 53.1 (standard deviation = 13.6) and 21.5 (standard deviation = 4.0), respectively. Positive and negative psychopathology, insight and mode of onset were significant factors associated with baseline functioning. Functioning by both instruments showed significant improvement after 6 months, and the gains were maintained at 12 months. For SOFAS, baseline insight (P = 0.008), education attainment (P = 0.016) and its own baseline score (P = 0.024) were predictive at 6 months, while for 12 months, only education attainment was predictive (P = 0.008). For Role Functioning Scale, its baseline score (P = 0.034) was predictive at 6 months, while at 12 months, only female gender predicted better role functioning. Conclusion Factors predictive of functioning levels at the three time points were different. Phase-specific intervention should be offered to enhance functional recovery of people with first-episode psychosis.

Background Most of the previous studies on help seeking for psychological distress were derived from Western countries. This study investigated the barriers to help-seeking for psychological distress among Chinese primary care attenders in Hong Kong. Methods Nine focus groups and 6 individual interviews were conducted among Chinese primary care attenders with/without known distress, patients' significant others and the general public. The identified barriers were investigated in a questionnaire survey with data from 1626 primary care attenders recruited from 13 private clinics and 6 public clinics. Results Worries about side effects of drugs (79.9%, 95% CI:(77.9%, 81.8%)) and drug dependency (74.7%, 95% CI:(72.5%, 76.8%)) were rated as the top barriers in the survey. Qualitative interviews found both worries and actual experience of the side effects of drugs, which weakened patients' trust in the treatment. Factor analysis on all barrier items suggested three factors: 1) worries of treatment, 2) uncertainties on primary care physicians' capacity, 3) public’s limited knowledge on distress and sources of help. Distress level, education level and age were associated with factor 1, whereas distress level and healthcare setting were associated with the other two factors. Qualitative interviews revealed that not having a regular primary care physician in the public setting discouraged disclosure of psychological problems. Limitations The findings were based on self-reported data from the respondents. Hong Kong is influenced by a mixed Chinese and Western culture. Conclusions Relevant public education in a Chinese context should target at reducing patients' worries of drug treatment and strengthening the image of primary care physicians as a feasible source of help.

Sox9, an SRY-related HMG box transcription factor, is a progenitor/precursor cell marker of the liver expressed during embryogenesis and following liver injury. In this study, we investigated the role of Sox9 and its molecular mechanism with reference to stemness properties in hepatocellular carcinoma (HCC). Here, we observed upregulation of Sox9 in human HCC tissues compared with the non-tumorous liver counterparts (p < 0.001). Upregulation of Sox9 transcript level was associated with poorer tumor cell differentiation (p = 0.003), venous invasion (p = 0.026), advanced tumor stage (p = 0.044) and shorter overall survival (p = 0.042). Transcript levels of Sox9 and CD24 were positively correlated. Silencing of Sox9 in HCC cells inhibited in vitro cell proliferation and tumorsphere formation, sensitized HCC cells to chemotherapeutic agents, and suppressed in vivo tumorigenicity. In addition, knockdown of Sox9 suppressed HCC cell migration, invasion, and in vivo lung metastasis. Further studies showed that Sox9 endowed stemness features through activation of Wnt/β-catenin signaling, which was confirmed by the partial rescue effect on tumorigenicity and self-renewal upon transfection of active β-catenin in Sox9 knockdown cells. By ChIP and luciferase promoter assays, Frizzled-7 was identified to be the direct transcriptional target of Sox9. In conclusion, Sox9 confers stemness properties of HCC through Frizzled-7 mediated Wnt/β-catenin pathway.

Providing optimal care to patients with recent‐onset psychosis can improve outcomes and reduce relapse. However, there is a lack of consistency of the implementation of guidelines for such patients across the Asia‐Pacific region. We determined a pragmatic set of recommendations for use on a day‐to‐day basis to help provide optimal care at this crucial stage of illness. The recommendations were developed over a series of meetings by an international faculty of 15 experts from the Asia‐Pacific region, Europe, and South Africa. A structured search of the PubMed database was conducted. This was further developed based on the faculty's clinical experience and knowledge of the literature into 10 key aspects of optimal care for patients during the first five years of a diagnosis of a psychotic disorder, with particular relevance to the Asia‐Pacific region. Several common principles emerged: adherence to antipsychotic medications is crucial; substance abuse, psychiatric and medical comorbidities should be addressed; psychosocial interventions play a pivotal role; and family members can play a vital role in overall patient care. By following these recommendations, clinicians may improve outcomes for patients with recent‐onset psychosis.

Cancer metastasis is a multistep process that involves a series of tumor-stromal interaction, including extracellular matrix (ECM) remodeling, which requires a concerted action of multiple proteolytic enzymes and their endogenous inhibitors. This study investigated the role of tissue inhibitor of metalloproteinases (TIMP) 2 in the context of hepatocellular carcinoma (HCC) metastasis. We found that TIMP2 was the most significantly down-regulated member among the TIMP family in human HCCs. Moreover, TIMP2 underexpression was frequent (41.8%; 23 of 55) in human HCCs and was significantly associated with liver invasion and poorer survival outcomes of HCC patients. Furthermore, stable silencing of TIMP2 in HCC cell lines enhanced cell invasive ability and ECM degradation associated with formation of invadopodia-like feature, suggesting that TIMP2 is a negative regulator of HCC metastasis. Using an orthotopic tumor xenograft model, we demonstrated that ectopic expression of TIMP2 open reading frame in the highly metastatic HCC cell line, MHCC-97L, significantly reduced HCC progression as well as pulmonary metastasis. Mechanistically, TIMP2 suppression, in a hypoxic environment, was induced through a regulatory feedback circuit consisting of hypoxia-inducible factor (HIF) 1 alpha, microRNA-210 (miR-210), and HIF-3α. Conclusion: TIMP2 is frequently down-regulated in human HCCs and its down-regulation is associated with aggressive tumor behavior and poorer patient outcome. Its suppression is under the regulation of a novel feedback circuit consisting of HIF-1α/miR-210/HIF-3α. TIMP2 is an important regulator of ECM degradation and HCC metastasis. (Hepatology 2016;64:473-487)

Mesenchymal tumors in the liver, whether primary or metastatic, are rare. Meningeal hemangiopericytoma (HPC) is characteristically associated with delayed metastasis and the liver is one of the most common sites. Despite its consistent histological features, a pathological diagnosis of HPC in the liver is sometimes not straightforward due to its rarity and usually remote medical history of the primary meningeal tumor. In this report, the clinicopathological features of 5 cases of metastatic HPC to the liver were reviewed and described.

The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process involving the progressive accumulation of molecular alterations pinpointing different molecular and cellular events. The next-generation sequencing technology is facilitating the global and systematic evaluation of molecular landscapes in HCC. There is emerging evidence supporting the importance of cancer metabolism and tumor microenvironment in providing a favorable and supportive niche to expedite HCC development. Moreover, recent studies have identified distinct surface markers of cancer stem cell (CSC) in HCC, and they also put forward the profound involvement of altered signaling pathways and epigenetic modifications in CSCs, in addition to the concomitant drug resistance and metastasis. Taken together, multiple key genetic and non-genetic factors, as well as liver CSCs, result in the development and progression of HCC.

Gender allegedly influences attitude and behaviour. Compared to the vast literature on gender and political culture, the role of gender in shaping legal values remains under-researched. Based on data from a 2015 survey in Hong Kong, this study fills a gap by ascertaining the gender effect on support for judicial independence. It found that, despite the significance of migrant status, education level and occupation, gender alone predicts support for judicial independence. Second, all things being equal, women are less supportive of judicial independence than men. Third, Hong Kong-born male professionals with tertiary education and China-born female manual workers with primary education or below registered the highest and lowest degree of support for judicial independence, respectively. Given the steady inflow of Mainland Chinese migrants after the city returned to Chinese rule in 1997, many of them wives of Hong Kong husbands, these findings raised questions about the former British colony's evolving legal culture.

Background Most of the previous studies of help seeking for psychological distress were conducted in Western countries. Chinese studies have had a stronger emphasis on psychosis. Objective This study aims to understand how Hong Kong Chinese primary care attenders see psychological distress, including its causes, management approaches and recovery, and whether their views are different from Western views. Method Nine focus groups and six individual interviews were conducted in Hong Kong among Chinese primary care attenders with/without known distress, patients' significant others and the general public, and a questionnaire survey was conducted with 1626 primary care attenders recruited from 13 private clinics and 6 public clinics. Results More survey respondents agreed with psychological counselling (95.3%) than drugs (69.0%) to relieve psychological distress. Despite the belief in self-resilience (77.7%), only 34.8% respondents agreed that psychological distress could get better without professional help. Respondents with younger ages, better education and higher incomes tended to have stronger trust in counselling and self-resilience than drugs. Qualitative interviews revealed that although participants regarded psychological distress as a common problem in modern societies, distressed patients might be seen as being weak and troublesome. Some distressed patients found their recovery process painful because of discouragement from family and personnel at their workplace. Conclusions Hong Kong Chinese patients' views of the causes and management approaches of psychological distress are similar to Western findings. However, help seeking and recovery are of greater concern in a Chinese context where patients may receive limited empathy for their conditions of psychological distress.

Accumulating evidence illustrates the significance of cell plasticity in the molecular biology of liver cancer. Reprogramming of mature parenchymal cells to a less differentiated state by key molecular targets contributes to the pathogenesis of hepatocellular carcinoma (HCC). Hereby, we investigated the role of GATA6, a transcription factor implicated in hepatocyte lineage specification, in HCC. Our results demonstrated a lower expression of GATA6 in HCC tissues compared to the corresponding nontumoral liver tissues. Moreover, GATA6 underexpression, as observed in about 50% cases in our clinical cohort, was associated with a poorer degree of tumor cell differentiation and worse disease-free survival outcome. In vitro, silencing of GATA6 in HCC cells augmented cell migration and invasion abilities of HCC cells by activating epithelial-mesenchymal transition. Self-renewal was also enhanced in vitro. Consistently, in vivo tumorigenicity and self-renewal was promoted upon GATA6 knockdown. Notably, suppression of GATA6 converts HCC cells to a metabolic phenotype recapitulating stem-cell state. Expression of glycolytic markers was elevated in GATA6-knockdown clones accompanied by increased glucose uptake; while overexpression of GATA6 resulted in opposite effects. Further to this, we identified that GATA6 bound to the promoter region of PKM gene and regulated PKM2 transcription. Taken together, downregulation of GATA6 directs HCC cells to glycolytic metabolism and fosters tumorigenicity, self-renewal and metastasis. GATA6 is a transcriptional regulator and a genetic switch that converts the phenotypic reprogramming of HCC cells. It is a potential prognostic biomarker and therapeutic target for liver cancer.

Summary Background The long-term consequences of discontinuing antipsychotic medication after successful treatment of first-episode psychosis are not well studied. We assess the relation between early maintenance therapy decisions in first-episode psychosis and the subsequent clinical outcome at 10 years. Methods This is a 10 year follow-up study, spanning Sept 5, 2003, to Dec 30, 2014, of a randomised, double-blind trial in seven centres in Hong Kong in which 178 patients with first-episode psychosis with full positive symptom resolution after at least 1 year of antipsychotic treatment were given maintenance treatment (n=89; oral quetiapine 400 mg daily) or early treatment discontinuation (n=89; placebo) for 12 months. After the trial, patients received naturalistic treatment. Overall this cohort of patients will have received about 3 years of treatment before entering the follow-up phase of the study: about 2 years of maintenance treatment before study entry and 1 year of treatment in the trial. The primary outcome of this follow-up was the proportion of patients in each group (including those for whom direct follow-up was not available) with good or poor long-term clinical outcomes at 10 years, with poor outcome defined as a composite of persistent psychotic symptoms, a requirement for clozapine treatment, or death by suicide. The randomised trial was registered with ClinicalTrials.gov, number NCT00334035, and the follow-up study was registered with ClinicalTrials.gov, number NCT01926340. Findings Poor 10 year clinical outcome occurred in 35 (39%) of 89 patients in the discontinuation group and 19 (21%) of 89 patients in the maintenance treatment group (risk ratio 1·84, 95% CI 1·15–2·96; p=0·012). Suicide was the only serious adverse event that occurred in the follow-up phase (four [4%] patients in the early discontinuation group vs two [2%] in the maintenance group). Interpretation In patients with first-episode psychosis with a full initial response to treatment, medication continuation for at least the first 3 years after starting treatment decreases the risk of relapse and poor long-term clinical outcome. Funding Food and Health Bureau, Research Grants Council of Hong Kong, and AstraZeneca.

In 2009, Liberal Studies, which can be used as a platform for human rights education, was newly introduced as a compulsory subject for the senior secondary students in Hong Kong. As teacher’s attitudes impact students’ learning largely, a survey was conducted in 2010 to measure Liberal Studies teachers’ attitudes towards human rights. This article focuses on the development and validation of the questionnaire instrument measuring Liberal Studies teachers’ human rights attitudes, which is one of the pioneers in Asian societies. The dimensions of the instrument were first explored by exploratory factor analysis, and were confirmed to include Social Welfare, Civilian Constraints, Personal Liberties, Equality, Privacy – School Management and Privacy –Others. Then, the six-dimensional instrument was validated by confirmatory factor analysis and Rasch analysis. It is expected that it will serve as a base to build a potential tool for comparative study of human rights attitudes in Asian societies.

This paper explored the effectiveness of Assertive Community Treatment (ACT) for severely ill mental patients during a period of rapid deinstitutionalization in Hong Kong. We employed a flanking historical control design. The treatment group comprised 70 participants with 3 or more admissions to psychiatric hospitals within the preceding 12 months, and received ACT. Two historical control groups (C1 and C2), each 70 participants, with similar inclusion criteria flanking the recruitment period of treatment group, were identified and received Treatment as Usual (TAU). Outcome data were measured at baseline, 6, 12 and 18 months of intervention. Readmission rates, bed-days, emergency room visits and days of missing medical appointments improved with time during the deinstitutionalization process, irrespective of treatment modality. In addition, ACT had superior effect in most of these outcome parameters, compared to the control groups. We reported that the current model of ACT, with a relatively small case load per case manager, round the clock services, multidisciplinary team approach, with psychiatrists integrated in the services and case managers responsible for health and social care, is an effective intervention for helping people with mental illness who pursue their chosen independent living in the community.

From 2009 to 2011, the authors launched the Basic Law Education Project: Education for Human Rights and the Rule of Law in Hong Kong. This article focuses on a subset of the overarching data-set and discusses the findings that resulted from a comparative analysis of two participating schools. A survey was deployed to assess the extent to which a human rights friendly ethos existed in several institutions. Randomly selected students and all teachers from both schools were invited to participate. The collected data revealed noteworthy trends in mean scores between teachers and students in areas such as equal and fair treatment; protection of and appeal for rights; and feelings of being loved, respected, and blessed. School mission and leadership style appeared to account for significant differences. Additionally, we offer recommendations for practices that may improve human rights ethos in schools.

// Carmen Oi-ning Leung 1 , Carmen Chak-lui Wong 1,2 , Dorothy Ngo-yin Fan 1 , Alan Ka-lun Kai 1 , Edmund Kwok-kwan Tung 1 , Iris Ming-jing Xu 1 , Irene Oi-lin Ng 1,2 and Regina Cheuk-lam Lo 1,2 1 Department of Pathology, The University of Hong Kong, Hong Kong, China 2 State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China Correspondence to: Regina Cheuk-lam Lo, email: // Irene Oi-lin Ng, email: // Keywords : PIM1, HCC, metastasis Received : October 30, 2014 Accepted : February 18, 2015 Published : March 12, 2015 Abstract Hepatocellular carcinoma (HCC) is characteristically one of the most rapidly proliferating tumors which outgrows functional blood supply and results in regional oxygen deprivation. Overexpression of PIM1, a serine/threonine kinase, has been identified recently in human cancers. Knowledge on PIM1 in HCC is however, scarce. By immunohistochemical analysis on 56 human primary HCC samples, we observed overexpression of PIM1 in 39% of the cases. In two independent cohorts of paired primary and extra-hepatic metastatic HCC tissues, PIM1 expression was higher (p=0.002) in the extra-hepatic metastatic HCC tissues as compared with the corresponding primary HCCs. PIM1 was markedly up-regulated in multiple HCC cell lines in hypoxic condition (1% O 2 ) versus normoxia (20% O 2 ). Silencing of PIM1 suppressed HCC cell invasion in vitro as compared to non-target control, and decreased HCC cell proliferation in vitro and tumor growth and metastatic potential in vivo . Knockdown of PIM1 significantly reduced glucose uptake by HCC cells and was associated with decreased levels of p-AKT and key molecules in the glycolytic pathway. Taken together, PIM1 is up-regulated by hypoxia in HCC and promotes tumor growth and metastasis through facilitating cancer cell glycolysis. Targeting PIM1 may have potential role in the management of HCC.

Background The stepped care model for psychological distress has been promoted in recent years, leading to the enhancing roles of primary care professionals and alternative sources of help. However, most of the research findings come from Western countries. This study investigates help-seeking behaviours of Chinese patients among different types of professional and alternative sources for psychological distress in Hong Kong. Methods A questionnaire survey was conducted with 1626 adult primary care attenders from 13 private and 6 public clinics, 650 (40.0%) reported that they had ever experienced psychological distress. Their help-seeking behaviours, demographic background and current distress level (measured by GHQ-12) were analysed. Results Among the respondents with experience of psychological distress, 48.2% had sought help from professional and/or alternative sources for their distress [10.2% from professionals only, 12.6% from alternative sources only, and 25.4% from both]. Those who had sought help from professionals only were more likely to be less educated and with lower income. In contrast, those using alternative sources only were more likely to be younger, better educated, and have higher income. Allowing multiple responses, psychiatrists (22.3%) was reported to be the most popular professional source, followed by primary care physicians (17.5%), clinical psychologists (12.8%) and social workers/counsellors (12.0%). Family members/friends (28.6%) was the top alternative source, followed by exercise/sports (21.8%), religious/spiritual support (16.9%) and self-help websites/books/pamphlets (8.9%). Conclusion While psychiatrists remain the most popular professional source of help to the Chinese patients in Hong Kong, primary care professionals and alternative sources also play significant roles. Distressed patients who are younger, better educated and have higher income are more likely to use alternative sources only. The outcomes need further research.

This study investigated enablers to seeking professional help for psychological distress among Chinese primary care attenders in Hong Kong. Nine focus groups and six individual interviews were conducted among adult patients with/without known distress, significant others of the distressed, and the general public. The identified potential enablers were further investigated in a questionnaire survey with data from 1626 patients. Survey respondents who had sought professional help for distress (n = 231) and those without this experience (n = 1395) showed similar attitudes to the enabler items. However, the first group had more “strongly agree” responses and their top five enablers were: crisis caused by distress, distress affecting daily life, wanting to treat associated physical symptoms, having trust in doctor, and encouragement by family/friends to seek help. Qualitative interviews found that the patients often somatised distress and they felt comfortable to consult for somatic symptoms. There was strong family involvement in help-seeking whereas the doctors were the authoritative figures to convince the patients for treatment. The findings, in line with Western literature, indicate that crisis and interference in daily life due to distress are the top enablers to seeking professional help. The other three key enablers are likely to be influenced by Chinese culture.

Presence of Met receptor tyrosine kinase in the nucleus of cells has been reported. However, the functions of Met which expresses in the nucleus (nMet) remain elusive. In this study, we found that nMet was increased in 89% of HCC tumorous tissues when compared with the corresponding non-tumorous liver tissues. nMet expression increased progressively along HCC development and significantly correlated with cirrhosis, poorer cellular differentiation, venous invasion, late stage HCC and poorer overall survival. Western blot analysis revealed that nMet is a 48-kDa protein comprising the carboxyl terminal of Met receptor. Induced expression of nMet promoted HCC cell growth, migration and invasiveness in vitro and tumorigenesis and pulmonary metastasis in vivo. Luciferase assay showed that nMet activated NF-κB pathway. Indeed, p-IKKα/β and nuclear p-p65 were higher in nMet stable cells than in the control cells. Perturbation of TAK1/NF-κB axis abrogated the aggressiveness of HCC cells, both in vitro and in vivo. In conclusion, nMet was overexpressed and as a potential prognostic biomarker of HCC. Functionally, nMet accelerated HCC tumorigenesis and metastasis via the activation of TAK1/NF-κB pathway.

Identification and characterization of functional molecular targets conferring stemness properties in hepatocellular carcinoma (HCC) offers crucial insights to overcome the major hurdles of tumor recurrence, metastasis and chemoresistance in clinical management. In the current study, we investigated the significance of Cripto-1 in contributing to HCC stemness. Cripto-1 was upregulated in the sorafenib-resistant clones derived from HCC cell lines and patient-derived xenograft that we previously developed, suggesting an association between Cripto-1 and stemness. By in vitro experiments, Cripto-1 fostered cell proliferation, migration, and invasion. It also enhanced self-renewal ability and conferred chemoresistance of HCC cells. Consistently, silencing of Cripto-1 suppressed in vivo tumorigenicity on serial transplantation. On the downstream signaling mechanism, expression of major components of Wnt/β-catenin pathway β-catenin, AXIN2, and C-MYC, accompanied by β-catenin activity was reduced upon Cripto-1 knockdown. The suppressive effects on stemness properties with Cripto-1 knockdown in vitro and in vivo were partially rescued by forced expression of constitutively active β-catenin. Further elucidation revealed the binding of Cripto-1 to Frizzled-7 (FZD7), low-density lipoprotein receptor-related protein 6 (LRP6) and Dishevelled-3 (DVL3) of the Wnt/β-catenin pathway and stabilized DVL3 protein. Analyses with clinical samples validated Cripto-1 overexpression in HCC tissues, as well as a positive correlation between Cripto-1 and AXIN2 expressions. High Cripto-1 level in tumor was associated with poorer disease-free survival of HCC patients. Taken together, Cripto-1 binds to FZD7/LRP6 and DVL3, stabilizes DVL3 expression and activates the Wnt/β-catenin signaling cascade to confer stemness in HCC. Our study findings substantiated the role of Cripto-1 in determining stemness phenotypes of HCC and mechanistically in modulating the Wnt/β-catenin signaling cascade, one of the most frequently deregulated pathways in liver cancer.

Background Advancing knowledge in molecular pathogenesis of hepatocellular carcinoma (HCC) opens up new horizons in the diagnostic, prognostic and therapeutic perspectives. Assessing the expression of molecular targets prior to definitive treatment is gaining importance in clinical practice. In this study, we investigated the variation in expression pattern of stemness markers in synchronous multi-focal HCC. Methods In the first cohort, 21 liver explants with multi-focal HCC were examined for expression of stemness markers EpCAM, Sox9 and CK19 by immunohistochemistry (IHC). Expression data of 50 tumor nodules were analyzed to determine the concordance of expression among nodules in the same livers. In the second cohort, 14 tumor nodules from 6 multi-focal HCC cases proven as intra-hepatic metastasis were examined for Soc9 immunoexpression. Results In the first cohort, thirty nodules from 16 cases expressed one or more markers, with Sox9 being most frequently expressed. Complete concordance of expression pattern for all 3 markers was observed in 6 cases. Discrepancy of staining degree was noted in 4 cases for EpCAM, 14 cases for Sox9, and 6 cases for CK19. A two-tier or three-tier difference in staining scores was noted in 5 cases for Sox9 and one case for CK19. With Sox9, identical tumor morphology in terms of Edmondson grading and growth pattern did not infer the same degree of immunoexpression; and the largest tumor nodule was not representative of highest IHC score. In the second cohort of intra-hepatic metastasis, complete concordance of Sox9 expression level was observed in 5 out of 6 cases; while the remaining case showed a 1-tier difference of positive staining. Conclusions Our findings suggested that clonality of tumor nodules is apparently an important factor to infer immunoexpression pattern. When there is limited information to discern multiple primaries versus intra-hepatic metastasis in multi-focal HCC, discordant degree of stemness markers expression among tumor nodules was commonly observed especially for markers with higher frequency of expression. Pathological features alone do not necessarily indicate the expression pattern of the synchronous nodule and in this scenario examination of each tumor nodule is justified.

AIM This study aims at assessing the rate and predictors of disengagement of patients with first-episode psychosis (FEP) from the early intervention (EI) service in Hong Kong (EASY) that covers age 15 to 64. METHODS All FEP patients aged 15 to 64 years who were newly registered with the EASY programme of Kowloon West Psychiatric Unit from January to December 2012 were included. Data on socio-demographic, clinical characteristics and disengagement over 3 years of the EI service were obtained retrospectively through systematic clinical record review. Predictors of 3 different types of disengagement and their rate of occurrence were identified: complete disengagement (type I), disengaged and re-engaged through hospitalization (type II) and re-engaged as outpatient (type III). RESULTS Among the 277 patients included for analysis, 36 patients (13%) had type I disengagement, 17.2% (N = 21) were of age 15 to 25 and 9.7% (N = 15) were of age 25 to 64. Type II and type III disengagements were 4.3% and 13.4%, respectively. Early-stage poor drug compliance significantly predicted type I and type II disengagements. History of substance use, suicidal attempts and poor drug compliance predicted type III disengagement. Younger patients had significant earlier disengagement (χ2 = 5.01, df = 1, P = .025). CONCLUSION Results of the current study highlighted the different patterns of disengagement for different age groups and the importance of identifying the high-risk group at early stage of the illness. With the expansion of EI service for wider age group, studies of the differential needs of patient with different ages would be important to guide the future service development.

Introduction Although physical activity helps to improve functioning and reduce the symptoms of mental illness, physical inactivity remains common in the mental illness population. This study aims to explore the associations between theoretical constructs in relation to physical activity behavior based on psychological theories to examine reasons for physical inactivity in psychosis population. Methods One hundred and eighty one Chinese outpatients diagnosed with psychotic disorders were recruited for this cross-sectional study. Sociodemographic data and responses to questionnaires measuring self-efficacy, decisional balance, processes of change, and stages of change on physical activity habit were collected. Results Ninety three subjects (51.4%) had the intention to engage in regular physical activity within the next six months. Significant differences were found in self-efficacy, pros of decisional balance and processes of change across the stages of change. Moreover, overall classification accuracy was 60.8% across the stages of change. Conclusions This study supports self-efficacy, pros of decisional balance and processes of change as useful factors in understanding physical activity behavior among patients with psychosis. Future promotions of regular physical activity can focus on improving self-efficacy, emphasizing on the benefits of regular physical activity and facilitating cognitive and behavior strategies from processes of change.

The hypoxic microenvironment is well-characterized in hepatocellular carcinoma (HCC). Delineation of hypoxia-responsive events is an integral part to understand the pathogenesis of HCC. We studied the functional role and clinical relevance of Stanniocalcin 1 (STC1), a hypoxia-induced molecular target, in HCC. In our clinical cohort, STC1 transcript was up-regulated in HCC tumor tissues. Moreover, STC1 protein was detected in the sera of HCC patients. A higher serum STC1 level was correlated with larger tumor size and poorer 5-year disease-free survival. Functionally, recombinant STC1 protein (rhSTC1) promoted cell migration and cell invasion in vitro; and the effect was abolished by co-treatment of anti-STC1 neutralizing antibody. By in vivo mouse model, silencing of STC1 in HCC cells downregulated secretory STC1 level and suppressed lung metastasis. Furthermore, we found that rhSTC1 activated the JNK pathway, as evidenced by altered expression of the key molecular targets pJNK and p-c-Jun. The functional effects conferred by rhSTC1 were abrogated by co-treatment of JNK inhibitor. In summary, secretory STC1 enhances metastatic potential of HCC via JNK signaling. It potentially serves as a prognostic serum biomarker and a therapeutic target for HCC.

Background & Aims We investigated the functional role and clinical significance of stearoyl-CoA desaturase-1 ( SCD1 ) mediated endoplasmic reticulum (ER) stress in regulating liver tumor-initiating cells (T-ICs) and sorafenib resistance, with the aim of developing a novel therapeutic strategy against hepatocellular carcinomas (HCCs). Methods We evaluated the clinic-pathological relevance of SCD1 and its correlation with sorafenib resistance in large cohorts of HCC clinical samples by qPCR and immunohistochemical analyses. Lentiviral-based overexpression and knockdown approaches were performed to characterize the functional roles of SCD1 in regulating liver T-ICs and sorafenib resistance. Molecular pathways mediating the phenotypic alterations were identified through RNA sequencing analysis and functional rescue experiments. The combinatorial effect of SCD1 inhibition and sorafenib was tested using a patient-derived tumor xenograft (PDTX) model. Results SCD1 overexpression was found in HCC, which was associated with shorter disease-free survival ( p = 0.008, log rank test). SCD1 was found to regulate the populations of liver T-ICs; while its suppression by a SCD1 inhibitor suppressed liver T-ICs and sorafenib resistance. Interestingly, SCD1 was markedly upregulated in our established sorafenib-resistant PDTX model, and its overexpression predicts the clinical response of HCC patients to sorafenib treatment. Suppression of SCD1 forces liver T-ICs to differentiate via ER stress-induced unfolded protein response, resulting in an enhanced sensitivity to sorafenib. The PDTX#1 model, combined with sorafenib treatment and a novel SCD1 inhibitor (SSI-4), showed a maximal growth suppressive effect. Conclusions SCD1 -mediated ER stress regulates liver T-ICs and sorafenib sensitivity. Targeting SCD1 alone or in combination with sorafenib might be a novel personalized medicine against HCC. Lay summary: In this study, SCD1 was found to play a critical role in regulating liver tumor-initiating cells and sorafenib resistance through the regulation of ER stress-mediated differentiation. Targeting SCD1 in combination with sorafenib may be a novel therapeutic strategy against liver cancer.

This paper investigates the effects of incremental and substantial innovations on aviation emissions and noise levels among aircraft/engine combinations belonging to the Boeing B737 and the Airbus A320 families. We find a statistically significant impact of incremental technical progress on all environmental externalities both at the flight level and the passenger level. Although substantial innovation is found to have a limited impact at the flight level, a noteworthy positive effect exists on per-passenger externalities. These results point to the need for incentives in aviation technical progress in order to neutralize future negative environmental effects due to the expected traffic growth.

Poor prognosis of cancers, including hepatocellular carcinoma (HCC), is mainly associated with metastasis; however, the underlying mechanisms remain poorly understood. This article investigates the role of lysyl oxidase-like 2 (LOXL-2) in the biology of HCC metastasis. First, we showed that HCC metastasis relies on a collagen-modifying enzyme, LOXL2, which was significantly overexpressed in tumorous tissues and sera of HCC patients, indicating that LOXL2 may be a good diagnostic marker for HCC patients. Second, we delineated a complex, interlinked signaling network that involves multiple regulators, including hypoxia, transforming growth factor beta (TGF-β), and microRNAs (miRNAs), converging to control the expression of LOXL2. We found not only that LOXL2 was regulated by hypoxia/hypoxia-inducible factor 1 alpha (HIF-1α), but also that TGF-β activated LOXL2 transcription through mothers against decapentaplegic homolog 4 (Smad4), whereas two frequently underexpressed miRNA families, miR-26 and miR-29, cooperatively suppressed LOXL2 transcription through interacting with the 3' untranslated region of LOXL2. Third, we demonstrated the imperative roles of LOXL2 in modifying the extracellular matrix components in the tumor microenvironment and metastatic niche of HCC. LOXL2 promoted intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells. Furthermore, LOXL2 facilitated extrahepatic metastasis by enhancing recruitment of bone-marrow–derived cells to the metastatic site. Conclusion: These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis. (Hepatology 2014;60:1645–1658)

There is a significant sex disparity favoring males among hepatocellular carcinoma (HCC) patients. Although various risk factors have been identified, the exact etiology of such sexual dimorphism(s) in HCC is uncertain. Previous studies showed that overexpression of the Y-located protooncogene, testis-specific protein Y encoded (TSPY), promotes cell proliferation and oncogenesis whereas its X-located homologue, TSPYhomologue X (TSPX), retards cell cycle and oncogenic progression. Furthermore, TSPX promotes proteasomal degradation of hepatitis B virus-encoded X oncoprotein and hence could serve as a tumor suppressor in virus-associated HCC. Using immunohistochemistry and reverse-transcription polymerase chain reaction analysis, we had examined the expression of TSPY and TSPX with reference to other established biomarkers in HCC and related liver cancers. Our results demonstrated that 55 (19.2%) of 287 male cases were TSPY positive in immunohistochemistry of tissue arrays, and 15 (46.9%) of 32 male cases were TSPY positive in reverse-transcription polymerase chain reaction analysis of clinical samples. TSPY expression was closely associated with the expression of HCC biomarkers, such as glypican 3. In contrast, TSPX expression was down-regulated in 54.5% of total tumor/nontumorous paired samples (18/33) and negatively associated with those of TSPY, glypican 3, and forkhead box M1 (FOXM1) and was positively associated with that of a tumor suppressor, insulin-like growth factor binding protein 3. The present findings support the hypothesis that the oncogenic events leading to an ectopic activation of the Y-located protooncogene TSPY and/or inactivating mutation/epigenetic silencing of the X-located tumor suppressor gene TSPX could collectively contribute to the sexual dimorphism(s) in HCC and related liver cancers in male-biased manners.

The objective of this study was to investigate the outcomes of high-intensity focused ultrasound (HIFU) ablation as a bridging therapy for patients with hepatocellular carcinoma (HCC) who had been wait-listed for deceased donor liver transplantation (DDLT). Adult patients with unresectable and unablatable HCCs within the University of California San Francisco criteria who had been wait-listed for DDLT were screened for their suitability for HIFU ablation as a bridging therapy if they were not suitable for transarterial chemoembolization (TACE). Treatment outcomes for patients receiving HIFU ablation, TACE, and best medical treatment (BMT) were compared. Fifty-one patients were included in the analysis. Before the introduction of HIFU ablation, only 39.2% of the patients had received bridging therapy (TACE only, n = 20). With HIFU ablation in use, the rate increased dramatically to 80.4% (TACE + HIFU, n = 41). The overall dropout rate was 51% (n = 26). Patients in the BMT group had a significantly higher dropout rate (P = 0.03) and significantly poorer liver function as reflected by higher Model for End-Stage Liver Disease scores and higher Child-Pugh grading. Clinically relevant ascites was found in 5 patients in the HIFU group and 2 patients in the BMT group, but none was found in the TACE group (P = 0.01 and P = 0.03, respectively). The TACE and HIFU groups had comparable percentages of tumor necrosis in excised livers (P = 0.35), and both were significantly higher than that in the BMT group (P = 0.01 and P = 0.02, respectively). In conclusion, HIFU ablation was safe even for HCC patients with Child-Pugh C disease. Its adoption increased the percentage of patients receiving bridging therapy from 39.2% to 80.4%. A randomized controlled trial for further validation of its efficacy is warranted. Liver Transpl 20:912–921, 2014. © 2014 AASLD.

Kwai Chung Hospital has undergone the deinstitutionalisation process with a number of projects, beginning with a pilot to test the case management model and psycho-education for the care of people with chronic mental illness, followed by a RCT (randomised control trial) study which confirmed the efficacy of case management, and the Intervention for Frequent Readmitters project which confirmed the efficacy of assertive community treatment for a group of patients who had problems living in the community. Since 2010, the hospital has adopted the recovery movement that involves shifting its paradigm, altering its environment, training staff, and developing recovery practices and peer support for the betterment of living for the people it serves.

This study aimed to study the clinicopathologic characteristics of epithelioid angiomyolipoma, a variant of angiomyolipoma (AML) in the liver; and to discuss the diagnostic challenges. Five cases of primary liver epithelioid AML were retrieved from our archives from January 2003 to October 2012. The clinicopathologic features of each case were retrospectively reviewed. All 5 patients were female, with age ranging from 36 to 70 years (median, 41 years). The size of the tumor ranged from 1.2 to 25 cm. Histologically, the tumor comprised polygonal cells with granular eosinophilic cytoplasm and accompanied by immunohistochemical expression of HMB-45 ± Melan-A. Variations in growth pattern and cytology were observed. Estrogen receptor was negative in all 5 cases. None showed cytologic atypia, coagulative necrosis, increased mitotic count, or vascular invasion. Epithelioid AML is an uncommon primary liver tumor with a female predominance. The size of the tumor can be variable. This tumor might impose diagnostic difficulty both clinically and histologically. Immunohistochemical staining with melanocytic markers is a promising means to confirm the pathologic diagnosis. A careful assessment of aggressive histologic features is recommended to stratify the risk of aggressive behavior of this tumor.

Hepatic progenitor cells (HPCs) are bipotential cells residing in normal liver. Their proliferation is observed in reactive conditions of the liver and in primary liver cancers. The observation that some hepatocellular carcinomas (HCCs) express a biliary-like immunophenotype has led to the identification of HPCs in HCC. Accumulating evidence suggests that HPCs play a role as the cell of origin in a variety of primary liver cancers. This has led to the development of revolutionary concepts in hepatocarcinogenesis. In this article, the role and significance of HPCs in HCC, including its classification, are summarized and discussed.

ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.ResultsWe showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.ConclusionsTaken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.

In solid tumors, hypoxia triggers an aberrant vasculogenesis, enhances malignant character, and elevates metastatic risk. The plasma membrane organizing protein caveolin-1 (Cav1) is increased in a variety of cancers, including hepatocellular carcinoma (HCC), where it contributes to metastatic capability. However, the reason for elevation of Cav1 in tumor cells and the mechanistic basis for its contributions to metastatic risk are not fully understood. Here, we show that in HCC cells, hypoxia elevates expression of Cav1, which then acts through the calcium-binding protein S100P to promote metastasis. Hypoxic regions of HCC xenografts displayed elevated expression of Cav1. Hypoxia promoted HCC cell migration and invasion and distant pulmonary metastases, whereas Cav1 silencing abolished these effects. Gene expression profiling revealed that hypoxia-induced Cav1 functioned as a positive regulator of S100P via activation of the NF-κB pathway. S100P elevation under hypoxic conditions was abrogated by silencing of Cav1 or NF-κB function. Conversely, restoring S100P in Cav1-silenced cells rescued the migratory potential of HCC cells along with tumor formation and lung metastasis. In clinical specimens of HCC, we observed S100P overexpression to correlate with venous invasion, microsatellites, direct liver invasion, and absence of tumor encapsulation. Collectively, our findings demonstrated how hypoxia-induced expression of Cav1 in HCC cells enhances their invasive and metastatic potential. Cancer Res; 76(24); 7242–53. ©2016 AACR.

A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. Conclusion: This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813)

Background and aim We reviewed the results and pattern of failure of the consensus HB/HCC 1996 treatment protocol for pediatric hepatoblastoma (HB) in Hong Kong. The role of SIOPEL and Children's Hepatic tumors International Collaboration (CHIC) risk stratification was evaluated. Methods Patients enrolled on the protocol from 1996 to 2014 were included. PRETEXT staging, SIOPEL, and CHIC risk groups were retrospectively assigned. Results Sixty patients were enrolled with median age at diagnosis of 1.1 years and median follow-up time of 6.8 years. Alpha-fetoprotein (AFP) was raised (>100 ng/mL) in 58 (97%) patients. Five (8%) had metastases at presentation and 7 (12%) experienced tumor rupture prior to or during treatment. Twenty-nine patients (48%) received a first-line cisplatin, 5-fluorouracil, and vincristine regimen only while 23 (38%) also had alternative chemotherapeutic agents. Hepatic resection could be performed in 48 (80%) patients. Three (5%) patients underwent upfront liver transplantation. Five-year event-free survival and overall survival rates were 69.2% ± 6.1% and 77.6% ± 5.5% respectively. Among the 16 patients with relapse/progression, 9 had intrahepatic failure only, 5 had distant failure only, and 2 had combined local and distant failure. Predictors of inferior outcome included advanced Evans staging, disease involving both lobes, rupture, low AFP, and suboptimal response to first-line chemotherapy. Assigned in 44 patients, PRETEXT staging, SIOPEL, and CHIC risk groups significantly predicted EFS and OS. Conclusions Although the consensus HB/HCC 1996 protocol led to cure in three-quarters of pediatric HB patients, an upfront risk stratification system is required to identify and improve the outcome of high-risk patients.