Dr Patricia Johnson

© 2015 by the American Association for the Study of Liver Diseases. Current guidelines recommend surgical resection as the primary treatment for a single hepatocellular cancer (HCC) with Child's A cirrhosis, normal serum bilirubin, and no clinically significant portal hypertension. We determined how frequently guidelines were followed and whether straying from them impacted survival. BRIDGE is a multiregional cohort study including HCC patients diagnosed between January 1, 2005 and June 30, 2011. A total of 8,656 patients from 20 sites were classified into four groups: (A) 718 ideal resection candidates who were resected; (B) 144 ideal resection candidates who were not resected; (C) 1,624 nonideal resection candidates who were resected; and (D) 6,170 nonideal resection candidates who were not resected. Median follow-up was 27 months. Log-rank and Cox's regression analyses were conducted to determine differences between groups and variables associated with survival. Multivariate analysis of all ideal candidates for resection (A+B) revealed a higher risk of mortality with treatments other than resection. For all resected patients (A+C), portal hypertension and bilirubin >1 mg/dL were not associated with mortality. For all patients who were not ideal candidates for resection (C+D), resection was associated with better survival, compared to embolization and "other" treatments, but was inferior to ablation and transplantation. Conclusions: The majority of patients undergoing resection would not be considered ideal candidates based on current guidelines. Not resecting ideal candidates was associated with higher mortality. The study suggests that selection criteria for resection may be modestly expanded without compromising outcomes, and that some nonideal candidates may still potentially benefit from resection over other treatment modalities.

© 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd. Background and Aims: The BALAD score is developed to provide an objective determination of prognosis for hepatocellular carcinoma (HCC) by incorporating five serum markers, namely albumin, bilirubin, alpha-fetoprotein (AFP), agglutinin-reactive alpha-fetoprotein (AFP-L3), and des-¿-carboxy prothrombin. We aim to study the applicability of BALAD score and prognostication of the three tumor markers in hepatitis B virus-related HCC. Methods: Patients with newly diagnosed HCC were prospectively enrolled. All of the baseline characteristics and serum albumin and bilirubin level were documented at baseline. The levels of the three tumor markers (AFP, AFP-L3, and des-¿-carboxy prothrombin) were determined in archival serum samples. Patients were followed up for survivals according to local practice. The prognostic performances of the three markers and BALAD score were studied in association with overall survival (OS). Results: A total of 198 patients with hepatitis B-related HCC were recruited. AFP and AFP-L3 levels were independent prognostic factors. The number of elevated tumor markers was also predictive of worse OS. BALAD score could stratify the cohort into different patient groups with distinct median OS. The median OS of BALAD score of 0, 1, 2, 3, and 4 was not reached, 26.6, 8.3, 2.6, and 1.9 months, respectively (P<0.0001). BALAD score could further stratify outcomes in each Barcelona Clinic Liver Cancer (BCLC) subgroup. In particular, BALAD score of 3-4 had median OS of 2.6 months only in BCLC stage C patients. Conclusion: BALAD score is applicable in the population of hepatitis B virus-related HCC. The combined use of BALAD score and BCLC staging system could help identify more suitable candidates for clinical trial.

© 2015 John Wiley & Sons A/S. Background & Aims: Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. The global HCC BRIDGE study was a multiregional, large-scale, longitudinal cohort study undertaken to improve understanding of real-life management of patients with HCC, from diagnosis to death. Methods: Data were collected retrospectively from January 2005 to September 2012 by chart reviews of eligible patients newly diagnosed with HCC at participating institutions. Results: Forty-two sites in 14 countries contributed final data for 18¿031 patients. Asia accounted for 67% of patients, Europe for 20% and North America for 13%. As expected, the most common risk factor was hepatitis C virus in North America, Europe and Japan, and hepatitis B virus in China, South Korea and Taiwan. The most common Barcelona Clinic Liver Cancer stage at diagnosis was C in North America, Europe, China and South Korea, and A in Taiwan and Japan. Across all stages, first HCC treatment was most frequently transarterial chemoembolization in North America, Europe, China and South Korea, percutaneous ethanol injection or radiofrequency ablation in Japan and resection in Taiwan. Survival from first HCC treatment varied significantly by region, with median overall survival not reached for Taiwan and 60, 33, 31, 24 and 23¿months for Japan, North America, South Korea, Europe and China respectively (P¿<¿0.0001). Conclusions: Initial results from the BRIDGE study confirm previously reported regional trends in patient demographic characteristics and HCC risk factors, document the heterogeneity of treatment approaches across regions/countries and underscore the need for earlier HCC diagnosis worldwide.

Cosmopolitanism has been approached from a multitude of perspectives yet it continues to pose theoretical challenges in application. This paper assumes a post-disciplinary approach to critique these writings and analyse the intersections of tourism/cosmopolitanism/worldmaking. Through these means a philosophical platform is built that advances cultural literacy as the defining principle of cosmopolitanism. Cosmopolitanism encompasses the both-and, and has much to do with cosmopolitics, worldview, cultural orientations and compossibilities of tourism populations. Tourism is at the coalface of inter- and intra-cultural exchange and cultural literacy provides an innovative tool to operationalize worldmaking and address the complexities of an increasingly cosmopolitanized world. These ideas constitute an ontological shift in thinking about tourism and its many contexts. © 2013 Elsevier Ltd.

Objectives: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. Setting: EMA licensing. Participants: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. Primary and secondary outcome measures: Data were collected on: the type of the biomarker, whether itselected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. Results: 49 biomarker-indication-drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-ID combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinationsintroduced each year; however, the numbers were too small to identify any trends. Conclusions: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice.

In cancer clinical proteomics, MALDI and SELDI profiling are used to search for biomarkers of potentially curable early-stage disease. A given number of samples must be analysed in order to detect clinically relevant differences between cancers and controls, with adequate statistical power. From clinical proteomic profiling studies, expression data for each peak (protein or peptide) from two or more clinically defined groups of subjects are typically available. Typically, both exposure and confounder information on each subject are also available, and usually the samples are not from randomized subjects. Moreover, the data is usually available in replicate. At the design stage, however, covariates are not typically available and are often ignored in sample size calculations. This leads to the use of insufficient numbers of samples and reduced power when there are imbalances in the numbers of subjects between different phenotypic groups. A method is proposed for accommodating information on covariates, data imbalances and designcharacteristics, such as the technical replication and the observational nature of these studies, in sample size calculations. It assumes knowledge of a joint distribution for the protein expression values and the covariates. When discretized covariates are considered, the effect of the covariates enters the calculations as a function of the proportions of subjects with specific attributes. This makes it relatively straightforward (even when pilot data on subject covariates is unavailable) to specify and to adjust for the effect of the expected heterogeneities. The new method suggests certain experimental designs which lead to the use of a smaller number of samples when planning a study. Analysis of data from the proteomic profiling of colorectal cancer reveals that fewer samples are needed when a study is balanced than when it is unbalanced, and when the IMAC30 chip-type is used. The method is implemented in the clippda package and is available in R at: http://www.bioconductor.org/help/bioc-views/release/ bioc/html/clippda.html. © 2012 De Gruyter. All rights reserved.

Background and Aim: Hepatitis B viral (HBV) infection is the predominant etiology of hepatocellular carcinoma (HCC) in Asia. Our group previously reported a staging system known as the Chinese University Prognostic Index (CUPI) for HCC populations of which HBV infection is the predominant etiology. This study aims to validate CUPI and compare with other published staging systems. Methods: We analyzed a prospective cohort of patients with newly diagnosed HCC from 2003 to 2005. All patients were staged with CUPI, Barcelona Clinic Liver Cancer Classification (BCLC), Cancer of the Liver Italian Program score (CLIP), tumor-node-metastasis (TNM) and Okuda systems at diagnosis. They were followed with survival data and the performance of each staging system (in terms of homogeneity, discriminatory ability and monotonicity of gradient) were analyzed and compared. Results: A total of 595 patients (80.2% with chronic HBV infection) were analyzed. The median follow-up was 41.4months and the median survival was 6.6months. Multivariate analyses identified symptomatic disease, ascites, vascular involvement, Child-Pugh-stage, alpha-fetoprotein and treatment to be the independent prognostic factors. CUPI could identify three groups with statistically significant survival difference (P<0.0001). Both CUPI and CLIP had the most favorable performance in terms of discriminatory ability, homogeneity and monotonicity. CUPI performed the best in predicting 3-month survival while CLIP performed better in predicting the outcome of 6- and 12-month survival rate. BCLC was inferior to CLIP and CUPI in the overall performance. Conclusion: We have validated CUPI in a population composed of predominant HBV-related HCC. CUPI is an appropriate staging system for HBV-related HCC. In patients with advanced HCC, both CUPI and CLIP offer good risk stratification. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Significant progress is being made in the prevention of hepatitis B-related hepatocellular carcinoma (HCC) but hepatitis C-related HCC is increasing in the West and therapeutic advances in established disease have been modest. Although ablative therapies, including surgical resection, seem effective in patients with small tumours these only represent a minority of patients. For the majority with advanced disease there is some evidence for survival benefit for transarterial chemoembolisation but only in very carefully selected patients. Systemic chemotherapy is of unproven benefit and is now largely confined to clinical trials. In contrast, there has been a steady improvement in the outlook of patients with established metastatic liver cancer when the primary site is colorectal. Survival has increased from around six months to almost two years with the introduction of new cytotoxic agents, irinotecan and oxaliplatin. Somatostatin analogues have had a dramatic impact on the symptomatic control of neuroendocrine tumours, metastatic to the liver that result in the carcinoid syndrome.

OGT 719 (Oxford GlycoSciences, Abingdon, UK) is a novel nucleoside analogue with a galactose molecule attached to a fluorinated pyrimidine. OGT 719 has the capacity selectively to bind to asialoglycoprotein receptors that are found exclusively on hepatocytes and hepatocellular carcinoma (HCC) cells. The aim of this study was to establish the safety and to examine the pharmacokinetics of this novel compound in patients with liver cancer. Fourteen patients received a total of 37 cycles of OGT 719 at four dose levels ([500 mg/m2 first cycle, 1 000 mg/m2 subsequent cycles], 1 000 mg/m2, 3 300 mg/m2 and 7 500 mg/m2). OGT 719 was administered as a 3-h intravenous infusion in a 250 ml saline solution, daily for 5 days every 4 weeks. Pharmacokinetic parameters were studied during the first cycle of dose levels 1 and 2 (500 mg/m2, and 1 000 mg/m2, respectively). The maximum plasma concentration was attained within 5 min of completing the infusion and almost doubled, dose dependently, with a doubling of the infused dose. The plasma level declined rapidly in a monophasic manner with an elimination half-life of 2.1 and 2.5 h for dose level 1 and 2, respectively. The mean area under the curve (AUCo-t, area under the curve to 24 h; AUCo-8, area under the curve to infinity) doubled at the higher dose level. None of the patients had a significant tumor response. Elimination half-life of OGT 719 by 3-h intravenous infusion is short and monophasic. Toxicity was minimal at the highest dose level.

OBJECTIVE. Routine screening for hepatocellular carcinoma among chronic carriers of hepatitis B virus using a combination of abdominal sonography and serum a-fetoprotein levels is widely practiced. Negative results on an abdominal sonogram generally indicate the absence of hepatocellular carcinoma despite the elevation of a-fetoprotein levels, but the false-negative rate of abdominal sonography has not been established prospectively. SUBJECTS AND METHODS. In our screening program, we routinely investigated patients with Lipiodol (iodized oil) CT when they presented with a-fetoprotein levels above 20 ng/mL or a focal lesion as depicted on abdominal sonography. Lipiodol CT comprised a hepatic angiogram with injection of Lipiodol selectively in the hepatic arteries, followed by an unenhanced CT scan 10 days later. Positive findings on Lipiodol CT were confirmed histologically by biopsy or surgical resection. We defined false-negative as histologic diagnosis of hepatocellular carcinoma within 3 months of normal findings on screening abdominal sonography. RESULTS. One hundred three patients with elevated a-fetoprotein levels were investigated with Lipiodol CT within 2 months of abdominal sonography. Of these, three of 70 patients with negative abdominal sonography had histologically confirmed hepatocellular carcinoma. Thus, abdominal sonography has a false-negative rate of 4.3%. Lipiodol CT is associated with a significant false-positive rate of 43.7%. The sensitivity, specificity, and positive predictive value of abdominal sonography for early detection of hepatocellular carcinoma among hepatitis B virus carriers with elevated a-fetoprotein levels was 85.7%, 81.7%, and 54.5%, respectively. CONCLUSION. Negative results on a screening abdominal sonogram among hepatitis B virus carriers with elevated a-fetoprotein levels does not rule out the presence of small hepatocellular carcinoma. Routine use of Lipiodol CT as a supplementary screening tool is not recommended.

Quality of life (QOL) is the main consideration in caring for advanced cancer patients, yet little is known about the QOL in the terminal phase. We profiled the QOL of 58 advanced cancer patients during their last 2 weeks of life using the McGill QOL questionnaire - Hong Kong version. The patients provided ratings of QOL an average of 5.6 (median 6) days pre-death. Palliative care services were successful in maintaining the total QOL score during the dying phase. The mean score was 7.0 of 10. Among the various domains, the physical and existential domains scored relatively poorly at 5.9 and 6 of 10, respectively. The worst physical symptom and meaning of life were the individual items with the poorest scores (4.8 and 5.4 of 10, respectively). Compared with admission, there was statistically significant improvement in the worst physical symptom (P = 0.02) and eating item (P = 0.002), but deterioration in physical well-being (P = 0.03), meaning of existence (P = 0.007), and satisfaction with oneself (P = 0.04). In conclusion, QOL evaluation during the terminal phase identifies important aspects requiring improvement during the last two weeks of life. Physical and existential domains of dying cancer patients needed more attention. © U.S. Cancer Pain Relief Committee, 2002.

BACKGROUND. Topotecan (9-dimethylaminomethyl-10-hydroxycampthothecin) is a new topoisomerase I inhibitor with promising efficacy in the treatment of patients with small cell lung carcinoma (SCLC). Combination with a topoisomerase II inhibitor may potentate the therapeutic effect of topotecan, although there has been conflicting preclinical information on the combination. The objectives of this study were to establish the maximum tolerated dose and to determine the efficacy of the sequential combination of intravenous topotecan and oral etoposide in the treatment of patients with SCLC. METHODS. Patients with histologically confirmed, limited or extensive stage SCLC were eligible. The dose escalation scheme of three cohorts (six patients per cohort) started at intravenous topotecan 0.5 mg/m2 per day for 5 days and oral etoposide 50 mg twice daily for 7 days (21-day cycles). Subsequent dose levels involved escalation of topotecan to 0.75 mg/m2 per day and 1.0 mg/m2 per day for 5 days. A Phase II study was conducted at one dose level below the maximum tolerated dose. The authors alternated the drug sequence with each consecutive cycle and compared the hematologic toxicity between the two sequences. RESULTS. Thirty-six patients (21 patients with limited disease and 15 patients with extensive disease) received a total of 173 courses of sequential combination chemotherapy (topotecan ¿ etoposide, 88 courses; etoposide ¿ topotecan, 85 courses). The authors identified dose levels for the Phase II study as follows: topotecan, 0.75 mg/m2 per day for 5 days; and etoposide, 50 mg twice daily for 7 days. The dose-limiting toxicity was neutropenia. At this dose level, the incidence of Grade 3-4 neutropenia and the incidence of Grade 3-4 thrombocytopenia were 25% and 10.9%, respectively. Two patients died from neutropenic sepsis. There was no significant difference in hematologic toxicities between the two sequences. Complete and partial response rates were 5.6% and 55.6%, respectively (limited disease, 9.5% and 66.75%; extensive disease, 0% and 40%, respectively). The median progression free survival was 31.9 weeks (limited disease, 36.1 weeks; extensive disease, 28.9 weeks; 95% confidence interval, 25.6-36.0 weeks), and the median overall survival was 52.4 weeks (limited disease, 54.9 weeks; extensive disease, 30.1 weeks; 95% confidence interval, 39.6-57.7 weeks). CONCLUSIONS. Combination therapy with topoisomerase I and II inhibitors is a safe and effective regimen for patients with SCLC. Future research on this combination should focus on an oral regimen for patients with extensive disease and poor tolerance to cisplatin. The authors recommend an oral dosage of topotecan at 1.2 mg/m2 per day (equivalent to intravenous topotecan at 0.75 mg/m2 per day) for 5 days followed by etoposide 50 mg twice daily for 7 days. © 2002 American Cancer Society.

BACKGROUND. In the current study the authors examined the pharmacokinetics of direct intralesional injection of cisplatin/epinephrine/bovine collagen gel in patients with hepatocellular carcinoma and cirrhosis. METHODS. Six patients with cirrhosis and unresectable hepatocellular carcinoma received a direct intralesional injection (range, 6.7-26.7 mg) into their tumors under ultrasonographic guidance. The authors determined the total cisplatin (Pt) concentration in the plasma and urine and nonprotein-bound free Pt in plasma ultrafiltrate using flameless atomic absorption spectrometry. Data from individual patients were analyzed to calculate the pharmacokinetic parameters via a non-compartmental method for constant infusion. To demonstrate that the changes in pharmacokinetics are not related to the underlying cirrhosis, a similar methodology was applied to measure the pharmacokinetic parameters of four similar patients who were treated with cisplatin, 75 mg/m2, as a 1-hour intravenous infusion. RESULTS. The time to attain maximum concentration of total Pt after intralesional injection was dose-dependent and ranged from 2-13 hours. The concentration-time curve was biphasic in nature. The initial half-life of total Pt in patients who received an intralesional injection varied with the cisplatin dose. The initial half-life for cisplatin doses < 15 mg was approximately 9 hours and the initial half-life at higher cisplatin doses (> 15 mg) was approximately 25 hours. The area under the curve (AUC) was dose-dependent with values ranging from 38-150 µm/mL · hour. Pharmacokinetic parameters for free Pt (ultrafiltrate) were significantly different. The time to attain maximum concentration (t-max) and terminal half-life were shorter and the average AUC was approximately 100-fold lower than total Pt. After the intravenous infusion of cisplatin, the t-max for total and free Pt was 1.3 hours and 1.1 hours, respectively. The terminal half-life and average AUC for total Pt was 194 hours and 247 µg/mL per hour, respectively, and its corresponding parameters for free Pt after intravenous infusion were much lower, similar to the findings for the intralesional injection. CONCLUSIONS. The prolonged t-max and initial half-life noted with the intralesional injection of cisplatin/epinephrine/collagen gel are consistent with its proclaimed ability to retain cisplatin at the tumor and delay its release in systemic circulation. The kinetics of intralesional cisplatin injection also suggest local sequestration of the drug in the injected site. Parameters of intravenous cisplatin infusion in cirrhotic patients are similar to those of patients from the historic control group. © 2001 American Cancer Society.

The main focus of palliative care services is to improve patients' quality of life (QOL). The potential value of assessment of QOL in palliative care is being increasingly recognized. The McGill Quality of Life questionnaire (MQOL) is designed specifically for palliative care patients, but its cross-cultural validity needs to be determined before it can be applied in populations of different cultures and ethnic groups. The cross-cultural validity of MQOL was investigated using a translated and modified version in Chinese - the MQOL-HK - in 462 palliative care patients in Hong Kong. Results show that the MQOL-HK is acceptable, valid and reliable. There is good acceptability, construct validity, convergent and divergent validity, test-retest and inter-rater reliability. Our study confirms that QOL does have cross-culturally robust constructs. Principal components analysis shows that the domains of physical, psychological, existential and support are all relevant and applicable in Chinese culture. Multiple regression analysis reveals that existential domain is the most important domain in predicting overall QOL. 'Face', eating and sex are additional facets of QOL that also need to be considered. The worst physical symptom on admission is the item of QOL with the lowest score, which need more care and attention by palliative care workers. A cross-culturally validated QOL instrument cannot just help ensure an accurate evaluation of profile, determinants, and changes of QOL, but is also a valuable asset for future comparison and evaluation of palliative care services and interventions across the world.

BACKGROUND. The authors have designed a non-cisplatin-based chemotherapy regimen for the treatment of patients with advanced nonsmall cell lung carcinoma (NSCLC). This regimen capitalizes on the mild toxicity of gemcitabine, a novel nucleoside analog. METHODS. A total of 46 chemotherapy-naive patients with histologically confirmed Stage IIIB or IV NSCLC were enrolled. Eligible patients were treated with gemcitabine 1000 mg/m2 on Days 1, 8, and 15, plus oral etoposide 50 mg daily for 14 days, which was increased to 21 days if there was no World Health Organization (WHO) Grade 3 or 4 toxicity in the 1st 2 cycles (each cycle was 28 days long). All patients were included for analysis of response and survival according to an intention-to-treat principle. RESULTS. The overall response rate was 43.5% (95% confidence interval [CI], 30.7-60.2%). There was 1 complete response (2.2%) and 19 partial responses (41.3%). The median survival was 48.0 weeks (95% CI, 38.1-75.9 weeks) and the 1-year survival rate was 45% (95% CI, 29-62%). The median time to progression for all patients was 39.2 weeks (95% CI, 35.7-49.7 weeks). World Health Organization (WHO) Grade 3 and 4 anemia, neutropenia, and thrombocytopenia was reported in 29%, 32%, and 18% of patients, respectively. Two patients had reactivation of hepatitis B viral infection that resulted in WHO Grade 4 hepatic dysfunction. Other nonhematologic toxicities were uncommon. CONCLUSIONS. This non-cisplatin-based regimen of gemcitabine and oral etoposide achieved a high response and survival rate. Toxicity appeared to be less severe than that associated with existing cisplatin-based regimens. A randomized study of this regimen versus a cisplatin-based regimen is indicated. (C) 2000 American Cancer Society.

Purpose: A multi-centre randomized phase II study of single agent nolatrexed dihydrochloride versus doxorubicin was undertaken in Chinese patients with advanced hepatocellular carcinoma (HCC) to study and compare the clinical efficacy of the two drugs. Methods: Fifty-four patients with clinical or histological diagnosis of HCC were randomized in a 2:1 ratio to receive nolatrexed or doxorubicin. Nolatrexed 725 mg/m2/day was given by continuous infusion via a central venous device for 5 days and doxorubicin 60 mg/m2was given as a rapid intravenous infusion every 3 weeks. Results: No objective responses were observed in either treatment arm. Two patients in the nolatrexed arm and none in the doxorubicin arm had >50% decline in serum a-fetoprotein. The median survival for the patients in the nolatrexed and doxorubicin arms was 139 days and 104 days, respectively. Moderate toxicities including leukopenia, thrombocytopenia, mucositis and skin rash were observed in both treatment arms. Conclusion: Nolatrexed and doxorubicin are minimally active in the treatment of advanced HCC. Given the small sample size, no difference is observed between the two drugs.

Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC. © 2007 Society of Surgical Oncology.