Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has been characterized by fever, respiratory, and gastrointestinal symptoms as well as shedding of virus RNA into feces. We performed a systematic review and meta-analysis of published gastrointestinal symptoms and detection of virus in stool and also summarized data from a cohort of patients with COVID-19 in Hong Kong. METHODS: We collected data from the cohort of patients with COVID-19 in Hong Kong (N = 59; diagnosis from February 2 through February 29, 2020),and searched PubMed, Embase, Cochrane, and 3 Chinese databases through March 11, 2020, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms (loss of appetite, nausea, vomiting, diarrhea, and abdominal pain or discomfort) using a random effects model. RESULTS: Among the 59 patients with COVID-19 in Hong Kong, 15 patients (25.4%) had gastrointestinal symptoms, and 9 patients (15.3%) had stool that tested positive for virus RNA. Stool viral RNA was detected in 38.5% and 8.7% among those with and without diarrhea, respectively (P = .02). The median fecal viral load was 5.1 log10 copies per milliliter in patients with diarrhea vs 3.9 log10 copies per milliliter in patients without diarrhea (P = .06). In a meta-analysis of 60 studies comprising 4243 patients, the pooled prevalence of all gastrointestinal symptoms was 17.6% (95% confidence interval [CI], 12.3-24.5); 11.8% of patients with nonsevere COVID-19 had gastrointestinal symptoms (95% CI, 4.1-29.1), and 17.1% of patients with severe COVID-19 had gastrointestinal symptoms (95% CI, 6.9-36.7). In the meta-analysis, the pooled prevalence of stool samples that were positive for virus RNA was 48.1% (95% CI, 38.3-57.9); of these samples, 70.3% of those collected after loss of virus from respiratory specimens tested positive for the virus (95% CI, 49.6-85.1). CONCLUSIONS: In an analysis of data from the Hong Kong cohort of patients with COVID-19 and a meta-analysis of findings from publications, we found that 17.6% of patients with COVID-19 had gastrointestinal symptoms. Virus RNA was detected in stool samples from 48.1% patients, even in stool collected after respiratory samples had negative test results. Health care workers should therefore exercise caution in collecting fecal samples or performing endoscopic procedures in patients with COVID-19, even during patient recovery.

Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma.

This study was designed to evaluate the efficacy, safety profile, pharmacokinetics, pharmacodynamics and quality of life of pegylated recombinant human arginase 1 (Peg-rhAgr1) in patients with advanced hepatocellular carcinoma (HCC). Patients were given weekly doses of Peg-rhAgr1 (1600 U/kg). Tumour response was assessed every 8 weeks using RECIST 1.1 and modified RECIST criteria. A total of 20 patients were recruited, of whom 15 were deemed evaluable for treatment efficacy. Eighteen patients (90%) were hepatitis B carriers. Median age was 61.5 (range 30-75). Overall disease control rate was 13%, with 2 of the 15 patients achieving stable disease for >8 weeks. The median progression-free survival (PFS) was 1.7 (95% CI: 1.67-1.73) months, with median overall survival (OS) of all 20 enrolled patients being 5.2 (95% CI: 3.3-12.0) months. PFS was significantly prolonged in patients with adequate arginine depletion (ADD) >2 months versus those who had ≤2 months of ADD (6.4 versus 1.7 months; p = 0.01). The majority of adverse events (AEs) were grade 1/2 non-hematological toxicities. Transient liver dysfunctions (25%) were the most commonly reported serious AEs and likely due to disease progression. Pharmacokinetic and pharmacodynamic data showed that Peg-rhAgr1 induced rapid and sustained arginine depletion. The overall quality of life of the enrolled patients was well preserved. Peg-rhAgr1 is well tolerated with a good toxicity profile in patients with advanced HCC. A weekly dose of 1600 U/kg is sufficient to induce ADD. Significantly longer PFS times were recorded for patients who had ADD for >2 months.

A phase 1 dose-escalating study of pegylated recombinant human arginase 1 (Peg-rhArg1) in patients with advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients. METHODS: Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design. RESULTS: Fifteen patients were enrolled at weekly doses of 500 U/kg (n = 3), 1000 U/kg (n = 3), 1600 U/kg (n = 3) and 2500 U/kg (n = 6). The median age was 57 years (33-74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600-2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients. CONCLUSION: Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.

Mapping the Functional Assessment of Cancer Therapy-general or -Colorectal to SF-6D in Chinese patients with colorectal neoplasm.

OBJECTIVES: To map Functional Assessment of Cancer Therapy-General (FACT-G) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C) subscale scores onto six-dimensional health state short form (derived from short form 36 health survey) (SF-6D) preference-based values in patients with colorectal neoplasm, with and without adjustment for clinical and demographic characteristics. These results can then be applied to studies that have used FACT-G or FACT-C to predict SF-6D utility values to inform economic evaluation. METHODS: Ordinary least square regressions were estimated mapping FACT-G and FACT-C onto SF-6D by using cross-sectional data of 537 Chinese subjects with different stages of colorectal neoplasm. Mapping functions for SF-6D preference-based values were developed separately for FACT-G and FACT-C in four sequential models for addition of variables: 1) main-effect terms, 2) squared terms, 3) interaction terms, and 4) clinical and demographic variables. Predictive performance in each model was assessed by the R(2), adjusted R(2), predicted R(2), information criteria (Akaike information criteria and Bayesian information criteria), the root mean square error, the mean absolute error, and the proportions of absolute error within the threshold of 0.05 and 0.10. RESULTS: Models including FACT variables and clinical and demographic variables had the best predictive performance measured by using R(2) (FACT-G: 59.98%; FACT-C: 60.43%), root mean square error (FACT-G: 0.086; FACT-C: 0.084), and mean absolute error (FACT-G: 0.065; FACT-C: 0.065). The FACT-C-based mapping function had better predictive ability than did the FACT-G-based mapping function. CONCLUSIONS: Models mapping FACT-G and FACT-C onto SF-6D reached an acceptable degree of precision. Mapping from the condition-specific measure (FACT-C) had better performance than did mapping from the general cancer measure (FACT-G). These mapping functions can be applied to FACT-G or FACT-C data sets to estimate SF-6D utility values for economic evaluation of medical interventions for patients with colorectal neoplasm. Further research assessing model performance in independent data sets and non-Chinese populations are encouraged.

The use of single-agent sorafenib in the treatment of advanced hepatocellular carcinoma patients with underlying Child-Pugh B liver cirrhosis: a retrospective analysis of efficacy, safety, and survival benefits.

BACKGROUND: This study explored the efficacy, tolerability, and survival benefits of using sorafenib in patients with Child-Pugh class B (CPB) cirrhosis. METHODS: Patients with advanced hepatocellular carcinoma who were treated with sorafenib at Queen Mary Hospital, Hong Kong, China, were analyzed retrospectively. Treatment outcomes were analyzed according to their respective Child-Pugh status. Patients with CPB disease were further divided into CPB7 (those with a score of 7) and CPB8-9 (a score of 8 or 9) subgroups. RESULTS: The baseline demographic parameters were comparable between 108 patients with Child-Pugh class A (CPA) disease and 64 CPB patients. Both clinical benefit rate (21.3% vs 32.4% vs 14.8%; P = .23) and progression-free survival (median: 3.2 months vs 3.2 months vs 2.3 months; P = .26) were similar among CPA, CPB7, and CPB8-9 groups, respectively. The overall survival was different among these groups (P = .002) and showed a trend toward worse outcome in CPB patients: the median was 6.1, 5.4, and 2.7 months among CPA, CPB7, and CPB8-9 patients, respectively. The commonest grade 3/4 adverse events were hand-foot syndrome (13.5%), diarrhea (9.9%), and rash (7.0%). Grade 3/4 leukopenia, thrombocytopenia, and anemia occurred in 2.9%, 5.3%, and 8.8% of the patients, respectively. Overall, the 3 groups of patients experienced similar incidence of most of these adverse events. Nonetheless, CPB patients experienced more anemia (P = .01), gastrointestinal bleeding (P = .02), and hepatic encephalopathy (P = .02). CONCLUSIONS: CPA and CPB patients tolerated sorafenib similarly and derived similar clinical and progression-free survival benefit. Among CPB patients, most benefits were observed in patients with a score of 7. Nevertheless, CPB patients were more susceptible to developing cirrhotic complications, and thus more vigilant surveillance is needed.

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease.

BACKGROUND: The combination of bevacizumab (B) and erlotinib (E) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients. We aimed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment. METHODS: Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited. All patients received bevacizumab(B) at 10 mg/kg every 2 weeks with erlotinib(E) at 150 mg daily for a maximum of 6 cycles. Response assessments using both RECIST and modified RECIST criteria were performed after every 6 weeks. The primary endpoint was clinical benefit (CB) rate and a Simon two-stage design was employed. RESULTS: The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited. The median age was 47 years (range, 28-61) and all patients were in ECOG performance status 1. Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis. Among these 10 patients, none of the enrolled patients achieved response or stable disease. The median time-to-progression was 1.81 months (95 % confidence interval [C.I.], 1.08-1.74 months) and overall survival was 4.37 months (95 % C.I., 1.08-11.66 months). Rash (70 %), diarrhea (50 %) and malaise (40 %) were the most commonly encountered toxicities. CONCLUSION: The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population. Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population.

Colon cancer in a patient with underlying aplastic anemia: A clinical challenge.

The association of gastrointestinal malignancy with aplastic anemia has rarely been reported in the literature. Although it is not clear whether there is any direct relationship between aplastic anemia and gastrointestinal cancers, a retrospective analysis did suggest the notion that patients with aplastic anemia might have a higher incidence of colorectal cancer. Here, we report the diagnostic and therapeutic challenges in managing a patient with aplastic anemia and advanced colorectal cancer. Early diagnosis is challenging due to overlapping symptomatology and clinical features, increased risk of diagnostic procedures, and confounding complications arising from aplastic anemia and its treatment. A high index of suspicion and multidisciplinary input are essential.

Being active or flexible? Role of control coping on quality of life among patients with gastrointestinal cancer.

OBJECTIVES: This study examined the link between coping and quality of life among patients with gastrointestinal (GI) cancer. Two hypotheses were tested. The active-personality hypothesis states that quality of life is associated with the predominant use of primary control coping (PCC) in general. The situational-flexibility hypothesis states that quality of life is related to flexible deployment of PCC and secondary control coping (SCC) according to situational controllability. METHODS: Participants were 180 Chinese adult patients diagnosed with colon or liver cancer. Their perceived controllability of stressors, coping, and quality of life were compared with those of a sex-and age-matched community sample. RESULTS: Three groups with distinct coping patterns were identified: (a) a flexible group characterized by the use of PCC in controllable situations but SCC in uncontrollable situations, (b) an active group characterized by predominant use of PCC in most situations, and (c) a passive group characterized by predominant use of SCC or avoidant coping in most situations. Patients in the active and the flexible groups had higher perceived controllability and psychological well-being scores than those in the passive group. CONCLUSIONS: Our results provide support for both the active-personality and the situational-flexibility hypotheses among GI cancer patients. Clinical and research implications of the findings are discussed.

Direct medical costs of care for Chinese patients with colorectal neoplasia: a health care service provider perspective.

OBJECTIVES: To estimate the direct medical cost of colorectal neoplasia (CRN) from newly diagnosed to the completion of the tumour-specific treatment in the initial year of disease across stages and tumour primary sites. METHODS: Only direct medical costs from the perspective of the health care service provider were incorporated in the cost analysis (in 2009 USD) using a bottom-up approach. Tumour-specific treatments of surgery, chemotherapy and radiotherapy data in the initial year of disease were identified from the 401 CRN adult patients by a review of their medical records. Service utilization for diagnosis, staging, pre-operative assessment and post-operative follow-up consultations was estimated from the recommendations of established surveillance and clinical practice guidelines. RESULTS: Direct medical cost for the care of a newly diagnosed CRN was ranging from $1941 for low-risk polyp to $45 115 for stage IV colorectal cancer in the initial year of care. Costs of care showed a gradient increase from $1748 for low-risk colonic polyps to $42 899 for stage IV colon cancer, and from $2232 for low-risk rectal polyps to $48 453 for stage IV rectal cancers. Diagnostic/pre-operative assessment and treatment accounted for most of total costs of colorectal polyp (58.9-76.7%) and cancer (60.8-85.2%) care. CONCLUSION: The results provided stage and site-specific estimations of the direct medical costs of CRN in a Chinese population that can assist policy decision making and facilitate health care service planning and cost-effectiveness evaluations.

Validity and reliability study on traditional Chinese FACT-C in Chinese patients with colorectal neoplasm.

OBJECTIVE: To establish the validity and reliability of traditional Chinese version of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C). METHODS: A total of 536 subjects self-administered (n = 331) or interviewer-administered (n = 205) FACT-C (version 4), EORTC QLQ-C30/CR38 and SF-12v2 instruments for health-related quality of life assessment. Construct validity was examined by item-scale correlation, scaling success and concurrent validity. Reliability was evaluated by test-retest reliability and internal consistency. Sensitivity was assessed by known-groups comparisons. RESULTS: The completion rates for FACT-C were almost perfect (>98%). The FACT-C demonstrated item-internal consistency and item discriminant validity through item-scale correlation. Scaling success and concurrent validity were satisfactory to support the construct validity. The five subscales of the FACT-C showed good internal consistency with Cronbach alpha coefficient and substantial reproducibility, demonstrating good reliability. Sensitivity was supported when there were significant differences in scores related to physical condition between patients who were receiving treatment and those who were not. CONCLUSION: Traditional Chinese version of the FACT-C was demonstrated to have satisfactory psychometric properties in terms of applicability, reliability, validity and sensitivity in Chinese patients with colorectal neoplasm. The FACT-C was valid colorectal-specific health-related quality of life tool for the Chinese population.

The outcomes and safety of single-agent sorafenib in the treatment of elderly patients with advanced hepatocellular carcinoma (HCC).

BACKGROUND: With the aging population, hepatocellular carcinoma (HCC) in the elderly represents a significant health burden. We aimed to evaluate and compare the efficacy and tolerability of single-agent sorafenib in treating elderly patients with advanced HCC versus the younger population. METHODS: We retrospectively analyzed a consecutive cohort of advanced HCC patients with Child-Pugh A or B liver function and an Eastern Cooperative Oncology Group performance status score of 0-2 treated with sorafenib. The patients were categorized into older (age ≥70 years) and younger (age <70 years) groups. Treatment outcomes and related adverse events (AEs) were compared. RESULTS: In total, 172 patients, 35 in the older (median age, 73 years) and 137 in the younger (median age, 55 years) group, were analyzed. The median progression-free survival time was similar in the older and younger groups (2.99 months versus 3.09 months; p = .275), as was the overall survival time (5.32 months versus 5.16 months; p = .310). Grade 3 or 4 AEs were observed in 68.6% of older and 62.7% of younger patients (p = .560), with neutropenia (11.4% versus 0.7%; p = .007), malaise (11.4% versus 2.2%; p = .033), and mucositis (5.7% versus 0.0%; p = .041) being more frequently reported in the elderly cohort. CONCLUSIONS: The survival benefits and overall treatment-related AEs of sorafenib are comparable in elderly and younger advanced HCC patients. Nevertheless, more vigilant monitoring in the elderly is warranted because they are more susceptible to develop neutropenia, malaise, and mucositis.

The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib.

BACKGROUND: he role of serum alpha-fetoprotein (AFP) changes in predicting the treatment outcomes of advanced hepatocellular carcinoma (HCC) patients to sorafenib remains unknown. METHODS: Serum AFP was collected prospectively at baseline and subsequent follow-up visits in parallel with clinical and survival outcomes. AFP response was defined as a relative drop of AFP >20% of the baseline level after 6 weeks of sorafenib. The relationship between AFP response and the treatment outcomes was first explored in patients who received sorafenib in a phase II study. Subsequently, an independent validation set of patients were obtained to validate the association of AFP response to clinical outcomes. RESULTS: Included in the exploration and validation sets for analysis were 41 and 53 patients, respectively, with baseline AFP level >20 µg/L. In the exploration cohort, AFP response was significantly associated with clinical benefit (CB) rate (relative chance 3.4, 95% confidence interval [CI], 1.1-11.1), and multivariate analysis indicated that AFP response was associated with significantly better progression-free survival (PFS) (hazard ratio [HR], 0.31; 95% CI, 0.13-0.76) and marginally better overall survival (OS) (HR, 0.30; 95% CI, 0.09-1.02). When applying AFP changes in the validation set, significant associations were again found between AFP response with CB rate (relative chance, 5.5; 95% CI, 2.3-13.6) and PFS (HR, 0.12; 95% CI, 0.04-0.30) but not OS (HR, 0.61; 95% CI, 0.27-1.26). CONCLUSION: Drop in AFP level at 6 weeks is an exploratory early surrogate for both CB and PFS in advanced HCC patients receiving sorafenib.

Phase I dose-finding study of pazopanib in hepatocellular carcinoma: evaluation of early efficacy, pharmacokinetics, and pharmacodynamics.

BACKGROUND: A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). RESULTS: Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise]. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C(max) and area under the concentration-time curve (AUC(0-6)) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K(trans) were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease. CONCLUSION: Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity.

Treatment of non-erosive reflux disease with a proton pump inhibitor in Chinese patients: a randomized controlled trial.

BACKGROUND: Evidence suggests that rates of gastroesophageal reflux disease are increasing in the Asia-Pacific region, where patients tend to have predominantly non-erosive reflux disease as opposed to erosive (reflux) esophagitis. At present, data for the responsiveness of non-erosive reflux disease to proton pump inhibition are scant. We aimed to study esomeprazole for the treatment of non-erosive reflux disease in Chinese patients. METHODS: Patients with a clinical diagnosis of gastroesophageal reflux, and a locally validated reflux index, the Chinese GerdQ, of equal to or greater than 12 were recruited and randomized to receive esomeprazole 20 mg daily or placebo for 8 weeks. Reflux index scores, quality of life (SF-36), and the hospital anxiety and depression (HAD) scale and symptom relief were evaluated before, during, and after treatment. RESULTS: A total of 175 patients were randomized. Patients in the esomeprazole group (n = 85) demonstrated statistically significant reductions in their GerdQ index, from 19.45 to 15.37 and to 14.32 (p = 0.013, p = 0.005) at weeks 4 and 8, respectively. Compared to placebo at week 8, 57.1% of patients on esomeprazole found that their symptoms had resolved or were acceptable compared with 37.2% in the placebo group (p = 0.001). There were no statistically significant differences in overall quality-of-life measures or the HAD scale related to treatment. CONCLUSIONS: This study suggests that esomeprazole is efficacious in treating Chinese patients with non-erosive reflux disease.

Prevalence of occult hepatitis B infection in a highly endemic area for chronic hepatitis B: a study of a large blood donor population.

BACKGROUND AND AIMS: The aim of the present study was to determine the population prevalence of occult hepatitis B (OHB) infection and its clinical profile in a highly endemic area of chronic hepatitis B virus disease. METHODS: OHB was first identified by individual sample testing for hepatitis B surface antigen (HBsAg) followed by nucleic acid testing (NAT) and vice versa for 3044 (cohort 1, stored sera from donation within 1 year) and 9990 (cohort 2, prospective study) blood donors, respectively. OHB was confirmed meticulously by ≥2 out of 3 tests with detectable hepatitis B virus (HBV) DNA using a sensitive standardised assay. Detailed serology and viral load in the serum and liver were studied. RESULTS: The prevalence of OHB was 0.13% (4/3044) and 0.11% (11/9967) for cohort 1 and 2, respectively. In cohort 2, 10 out of 11 OHB samples were positive for anti-HBc (hepatitis B core antigen) antibody (all were immunoglobulin G). Seven had detectable anti-HBs. The serum HBV DNA levels were extremely low (highest 14.1 IU/ml). Of the six donors who underwent liver biopsies, all had normal liver biochemistry, extremely low liver HBV DNA (highest 6.21 copies/cell) and nearly normal liver histology. For those with viral sequence generation, none had the common HBsAg mutant G145R. CONCLUSIONS: The prevalence of OHB in a highly endemic area of chronic HBV was very low, thus implying a low impact on transfusion services. To implement universal screening, the high cost of NAT should be taken into account. OHB blood donors had very low HBV replication, and normal liver biochemistry and histology, conferring a favourable prognosis.

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib.

IMPORTANCE OF THE FIELD: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC. AREAS COVERED IN THIS REVIEW: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor. WHAT THE READER WILL GAIN: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC. TAKE HOME MESSAGE: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.

Phase 1-2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma: implication for antiangiogenic approach to hepatocellular carcinoma.

BACKGROUND: This phase 1-2 trial assessed the efficacy and tolerability of an oral angiogenesis inhibitor-PTK787/ZK222584 (PTK)-in combination with intravenous doxorubicin for the treatment of advanced hepatocellular carcinoma (HCC) patients. METHODS: In phase 1, advanced HCC patients received PTK at escalating doses together with doxorubicin 60 mg/m2 given as an intravenous bolus every 3 weeks to establish the maximum tolerated dose (MTD). Subsequently, in phase 2, all patients received the same regimen with oral PTK at the MTD dose every 3 weeks for a maximum of 6 cycles. RESULTS: Nine patients were recruited in phase 1, with the MTD established as 750 mg daily. Overall, 27 patients received the regimen with PTK at 750 mg daily. The median age was 52 years (range, 23-73 years), and 63 percent of patients were chronic hepatitis B carriers. Notably, the majority of patients had Child-Pugh B cirrhosis. The overall response rate was 26.0%, with all the responding patients having partial response. Another 20% of patients achieved stable disease for at least 12 weeks. The median progression-free survival was 5.4 months (range, 0.27-23.6 months), and overall survival was 7.3 months (range, 0.8-23.6 months). The commonest grade 3 or 4 nonhematological toxicities were mucositis (11%) and alopecia (7%), respectively. Grade 3 or 4 neutropenia was observed in 7 (26%) patients; 2 had neutropenic sepsis. CONCLUSIONS: The combination of PTK with intravenous doxorubicin shows encouraging activity in treating advanced HCC patients.

Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use.

Colorectal cancer (CRC) is the second most common lethal cancer in the Western world. There is a 10 to 20 years lead time from normal mucosa to carcinoma which offers a window of opportunity to modify and prevent the outcome of CRC, with its incipient morbidity and mortality. The objective of this paper is to review the evidence for chemoprophylaxis in CRC, identify currently used agents and determine their role in the current management algorithm of CRC. Large cohort-control and randomised controlled trials in the most studied chemoprophylaxis agents are reviewed. Currently, the role for chemoprophylaxis in CRC remains a niche area, with celecoxib the only recommended agent for use in patients with familial polyposis syndromes. However, the role of chemoprophylaxis is likely to grow significantly in the next decade as understanding of the stepwise tumorigenesis cascade becomes better understood and current clinical trials are completed.

Transient carcinoembryonic antigen elevations during adjuvant chemotherapy for colorectal cancer reflect the burden of residual micrometastatic disease.

BACKGROUND: Carcinoembryonic antigen (CEA) testing is routinely used to monitor the progress of patients with advanced cancer on treatment, or else to detect relapse during follow-up, particularly in colorectal cancer (CRC). Although CEA levels have been reported to rise during adjuvant drug therapies, the mechanism of such 'surges' is not clear. This study was conducted to clarify the clinical significance of this phenomenon. PATIENTS AND METHODS: We conducted a retrospective analysis of CEA levels in 88 consecutive patients receiving adjuvant chemotherapy in our center: 39 patients with primary CRC and a comparison cohort of 49 patients with breast cancer treated with adjuvant chemotherapy. In the event of 2 serial CEA increases, endoscopic and/or imaging investigations were performed to exclude recurrence. Subset analyses were based on nodal status and primary tumor type. RESULTS: Primary resection was associated with significant CEA decline in patients with CRC but not in those with breast cancer. Forty-three patients (48.9%) experienced CEA fluctuations exceeding 0.5 ng/mL during adjuvant chemotherapy; CEA increases indicated true recurrence in 2 patients (4.7%). Adjuvant CEA surges occurred both more often and more extensively in disease associated with >or= 4 positive nodes in patients with CRC but not in patients with breast cancer (P < .05). CONCLUSION: Both the frequency and extent of CEA surges during adjuvant chemotherapy parallel the severity of preoperative nodal involvement in CRC but not in breast cancer, suggesting that such surges reflect tumorilytic effects on occult disease in patients with CRC only. However, whether these CEA surges predict survival that is inferior (ie, because of greater burden of residual disease) or superior (ie, because of greater tumorilytic efficacy) to that of stagematched 'nonsurge' patients, remains to be determined by larger, prospective CRC studies.