Patient characteristics, treatment patterns, and outcomes among black and white patients with multiple myeloma initiating daratumumab: A real-world chart review study.

BACKGROUND: Daratumumab was approved for multiple myeloma (MM) in 2015. While its safety and efficacy are well documented, there is limited real-world information on its use and outcomes in patients of different races. METHODS: We conducted a retrospective chart review of adult patients with MM initiating daratumumab in any line of therapy (LOT) between November 2015 and May 2020. De-identified data were retrieved from 2 US clinical sites; patient characteristics, treatment patterns, and response rate were described for black and white patients, stratified by LOT. Overall response rate (ORR), progression-free survival (PFS), and time to next LOT (TTNT) were compared between black and white patients initiating daratumumab in second line (2L) or later, adjusting for age and number of prior lines. RESULTS: Two hundred and fifty-two patient charts (89 black, 163 white) were extracted. Black patients were younger at diagnosis (61.7 vs. 67.0 years) and had a similar proportion of females (black: 44.9%, white: 46.6%). Black patients had longer time between MM diagnosis and daratumumab initiation (43.2 vs. 34.1 months) and received more prior LOTs (median 3.0 vs. 2.0). ORR for black and white patients initiating daratumumab in 1L was 100.0%, with very good partial response or better in 75.0% and 66.7%, respectively. Similar trends were observed in 2L and 3L+. There were no significant differences in ORR, PFS, or TTNT between groups. CONCLUSION: Daratumumab had similar clinical outcomes (ORR, PFS, and TTNT) in black and white patients. Black patients initiated daratumumab later in their treatment, suggesting potential discrepancies in access to new MM treatments.

Treatment patterns and effectiveness of patients with multiple myeloma initiating Daratumumab across different lines of therapy: a real-world chart review study.

BACKGROUND: Daratumumab, a CD38 monoclonal antibody, has demonstrated efficacy as monotherapy and combination therapy across several indications, both among newly-diagnosed and refractory patients with multiple myeloma (MM). However, there is limited evidence on treatment patterns and effectiveness of daratumumab in the real-world setting, particularly in first line (1 L). This study aimed to describe real-world treatment patterns and clinical outcomes among patients initiating daratumumab across different lines of therapy. METHODS: A retrospective chart review of adult patients with MM initiating daratumumab between November 2015 and March 2021 was conducted at two clinical sites in the United States. De-identified patient-level data were abstracted in an electronic case report form. Patient characteristics and treatment patterns were described. Clinical outcomes including overall response rate (ORR), progression-free survival, and time to next line of therapy were reported using descriptive statistics and stratified by line of therapy (1 L, second line [2 L] or third line or later [3 L+]). A sub-group analysis evaluated treatment patterns and ORR among patients re-treated with daratumumab. RESULTS: A total of 299 patients were included in the study (mean age: 68 years; 55% male). Among them, 26 were 1 L patients, 66 were 2 L patients, and 207 were 3 L+ patients; 110 patients (36.8%) received a stem cell transplant prior to daratumumab initiation. The mean duration of follow-up was 10 months among 1 L patients and 19 months among 2 L and 3 L+ patients. Patients who initiated daratumumab in 1 L had a 100% ORR, while those initiating in 2 L and 3 L+ had an ORR of 78.8 and 65.2%, respectively. Among re-treated patients, ORR was 66.7% during the first treatment segment, and 52.9% during the second treatment segment. Kaplan-Meier rates of progression-free survival at 12 months were 89.9, 75.2, and 53.1% among patients who initiated daratumumab in 1 L, 2 L, and 3 L+, respectively. Kaplan-Meier rates of time to next line of therapy at 12 months were 94.1, 73.4, and 50.0% among patients who initiated daratumumab in 1 L, 2 L, and 3 L+, respectively. CONCLUSIONS: These findings suggest that daratumumab-based regimens are an effective treatment option across all lines of therapy, with highest response rate in 1 L.

Statin dose titration patterns and subsequent major cardiovascular events in very high-risk patients: estimates from Swedish population-based registry data.

AIMS: Clinical studies have demonstrated the efficacy of intensive statin therapy in lowering low-density lipoprotein cholesterol and cardiovascular (CV) events. Our objective was to examine statin titration patterns and the association between titration patterns and subsequent CV events in very high-risk patients. METHODS AND RESULTS: Using Swedish national population-based registry data, we identified 192 435 patients with very high risk of atherosclerotic CV disease initiated on moderate-intensity statin therapy between 2006 and 2013. Outcomes of interest were titration to high-intensity therapy and the major adverse cardiovascular events (MACE) composite (myocardial infarction, ischaemic stroke, and CV death) outcome. Cumulative incidence of MACE was assessed by titration status 1-year post-treatment initiation in patients adherent to treatment during the first year, using a 12-week cut-off from initiation to define early, delayed and no up-titration to high-intensity statins. Cox regression analysis was used to estimate adjusted hazard ratios (HRs). In 144 498 eligible patients, early titration was associated with significantly lower risk of MACE in the subsequent 2 years compared to no up-titration (HR 0.76, P < 0.01]. Delayed up-titration was associated with a smaller reduction (HR 0.88, P = 0.08). The majority of patients did not up-titrate. CONCLUSION: Early up-titration to high-intensity statins was independently associated with lower risk of subsequent CV events compared to no up-titration. Delayed up-titration was not associated with the same benefit. Despite the higher risk associated with no up-titration, few patients at very high CV risk who started treatment on moderate-intensity up-titrated to high intensity, indicating a potential need for more aggressive lipid management of these patients in clinical practice.

Treatment and Low-Density Lipoprotein Cholesterol Management in Patients Diagnosed With Clinical Atherosclerotic Cardiovascular Disease in Alberta.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is an important indicator in the development and management of atherosclerotic cardiovascular disease (ASCVD). Herein, we describe the management of LDL-C with lipid-lowering therapy, among patients diagnosed with clinical ASCVD in Alberta, Canada. METHODS: A retrospective study was conducted by linking multiple health system databases to examine clinical characteristics, treatments, and LDL-C assessments. Patients with ASCVD were identified using a specific case definition on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification/International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada codes between 2011 and 2015. LDL-C was assessed at the first measurement (index test) and second measurement (follow-up test) during the study period. LDL-C levels were evaluated on the basis of the 2016 Canadian Cardiovascular Society guideline recommendations for achieving < 2.0 mmol/L or a 50% reduction. Statin therapies were categorized as low-, moderate-, and high-intensity. RESULTS: Among the 281,665 individuals identified with ASCVD during the study period, 219,488 (77.9%) had an index LDL-C test, whereas 120,906 (55.1%) and 144,607 (65.9%) were prescribed lipid-lowering therapy before and after their index test, respectively. Most patients who received any lipid-lowering therapy were receiving moderate-/high-intensity statins (n = 133,029; 60.6%). Among the study cohort who had 2 LDL-C tests (n = 91,841; 32.6%), 48.5% of patients who received any lipid-lowering therapy did not achieve LDL-C levels < 2.0 at index date, whereas 36.6% did not achieve LDL-C levels < 2.0 or a 50% reduction at the follow-up test. CONCLUSIONS: The current study revealed that only two-thirds of patients with ASCVD were receiving pharmacotherapy and of those, a significant proportion did not reach recommended LDL-C levels. A remarkable treatment gap was identified for at-risk ASCVD patients. Further implementation strategies are required to address this undermanagement.

Comparison of Recommendations and Use of Cardiovascular Risk Equations by Health Technology Assessment Agencies and Clinical Guidelines.

OBJECTIVES: To identify risk equations for cardiovascular diseases (CVDs) in primary and secondary prevention settings that are used or recommended by health technology assessment (HTA) organizations and in clinical guidelines (CGs). METHODS: A targeted literature review was conducted using a two-stage search strategy. First, HTA reviews of manufacturers' drug submissions, reports from established HTA organizations (Europe, Canada, and Australia), and CGs from countries with and without HTA organizations, including the United States, were identified. Documents published between September 30, 2006 and September 30, 2016, were examined for cardiovascular risk equations, recommendations, and commentaries. Next, publications associated with risk equations and cited by HTA and CG documents were retrieved. This literature was examined to extract commentaries and risk equation study characteristics. RESULTS: The review identified 47 risk equations, 25 in the primary CVD prevention setting (i.e., patients with no CVD history), including 5 for CVD prevention in diabetes and 22 solely in secondary prevention settings; 11 were identified for heart failure, 3 for stroke or transient ischemic attack, 2 for stable angina, and 11 for acute coronary syndrome or related conditions. A small set of primary prevention equations was found to be commonly used by HTAs, whereas secondary prevention equations were less common in HTA documents. CGs provided more risk equations as options than HTA documents. CONCLUSIONS: Although there is an abundance of risk equations developed for primary and secondary prevention, there remains a need for additional research to provide sufficient clinical and HTA guidance for risk estimation, particularly in high-risk or secondary prevention settings.

Cardiovascular event rates in a high atherosclerotic cardiovascular disease risk population: estimates from Swedish population-based register data.

AIMS: This study aimed to estimate the rate of cardiovascular (CV) events in the real world in patients at high risk of recurrent CV events similar to the FOURIER trial population. METHODS AND RESULTS: A retrospective population-based cohort study was conducted using Swedish national registers from 1 July 2001 to 31 December 2015. Patients in the atherosclerotic cardiovascular disease (ASCVD) prevalent cohort met the FOURIER-like inclusion criteria, including treatment with high/moderate-intensity statins, on 1 July 2006. Additionally, two cohorts defined by diagnosis of incident ischaemic stroke (IS) and incident myocardial infarction (MI), meeting the FOURIER-like inclusion criteria were followed from date of diagnosis. Event rates were calculated for the hard major adverse cardiovascular events (MACE) composite: MI, IS, and CV death; and the ASCVD composite: MI, IS, unstable angina, coronary revascularization, and CV death. Approximately half of patients experienced a CV event (ASCVD composite) during follow-up. The MACE composite rates/100 person-years were 6.3, 11.9, and 12.3 in the ASCVD prevalent (n = 54 992), MI incident (n = 45 895), and IS incident (n = 36 134) cohorts, respectively. The ASCVD composite rates/100 person-years were 7.0, 21.7, and 12.9 in the ASCVD prevalent, MI incident, and IS incident cohorts, respectively. The multiple-event MACE composite rates/100 person-years were 8.5 (ASCVD prevalent cohort), 15.4 (MI incident cohort), and 14.4 (IS incident cohort). CONCLUSION: In this real-world setting, CV event rates were high in all studied cohorts. In particular, the MACE composite rates were two to three times higher than in the FOURIER clinical trial, indicating a substantial disease burden despite treatment with moderate or high-intensity statins.

Real-world treatment patterns of PCSK9 inhibitors among patients with dyslipidemia in Germany, Spain, and the United Kingdom.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 antibody inhibitors (PCSK9i) are approved as adjuncts to maximal tolerated statin therapy to lower low-density lipoprotein cholesterol (LDL-C). This study describes real-world use, characteristics of PCSK9i users and non-users, and factors influencing treatment choice. METHODS: A physician and patient survey was conducted in Germany, Spain, and the UK from December 2016 to April 2017 through the Adelphi Dyslipidemia Disease Specific Program. Physicians reported patients' lipid-lowering therapy (LLT) history and characteristics. PCSK9i users were systematically over-sampled. Results were summarized using frequencies and proportions. RESULTS: The study included 110, 123, and 117 physicians from Germany, Spain, and the UK, respectively, providing data on 3,073 patients (mean age = 62 years; 60% male). Most patients (63-73%) had prior statin and/or ezetimibe use. Compared to patients receiving other LLT (n = 2686), PCSK9i users (222 in Germany, 97 in Spain, 68 in the UK) were, on average, 5-7.5 years younger and had LDL-C at diagnosis averaging 23-53 mg/dl higher. Familial hypercholesterolemia (FH), coronary heart/artery disease, myocardial infarction, and acute coronary syndrome were more common among PCSK9i users than non-users. PCSK9i users were also more likely to use high-intensity statins in their current LLT regimen (64-89% vs 28-50%). Physicians commonly reported PCSK9i benefits on LDL-C and total cholesterol as reasons for initiating these agents, and PCSK9i users reported good knowledge of cardiovascular disease and treatment options. CONCLUSIONS: Results indicate that physicians are prescribing PCSK9i to patients with high cardiovascular risk in accordance with European guidelines and reimbursement requirements.

Treatment patterns and healthcare resource utilization among patients with hereditary angioedema in the United States.

BACKGROUND: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim. RESULTS: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD. CONCLUSIONS: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.

Impact of a Care Management Entity on Use of Psychiatric Services Among Youths With Severe Mental or Behavioral Disorders.

OBJECTIVE: Care management entity models have a positive impact on functioning and symptom control among youths with serious emotional and behavioral disorders. However, little is known about whether treatment benefits are sustained after discharge. The study objective was to examine the association between enrollment in a care management entity and mental health outcomes during the year after discharge. METHODS: Data from care management entity administrative claims were linked with Medicaid claims for youths enrolled in a care management entity anytime from December 2009 through December 2013. Inverse probability treatment weighting was used to balance baseline characteristics between the youths enrolled in the care management entity and a comparison group. Study outcomes were psychiatry-related hospitalizations and emergency department (ED) visits during the year after discharge. Two models were used to compare the two groups, one modeling the probability of using any psychiatric service and one modeling the number of visits for each outcome among users of either service. RESULTS: After adjustment with inverse probability treatment weighting, 2,381 youths (care management, N=488; comparison, N=1,893) were identified. Care management was associated with a significantly lower likelihood of any psychiatry-related ED visit (odds ratio [OR]=.65, p=.017) and any psychiatric hospitalization (OR=.60, p=.011). No significant differences in outcomes were observed when the comparison was limited to users of services. CONCLUSIONS: Reduced use of psychiatric inpatient and ED services among youths enrolled in a care management entity was sustainable after discharge. Multiagency collaboration is needed to enrich the ability to assess outcomes across broader domains.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis.

BACKGROUND: In this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. PATIENTS AND METHODS: Quality-adjusted overall survival was estimated using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A ≥ 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. RESULTS: In the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], -0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). CONCLUSION: In its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality-adjusted survival time versus Pac in the 2L+ subpopulation.

Psychotropic Polypharmacy Among Youths With Serious Emotional and Behavioral Disorders Receiving Coordinated Care Services.

OBJECTIVE: The study examined differences in psychotropic polypharmacy among youths with serious emotional and behavioral disorders who received coordinated care services (CCS) that used a wraparound model and a matched sample of youths who received traditional services. METHODS: A quasi-experimental design compared psychotropic polypharmacy one year before and one year after discharge from CCS. The cohort was youths with serious emotional and behavioral disorders who were enrolled in CCS from December 2009 through May 2014. The comparison group was youths with serious emotional and behavioral disorders who received outpatient mental health services during the same time. Administrative data from Medicaid, child welfare, and juvenile justice services were used. A difference-in-difference analysis with propensity score matching evaluated the CCS intervention by time effect on psychotropic polypharmacy. RESULTS: In both groups, most youths were male, black, and 10-18 years old, with attention-deficit hyperactivity disorder (54%-55%), mood disorder (39%-42%), depression (26%-27%), and bipolar disorder (25%-26%). About half of each group was taking an antipsychotic. The percentage reduction in polypharmacy from one year before CCS enrollment to one year after discharge was 28% for the CCS group and 29% for the non-CCS group, a nonsignificant difference. CCS youths excluded from the analysis had more complex mental health needs and a greater change in polypharmacy than the CCS youths who were included in the analytic sample. CONCLUSIONS: Mental health care coordination had limited impact in reducing psychotropic polypharmacy for youths with less complex mental health needs. Further research is needed to evaluate the effect on psychotropic polypharmacy among youths with the greatest mental health needs.

Treatment patterns and low-density lipoprotein cholesterol (LDL-C) goal attainment among patients receiving high- or moderate-intensity statins.

BACKGROUND: European clinical guidelines recommend a low-density lipoprotein cholesterol (LDL-C) goal of < 70 mg/dL. Statin use varies and past studies suggest low rates of real-world goal attainment. This study describes LDL-C goal attainment among atherosclerotic CV disease (ASCVD) patients with various utilization patterns of moderate- or high-intensity statins in routine care. METHODS: This retrospective cohort study used electronic medical records data from the QuintilesIMS® Disease Analyzer (> 2 million individuals annually) to identify ASCVD (coronary atherosclerosis, stable/unstable angina, myocardial infarction, ischemic stroke, transient ischemic attack, aneurysm, peripheral artery disease) patients on moderate-/high-intensity statin in Germany. Proportion of patients with LDL-C < 70 mg/dL was determined using the lowest LDL-C value for each patient (index) in 2012, 2013, and 2014, while on statin. Treatment patterns were assessed for patients with at least 1 year of post-index follow-up. Results were stratified by year and treatment pattern [no change, switch, dose up-/down-titration, discontinuation (≥ 90 day gap)]. RESULTS: In > 14,000 patients assessed in each year (mean age 71 years, 35% female, 8-12% taking high-intensity statins), approximately 80% had LDL-C ≥ 70 mg/dL. Treatment patterns were assessed for most (88-93%) patients. Approximately 79-81% of patients made no change to statin regimens, 1% switched statins, 14-16% discontinued; 1% of moderate-intensity patients up-titrated, and 3% of all patients down-titrated. LDL-C goal attainment in these treatment pattern groups was 20, 16-24, 17, 11-14, and 17-19%, respectively. CONCLUSIONS: Majority of ASCVD patients had LDL-C ≥ 70 mg/dL while on moderate-/high-intensity statins. Despite low LDL-C goal attainment, few patients changed their treatment regimens.

Impact of Coordinated Behavioral Health Management on Quality Measures of Antipsychotic Use.

A state Care Management Entity (CME) using the wraparound practice model provided intensive care coordination for youth with severe mental illness, those most likely to receive antipsychotics. The model has led to improved clinical/functional outcomes, but little is known about the impact on antipsychotic prescribing and safety monitoring. A pre-post study was conducted to evaluate antipsychotic dosing, concomitant antipsychotic use, and metabolic monitoring among CME-enrolled and non-CME-enrolled comparison groups. CME-enrolled youth had greater decrease in concomitant antipsychotic use than non-CME-enrolled youth, but no difference in dosing or metabolic monitoring. More education of prescribing antipsychotics and team-based engagement in care coordination are needed.

A National Survey of State Medicaid Psychotropic-Monitoring Programs Targeting Youths.

OBJECTIVE: This study aimed to describe state Medicaid psychotropic-monitoring programs targeting youths. METHODS: Key informants from each state Medicaid administration and the District of Columbia were invited to participate in a telephone-administered survey designed to assess the implementation strategies of the state psychotropic-monitoring program. Data were collected from August 2011 through December 2012. A total of 38 states participated, four declined, and nine did not respond to the invitation. Descriptive statistics were used to characterize monitoring programs. RESULTS: Key informants from 28 of the 38 states (74%) reported a program in place, mostly prior authorization (68%). One-third of the programs (32%) had a two-tier review involving pharmacists and child psychiatrists. CONCLUSIONS: Although variability in psychotropic-monitoring programs may limit comparison of program impact across states, the variability provides an opportunity to investigate the impact of different models on best practices and the quality of care.

The Prognostic Value of Platelet Count in Patients With Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Thrombocytopenia has been acknowledged to be a crucial risk factor for cirrhosis formation and hepatocarcinogenesis in chronic liver diseases. However, to date, the association between platelet count (PLT) and the prognosis of hepatocellular carcinoma (HCC) remains inconsistent and controversial. The aim of the present study was to determine whether PLT could be used as a useful predictor of survival in patients with HCC. We performed systematic review in online databases, including PubMed, EmBase, and Web of Science, from inception until 2014. Studies were included if a statistical relationship was investigated between PLT and survival for HCC, and hazard ratio (HR) and 95% confidence intervals (CIs) for overall survival (OS) or recurrence-free survival (RFS) were provided. The quality of each included study was assessed by Newcastle-Ottawa scale score. To synthesize these studies, a random-effects model or a fixed-effects model was applied as appropriate. Then, we calculated heterogeneity, performed sensitivity analysis, tested publication bias, and did subgrouped and meta-regression analysis. Finally, we identified 33 eligible articles (published from 1998 to 2014) involved 5545 patients by retrieval. A low level of preoperative PLT was found to be significantly associated with a poor survival of HCC. Irrespective of the therapy used, the pooled HRs for OS and RFS were 1.41 (95% CI, 1.14-1.75) and 1.44 (95% CI, 1.13-1.83), respectively. Specifically, in patients who underwent liver resection, the pooled HRs for OS and RFS were 1.67 (95% CI, 1.22-2.27) and 1.44 (95% CI, 1.04-1.99), respectively. Furthermore, patients with preoperative thrombocytopenia (PLT < 100 × 109/L) had a worse OS (HR: 1.73, 95% CI, 1.29-2.32) and RFS (HR: 1.57, 95% CI, 1.31-1.87) in comparison with patients without thrombocytopenia. All our findings showed no significant changes due to the removal of any study or the use of an opposite-effects model, and there was no significant publication bias. The limitations of this meat-analysis were nonuniform cut-off values of PLT, high between-study heterogeneities, potential confounders, and a bias of publication year. A low preoperative PLT level results in an unfavorable outcome in HCC. PLT is a simple, inexpensive, and useful predictor of survival in patients with HCC.

Thrombocytopenia for prediction of hepatocellular carcinoma recurrence: Systematic review and meta-analysis.

AIM: To investigate the association between thrombocytopenia and relapse after treatment for hepatocellular carcinoma (HCC). METHODS: We searched the PubMed, EMBASE, and Web of Science databases to obtain eligible studies. The hazard ratios (HRs) values and 95% confidence intervals (CIs) were pooled by random effects model. Subsequently, we estimated the heterogeneity, performed a sensitivity analysis, determined the publication bias, and performed subgroup and meta-regression analyses. Study quality was assessed by using the Oxford Center for Evidence Based Medicine tool. RESULTS: We identified 18 eligible studies by retrieval (published during 2000-2014). Out of the 4163 patients with HCC who were recruited, 2746 (66.0%) experienced recurrence. In general, our meta-analysis suggested that low platelet count (PLT) before therapy significantly increased the probability of postoperative recurrence (HR = 1.53, 95%CI: 1.29-1.81). PLT was also valuable in the prediction of intrahepatic distant recurrence (HR = 1.49, 95%CI: 1.25-1.77). Subgroup and meta-regression analyses identified various therapeutic modalities as the source of a high degree of heterogeneity. The pooled HR values showed no obvious change when a single study was removed, but otherwise, an opposite-effects model was used. In addition, no significant publication bias was detected. CONCLUSION: Thrombocytopenia before treatment might be an inexpensive and useful predictor of postoperative recurrence in patients with HCC.

FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma.

AIM: To investigate the expression of forkhead box protein M1 (FoxM1) in the process of epithelial mesenchymal transition in hepatocellular carcinoma (HCC) and its role in metastasis. METHODS: FoxM1 and E-cadherin expression in HCC tissue microarray specimens was evaluated by immunohistochemical staining, and statistical methods were applied to analyze the correlation between FoxM1 and epithelial-mesenchymal transition (EMT). Kaplan-Meier analysis of the correlation between the FoxM1 expression level and recurrence or overall survival of HCC patients was performed. The expression of FoxM1, E-cadherin and snail homologue 1 (SNAI1) in HCC cell lines was evaluated by real-time reverse transcription-polymerase chain reaction and Western blot. Hepatocyte growth factor (HGF) was used to induce EMT and stimulate cell migration in HCC cells. The expression of FoxM1 and SNAI1 was regulated by transfection with plasmids pcDNA3.1 and siRNAs in vitro. The occurrence of EMT was evaluated by Transwell assay, morphologic analysis and detection of the expression of EMT markers (E-cadherin and vimentin). Luciferase and chromatin immunoprecipitation assays were used to evaluate whether SNAI1 is a direct transcriptional target of FoxM1. RESULTS: FoxM1 expression was increased significantly in HCC compared with para-carcinoma (10.7 ± 0.9 vs 8.2 ± 0.7, P < 0.05) and normal hepatic (10.7 ± 0.9 vs 2.7 ± 0.4, P < 0.05) tissues. Overexpression of FoxM1 was correlated with HCC tumor size, tumor number, macrovascular invasion and higher TNM stage, but was negatively correlated with E-cadherin expression in microarray specimens and in cell lines. FoxM1 overexpression was correlated significantly with HCC metastasis and EMT. In vitro, we found that FoxM1 plays a key role in HGF-induced EMT, and overexpression of FoxM1 could suppress E-cadherin expression and induce EMT changes, which were associated with increased HCC cell invasiveness. Next, we confirmed that FOXM1 directly binds to and activates the SNAI1 promoter, and we identified SNAI1 as a direct transcriptional target of FOXM1. Moreover, inhibiting the expression of SNAI1 significantly inhibited FoxM1-mediated EMT. CONCLUSION: FoxM1 overexpression promotes EMT and metastasis of HCC, and SNAI1 plays a critical role in FoxM1-mediated EMT.

Overexpression of PSF1 is correlated with poor prognosis in hepatocellular carcinoma patients.

BACKGROUND: PSF1 is a subunit of the GINS complex which is essential for establishment of DNA replication forks, and the progression of the replisome. Previous studies have shown a close relationship between PSF1 and cell cycle in the proliferation of immature cells as well as tumors. The purpose of this study was to measure PSF1 expression in hepatocellular carcinoma (HCC) tissues, and determine the effects of down-regulation of PSF1 expression on growth of cancer cells, the cell cycle, apoptosis and cell invasiveness. METHODS: Samples from 137 HCC tissues, 67 from adjacent nontumor tissue and 15 from normal liver were studied using immunochemistry. The HepG2 cell line was used for knockdown experiments studied by RT-PCR, real-time PCR, apoptosis and invasiveness assays. RESULTS: PSF1 was overexpressed in HCC tissues compared with normal liver tissues. High PSF1 expression correlated with a more aggressive phenotype as well as worse prognosis in HCC patients. Knockdown of PSF1 expression using small interfering RNA (siRNA) slowed the growth of cancer cell by suppressing the cell cycle progression as well as increasing apoptosis, especially early apoptosis. In addition, the invasiveness of HepG2 cells was also reduced by down-regulation of PSF1. CONCLUSIONS: These results suggest that the inhibition of PSF1 might provide new therapeutic approaches for HCC.