The mitochondrial hinge protein, UQCRH, is a novel prognostic factor for hepatocellular carcinoma.

Alterations in mitochondrial respiration contribute to the development and progression of cancer via abnormal biogenesis, including generation of reactive oxygen species. Ubiquinol-cytochrome c reductase hinge protein (UQCRH) consists of the cytochrome bc1 complex serving respiration in mitochondria. In the present study, we analyzed UQCRH abnormalities in hepatocellular carcinoma (HCC) and its association with clinical outcomes of patients. UQCRH expression in HCC was determined via semiquantitative and quantitative real-time reverse transcriptase polymerase chain reaction of 96 surgically resected HCC tissues positive for hepatitis B virus surface antigen. UQCRH was frequently overexpressed in HCC tissues (46.8%, based on 2.1-fold cutoff). UQCRH overexpression was observed in HCCs with larger tumor size, poorer differentiation, or vascular invasion. Kaplan-Meier analysis revealed significantly shorter overall (P = 0.005) and recurrence-free survival (P = 0.027) in patients with tumors overexpressing UQCRH. The prognostic impact of UQCRH was significant in subgroups of patients divided according to the α-fetoprotein (AFP) level. The patient subgroup with higher AFP levels (≥20 ng/mL) exhibited significant differences in 5-year overall (18.5% vs. 67.9%) and recurrence-free survival rates (11.1% vs. 46.4%) between groups with and without UQCRH overexpression. In contrast, no marked survival differences were observed between subgroups with lower AFP levels (<20 ng/mL). Multivariate analysis defined UQCRH as an independent poor prognostic factor. Conclusively, our results indicate that UQCRH overexpression is correlated with poor outcomes of HCC patients. Furthermore, in patients grouped as high risk based on elevated AFP, lack of UQCRH overexpression could be a useful indicator for clinical treatment.

A model predicting survival of patients with recurrent or progressive hepatocellular carcinoma: the MORE score.

BACKGROUND AND AIM: Most prognostic models for hepatocellular carcinoma are based on data at the time of diagnosis. However, the disease frequently recurs or progresses after initial treatment, with changes in tumor burden and clinical status. Therefore, we developed a risk score model to predict survival of hepatocellular carcinoma patients at the time of disease recurrence or progression. METHODS: Of 1972 patients newly diagnosed with hepatocellular carcinoma at the National Cancer Center, Korea, between January 2004 and December 2009, 1301 with recurrent or progressive disease were enrolled. They were randomly classified into a development (75%, n = 976) and a validation cohort (25%, n = 325). A survival prediction method was established in the development cohort using the multivariate Cox proportional hazards model, and its performance was evaluated on the validation cohort. RESULTS: A model predicting survival of patients with recurrent or progressive hepatocellular carcinoma was developed using some known independent prognostic factors for overall survival: age, albumin, Model for End-Stage Liver Disease score, tumor burden, serum alpha-fetoprotein level, and presence of ascites. In addition, initial treatment modality and best response after initial treatment were also independent prognostic factors and were incorporated in the model. The C-statistics and χ2 statistics of this novel score for the validation cohort were 0.808 (95% CI: 0.781-0.834) and 4.408 for 3-year survival. CONCLUSIONS: A new model to predict survival of patients with recurrent or progressive hepatocellular carcinoma was developed and validated. This model may be useful for planning subsequent treatments.

Clinical Characteristics of Patients with Cryptogenic Hepatocellular Carcinoma in a Hepatitis B Virus-Endemic Area.

OBJECTIVES: Chronic hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma (HCC) in South Korea, but a high prevalence of metabolic diseases may result in increases in the incidence of cryptogenic HCC (cHCC). We studied characteristics of the cHCC in a single-center cohort. METHODS: A cohort of 1,784 HCC patients newly diagnosed and treated at the National Cancer Center, Korea, between 2004 and 2009 was reviewed and analyzed. RESULTS: The cause of HCC was categorized as cHCC, HBV, hepatitis C virus (HCV), or alcohol. Overall, 162 (9.1%) patients of the HCC cohort had cHCC, and their mean age was 61.9 years. The median survival of cHCC patients was 24.7 months, which was the second shortest among the four groups after HBV HCC. cHCC patients had the largest tumor size (mean 7.4 cm) and the second highest proportion of poor prognostic factors such as the proportion of poorly defined tumors and extrahepatic spread in imaging studies. cHCC patients had better survival than HBV HCC patients according to multivariate analysis. Among cHCC patients, 137 (84.6%) had anti-HBc IgG antibodies, but this sub-group had different clinical features to those of HBV HCC patients. The body mass index (BMI) and hyperglycemia and hypercholesterolemia levels in cHCC patients were similar to those in HCV and alcoholic HCC patients. CONCLUSIONS: Anti-HBc IgG antibodies were present in most cHCC patients, but cHCC patients had better survival than HBV HCC patients on multivariate analysis. However, cHCC patients had a larger mean tumor size and more aggressive tumor characteristics than HCV HCC or alcoholic HCC patients did. It is hoped that this study will contribute to a better understanding of cHCC in HBV-endemic areas.

Development and Validation of a Prediction Model to Estimate Individual Risk of Pancreatic Cancer.

INTRODUCTION: There is no reliable screening tool to identify people with high risk of developing pancreatic cancer even though pancreatic cancer represents the fifth-leading cause of cancer-related death in Korea. The goal of this study was to develop an individualized risk prediction model that can be used to screen for asymptomatic pancreatic cancer in Korean men and women. MATERIALS AND METHODS: Gender-specific risk prediction models for pancreatic cancer were developed using the Cox proportional hazards model based on an 8-year follow-up of a cohort study of 1,289,933 men and 557,701 women in Korea who had biennial examinations in 1996-1997. The performance of the models was evaluated with respect to their discrimination and calibration ability based on the C-statistic and Hosmer-Lemeshow type χ2 statistic. RESULTS: A total of 1,634 (0.13%) men and 561 (0.10%) women were newly diagnosed with pancreatic cancer. Age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation were included in the risk prediction model for men. Height, BMI, fasting glucose, urine glucose, smoking, and drinking habit were included in the risk prediction model for women. Smoking was the most significant risk factor for developing pancreatic cancer in both men and women. The risk prediction model exhibited good discrimination and calibration ability, and in external validation it had excellent prediction ability. CONCLUSION: Gender-specific risk prediction models for pancreatic cancer were developed and validated for the first time. The prediction models will be a useful tool for detecting high-risk individuals who may benefit from increased surveillance for pancreatic cancer.

What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy?

PURPOSE: Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system. MATERIALS AND METHODS: This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chi-square and C statistics. RESULTS: All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone. CONCLUSION: The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone.

A Study of Relationship of Atheroembolic Risk Factors with Postoperative Recovery in Renal Function after Partial Nephrectomy in Patients Staged T1-2 Renal Cell Carcinoma during Median 4-Year Follow-up.

PURPOSE: The objective of this study is to evaluate the relationship of atheroembolic risk factors with postoperative recovery of renal function after on-clamp partial nephrectomy (PN) with warm ischemia in patients with staged T1-2 renal cell carcinoma (RCC). MATERIALS AND METHODS: A total of 234 patients from 2004 to 2012 were included, and their clinicopathologic and operative parameters, including atheroembolic risk factors were reviewed retrospectively. Renal function, as determined by estimated glomerular filtration rate (eGFR) and measurement of serum creatinine level (Cr) at each scheduled follow-up for a median four years, was compared between the high-risk (HR) group (n=49, ≥ five risk factors) and the low-risk (LR) group (n=185, < five risk factors). RESULTS: Except for baseline renal function and number of risk factors for atheroembolism, differences in characteristics between groups were comparatively insignificant. At 3 months after the operation, Cr and eGFR differed significantly between the two groups (p < 0.05), but no differences were observed afterward. Significant deterioration from baseline in Cr and eGFR was observed in both groups at 1 month after the operation, with a greater change in the HR group (p < 0.05). From measurement to measurement, significantly faster deterioration in Cr and eGFR was observed in the HR group than in the LR group until 6 months after the operation (Cr: LR, 0.02 mg/dL and HR, 0.13 mg/dL; eGFR: LR, 1.50 mL/min/1.73 m(2) and HR, 6.38 mL/min/1.73 m(2); p < 0.05). CONCLUSION: The presence of atheroembolic risk factors may negatively influence postoperative recovery of renal function after PN in patients with localized RCC.

Korean Version of a Model to Estimate Survival in Ambulatory Patients with Hepatocellular Carcinoma (K-MESIAH).

BACKGROUND AND AIM: A model to estimate survival in ambulatory hepatocellular carcinoma patients (MESIAH) is useful for estimating patient prognosis but needs improvement for Korean patients, most of whom have a hepatitis B virus. We aimed to modify the MESIAH for better prognostication through enhancing calibration for Korean patient population (K-MESIAH). METHODS: Utilizing a cohort of 1,969 hepatocellular carcinoma (HCC) patients from the National Cancer Center of Korea between 2004 and 2009, a survival prediction model was developed using the Cox proportional hazards model. The model's performance was evaluated using C-statistical and χ2-statistical analyses. External validation was performed using an independent cohort of 328 patients from the Seoul National University Bundang Hospital. RESULTS: To develop the K-MESIAH, etiology was added to the original risk factors (age, Model for Endstage Liver Disease, albumin, size of the largest nodule, number of tumor nodules, vascular invasion, metastasis, and alpha fetoprotein) in the MESIAH. From the internal validation study, the C-statistics and χ2-statistics for one-, three-, and five-years of survival were 0.83 (95% Confidence Interval: 0.82-0.85), 49.07; 0.81 (95% Confidence Interval: 0.79-0.82), 28.95; and 0.80 (95% Confidence Interval: 0.79-0.81), 20.93, respectively. The K-MESIAH also showed a high prediction ability for the external validation cohort. CONCLUSIONS: A survival prediction model for Korean HCC patients was developed and validated to have a high level of performance. This K-MESIAH may be more useful in clinical practice and personalized care in a hepatitis B virus endemic area.

Overexpression of ERG and Wild-Type PTEN Are Associated with Favorable Clinical Prognosis and Low Biochemical Recurrence in Prostate Cancer.

OBJECTIVES: The aim of this study was to investigate the expression of two commonly altered genes ERG and PTEN in prostate cancer (PC) and evaluate their prognostic significance. Despite conflicting published results, TMPRSS2-ERG gene fusion and PTEN loss are generally considered unfavorable markers for PC progression. MATERIALS AND METHODS: Of the 762 prostatic adenocarcinoma specimens obtained from radical prostatectomy, 613 without neoadjuvant hormone therapy were included in tissue microarrays for quantitatively assessment of ERG and PTEN expression via immunohistochemistry. Statistical analysis of the association between such expression and clinicopathological parameters, including clinical prognosis, was performed with a p-value of <0.05 considered significant. RESULTS: During a median follow-up period of 44.0 months, 132 (21.5%) patients developed biochemical recurrence (BCR). ERG overexpression and PTEN loss were observed in 145 (23.7%) and 253 (41.3%) cases, respectively. BCR-free survival was significantly better in patients with ERG overexpression (p=0.005), but unfavorable among those with PTEN loss (p=0.142). Sub-group analysis revealed that patients with PTEN loss and negative ERG expression had the worst BCR-free survival outcome (p=0.021). Furthermore, multivariate analysis identified prostate-specific antigen level (≥10 ng/mL), Gleason score (>6), pathologic T stage (≥T3), positive surgical margin, and extraprostatic capsule extension as significant risk factors for BCR (p<0.05). CONCLUSIONS: Our results indicated that ERG overexpression was associated with favorable BCR-free survival after radical prostatectomy for PC, whereas PTEN loss was with unfavorable outcomes.

Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma.

BACKGROUND: Despite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence. RESULTS: By implementing a permutation-based semi-supervised principal component analysis algorithm using the optimal principal component, we selected sixty-four pathways associated with hepatitis B virus (HBV)-positive HCC recurrence (p < 0.01), from our microarray dataset composed of 142 HBV-positive HCCs. In relation to the public HBV- and public hepatitis C virus (HCV)-positive HCC datasets, we detected 46 (71.9%) and 18 (28.1%) common recurrence-associated pathways, respectively. However, overlap of recurrence-associated genes between datasets was rare, further supporting the utility of the pathway-based approach for recurrence analysis between different HCC datasets. Non-supervised clustering of the 64 recurrence-associated pathways facilitated the classification of HCC patients into high- and low-risk subgroups, based on risk of recurrence (p < 0.0001). The pathways identified were additionally successfully applied to discriminate subgroups depending on recurrence risk within the public HCC datasets. Through multivariate analysis, these recurrence-associated pathways were identified as an independent prognostic factor (p < 0.0001) along with tumor number, tumor size and Edmondson's grade. Moreover, the pathway-based approach had a clinical advantage in terms of discriminating the high-risk subgroup (N = 12) among patients (N = 26) with small HCC (<3 cm). CONCLUSIONS: Using pathway-based analysis, we successfully identified the pathways involved in recurrence of HBV-positive HCC that may be effectively used as prognostic markers.

Oncological and surgical results of laparoscopic versus open liver resection for HCC less than 5 cm: case-matched analysis.

BACKGROUND: The purpose of this study is the evaluation of the surgical and oncological results of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) by comparing laparoscopic and open liver resection (OLR) in the treatment of this disease. Retrospective analysis of laparoscopic and OLR for HCC (<5 cm) performed over a 4-year period was conducted. The LLR was done by a single surgeon. METHODS: The study was performed on patients who received liver resection for HCC between July 2007 and August 2011 in our institution. Propensity-based matched analyses were used to account for operative method selection biases. During the 4 years, 1,050 patients with HCC received an operation. Among them patients who never received TACE or RFA before surgery and had HCC (<5 cm) were selected for this study. RESULTS: 174 patients had OLR, and 58 patients underwent LLR. Patients who received LLR had lower operative time, transfusion rate, complication rate, and shorter hospital days. There were significant differences in hospital mortality and morbidity between the two groups. Dietary recovery was relatively fast in the group of LLR. Overall and disease-free survival rates during the 4 years were also not significantly different between the two groups. CONCLUSIONS: LLR is a developing and safe technique in a select group of patients including those with malignancies, and use of this procedure is associated with short hospital stays, a rapid return to a normal diet, full mobility, and minimal morbidity, with acceptable oncological parameters. It may be an optimal method of hepatectomy in HCC (<5 cm). Further, long-term follow-up should be acquired for adequate evaluation for survival.

Incidence and risk factors of 30-day early and 90-day late morbidity and mortality of radical cystectomy during a 13-year follow-up: a comparative propensity-score matched analysis of complications between neobladder and ileal conduit.

OBJECTIVE: We report on the short and late morbidity and mortality of ileal conduit and neobladder after radical cystectomy with their associated risk factors. METHODS: We retrospectively collected data on 308 non-metastatic bladder cancer patients who underwent radical cystectomy with either ileal conduit or neobladder for a curative intent from January 1999 to December 2011. Post-operative morbidity and mortality of 30-day (early) and 90-day (late) complication with their risk factors were examined in association with different types of urinary diversion. A comparative analysis using propensity-score matching was performed with matching variables of age, sex, number of underlying diseases and pathologic T and N stages, lymph node dissection, operative time and time of surgical year for comparison of the early and late morbidities between ileal conduit and neobladder. RESULTS: During the median follow-up of 46.6 months, early and late morbidities were 29.5% (n=91) and 19.8% (n=61), and complication-related mortalities were 2.2 and 6.6%, respectively. The type of urinary diversion significantly affected only the late complications (early: neobladder 57 vs. ileal conduit 47, P=0.096; late: neobladder 67 vs. ileal conduit 37, P<0.001). However, after propensity-score matching, no significant differences in early and late morbidities were observed between neobladder and ileal conduit. For risk factors of morbidity, number of removed lymph node states and hypertension were independently significant for both early and late complications (P<0.05). CONCLUSIONS: The type of urinary diversion affected only late complication, however, results of the matching analysis showed no significant differences in early and late morbidities between neobladder and ileal conduit.

Clinical outcomes of a cohort series of patients with hepatocellular carcinoma in a hepatitis B virus-endemic area.

BACKGROUND AND AIMS: To evaluate the clinical outcomes of patients with hepatocellular carcinoma (HCC) and compare the findings with that of a previous cohort. METHODS: Overall, 1972 HCC patients diagnosed and treated at the National Cancer Center, Korea between 2004 and 2009 were enrolled. The data of this cohort were compared with those of a previous cohort (2000-2003) from the same institution. RESULTS: In all (mean age, 56.4 years; 1642 men), 74.6% was hepatitis B virus (HBV) positive, 81.6% were Child-Pugh (CP) class A, and 64.4% was Barcelona Clinic Liver Cancer (BCLC) stage C. The modified Union for International Cancer Control (mUICC) stage I, II, III, IVa, and IVb was found in 8.9%, 29.6%, 24.8%, 23.1%, and 13.6% patients, respectively. The most common initial treatment was transarterial chemotherapy (58.3%), followed by resection (18.6%). The 5-year survival rate of BCLC stage 0, A, B, and C were 79.6%, 67.2%, 33.9%, and 17.1%, respectively. The performance status, BCLC stage, mUICC stage, CP class, model for end-stage liver disease score, tumor characteristics, portal vein tumor invasion, and serum alpha-fetoprotein level proved to be independent prognostic variables. Overall survival in the present cohort was better than that in the previous cohort (hazard ratio, 0.829; 95% confidence interval, 0.754-0.912), especially for advanced HCC patients with HBV-positive status. CONCLUSIONS: This cohort study provides valuable insights into the characteristics of HCC in Korean patients. Our findings may help develop clinical trials, treatment strategies, and prognosis systems for HCC patients in HBV-endemic areas.

Validation of the MSKCC and Heng risk criteria models for predicting survival in patients with metastatic renal cell carcinoma treated with sunitinib.

PURPOSE: To validate the Memorial Sloan-Kettering Cancer Center (MSKCC) and Heng models with metastatic renal cell carcinoma treated with sunitinib, and to investigate prognostic factors in these patients. METHODS: This study included 106 patients with metastatic renal cell carcinoma who were treated with sunitinib from April 2007 to July 2012 including 35 patients who received systemic treatment before sunitinib and 71 that were naive to systemic treatment. Patients were evaluated using the MSKCC and Heng models, and the significance of several prognostic factors were evaluated. RESULTS: The application of the MSKCC and Heng risk criteria resulted in stratification into 3 groups (favorable, intermediate, and poor risk) with distinctly different overall survival (OS) curves (P < 0.001 and P < 0.001, respectively), for the pretreated patients (P < 0.001 and P < 0.001, respectively). The Heng model had slightly better discriminatory ability (χ (2) = 30.82, Harrell's C = 0.6895) than the MSKCC model (χ (2) = 25.13, Harrell's C = 0.6532). Multivariate analysis revealed that the absence of nephrectomy and no hypertension at baseline, along with elevated C-reactive protein levels, were independent risk factors for poorer OS. CONCLUSIONS: The MSKCC and Heng model were both valid models for predicting OS. The no nephrectomy, no hypertension at baseline, and high C-reactive protein levels were independently associated with poorer OS.

Use of MDLC-DIGE and LC-MS/MS to identify serum biomarkers for complete remission in patients with acute myeloid leukemia.

The response criteria for complete remission (CR) in acute myeloid leukemia (AML) are currently based on morphology and blood cell counts. However, these criteria are insufficient to establish a diagnosis in cases with poor quality bone marrow (BM) samples demonstrating a loss of cellular morphology. We investigated whether the sera of patients contained biomarkers that indicate disease response status. First, we performed multidimensional liquid chromatography-differential gel electrophoresis (MDLC-DIGE) to generate protein profiles of two pooled, paired serum samples from patients who had achieved CR; one collected at diagnosis (PreCR) and the other collected after chemotherapy (CR). Then, with the biomarker candidates found, ELISA was carried out for individual PreCR and CR samples, and for other verification sets including nonremission (NR) patients and normal samples. We selected two proteins, complement factor H (CFH) and apolipoprotein H (ApoH), with dye (Cy) ratios showing greater than 2.0-fold differences between the pooled samples. ELISA showed that CFH and ApoH are useful for distinguishing between the recovered (CR and normal) and nonrecovered (PreCR, PreNR, and NR) states in AML (p <0.001). We successfully applied a protein profiling technology of MDLC-DIGE and LC-MS/MS to discover two biomarkers for CR which needs further validation for a clinical setting.