|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.03.7499 on June 5 2006 © 2006 American Society of Clinical Oncology. Proline-Directed Protein Kinase FA Is a Powerful and Independent Prognostic Predictor for Progression and Patient Survival of Hepatocellular Carcinoma
From the Laboratory of Molecular and Cellular Oncology, Institute of Molecular and Cellular Biology, and Department of Life Science, National Tsing Hua University, Hsinchu; and the Department of Pathology and Surgery, National Taiwan University Hospital, Taipei, Taiwan. Address reprint requests to Shiaw-Der Yang, PhD, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC; e-mail: lsysd{at}life.nthu.edu.tw
Purpose Molecular, cellular, and animal studies have established that overexpressed proline-directed protein kinase FA (PDPK FA) is essential for the development of tumorigenesis, invasion, and metastasis of human cancer cells. However, the prognostic role of PDPK FA in cancer patients remains largely unknown. In this study, association of PDPK FA expression with poor prognosis of hepatocellular carcinoma (HCC) patients was examined. Patients and Methods PDPK FA expression in the resected tumors of 134 HCC patients (112 men and 22 women) with ages ranging from 33 to 83 years (mean, 55 years) was analyzed by immunohistochemistry. Highly condensed cytoplasmic and nuclear PDPK FA associated with tumor cells was used as the major scoring parameter for positive PDPK FA expression. Results Approximately 68% of the patients (91 of 134) exhibited positive PDPK FA expression. Patients with positive PDPK FA showed poorer disease-free survival and overall survival (P < .001). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for progression and patient survival of HCC (hazard ratio [HR], 2.878; 95% CI, 1.634 to 5.067 for disease-free survival; and HR, 5.035; 95% CI, 2.137 to 11.866 for overall survival; P < .001). Conclusion Consistent with PDPK FA’s essential role in the development of highly malignant phenotypes, the present study establishes the potential prognostic role of PDPK FA in progression and patient survival of surgically resected primary HCC. Taken together, PDPK FA represents a new modifiable signal-transducing target for prognostic prediction and adjuvant treatment of patients with aggressive HCC after hepatic resection.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Unfortunately, the disease-free survival and overall survival of patients with HCC remain unsatisfactory despite recent advances in surgical and medical treatments.1-6 Therefore, there is intense interest in gaining a better understanding of the molecular and cellular processes involved in HCC to develop more reliable biomarkers to predict relapse and poor outcome of patients with particularly aggressive disease for optimal medical management.7-10 However, the molecular and cellular action mechanisms for tumor aggressiveness and the progression of HCC remain largely unclear and need to be further established.1-10 Proline-directed protein kinase FA (PDPK FA) was originally identified as a specific phosphatase activating factor (FA),11,12 but has subsequently been characterized as a multisubstrate/multifunctional PDPK.13-19 In recent years, the molecular, cellular and animal studies using the specific antisense gene therapeutic approach have established that overexpressed PDPK FA is essential for the development of malignant growth, tumorigenesis, antiapoptosis, antidifferentiation, chemoresistance, invasion, and metastasis of human cancer cells.20-30 The results suggest a potential role of overexpressed PDPK FA in cancer progression even after aggressive treatments including surgery and chemotherapy.31 However, a comprehensive analysis of this novel signaling oncogenic PDPK in relation to survival of cancer patients remains largely unknown and needs to be further established. In this study, accumulation of positive PDPK FA in HCC was examined by immunohistochemical analysis, and its correlation with poor prognosis of patients with HCC was evaluated.
Patients Clinicopathologic data and the specimens used for immunohistochemical analysis were obtained through a detailed retrospective review of the medical records of patients who had undergone initial surgical resection for primary HCC at National Taiwan University Hospital (Taipei, Taiwan) between April 1995 and April 1997. Clinicopathologic data collected included age, sex, date of diagnosis and surgery, tumor size, tumor multiplicity based on the number of tumors, presence of microsatellite nodules, formation of fibrous capsule around the tumor, tumor differentiation based on the criteria proposed by Edmonson and Steiner,32 tumor staging according to the Internation Union Against Cancer (UICC) criteria with slight modification as previously described,33-35 liver cirrhotic status, the preoperative hepatic function assessed by Child-Pugh classification,6 venous invasion, serum alpha-fetoprotein (AFP), hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), tumor recurrence, metastasis, and date of last follow-up or death as a result of HCC. Surgically resected specimens were fixed in 10% formalin and routinely processed for paraffin embedding. Serial sections were stained with hematoxylin and eosin for histologic evaluation. Patients were observed until January 2005. Five-year follow-up survival data are available for all surviving patients. The study was approved by the institution’s surveillance and ethics committee.
Production, Identification, and Characterization of Specific Anti-PDPK FA Antibody for Immunohistochemical Analysis
Immunohistochemical Analysis
Immunohistochemical Scoring
Statistical Analysis
There were 134 patients who had complete clinicopathologic data and specimen available for immunohistochemistry analysis from April 1995 to April 1997. The clinicopathologic features of the patients studied are summarized in Table 1. Of 134 HCC patients studied (112 men and 22 women) with ages ranging from 33 to 83 years (mean, 55 years), the average tumor size was 6.7 ± 4.7 cm (median, 5.5 cm). Tumor multiplicity, microsatellite nodules and formation of fibrous capsule around the tumor were found in 28 patients (21%), 55 patients (41%), and 72 patients (54%), respectively. The extent of differentiation in HCC samples were graded as well differentiated in 16 patients (12%), moderately differentiated in 71 patients (53%) and poorly differentiated in 47 patients (35%). The resected HCC was staged as stage I, II, III, and IV in 14 patients (10%), 53 patients (40%), 54 patients (40%), and 13 patients (10%), respectively. In the background of adjacent nontumor sections, cirrhosis was found in 71 patients (53%), and noncirrhotic tissue was found in 63 patients (47%). The preoperative hepatic function assessed by Child-Pugh classification was 115 patients (86%) in class A and 19 patients (14%) in class B. Of these patients, 91 (68%) were positive for HBsAg. Thirty-two patients (24%) were positive for HCV antibody, 69 patients (51%) were negative, and 33 patients (25%) were unknown. The preoperative laboratory data for GOT, GPT and AFP was 64.8 ± 47.5, 60.6 ± 65.5, and 7,064.1 ± 20,206.6, respectively. Five-year disease-free survival and overall survival of the 134 patients with HCC were 20.9% and 42.5%, respectively.
PDPK FA immunoreactivity was observed to be highly condensed in both cytoplasm and nucleus of tumor cells (Fig 1A). In sharp contrast, PDPK FA immunoreactivity was observed to be negative in non-neoplastic hepatic cells (Fig 1B). PDPK FA was considered positive when there were more than 5% of tumor cells demonstrating highly condensed cytoplasmic and nuclear PDPK FA protein accumulation (median, approximately 15%; range, 0% to 60%). The dichotomized 5% value was derived from cutoff analysis of the receiver operating statistics curves. The different cutoff values used for the analysis would decrease the sensitivity of this methodology. For instance, by shifting the cutoff point to more than 10% positive tumor cells accumulation, we found that there were too many false-negative patients (> 80%) with poor prognosis. According to this criteria, approximately 68% (91 of 134) of the HCC patients exhibited positive PDPK FA expression. Of the 43 negative patients, there were seven patients without any PDPK FA expression and 36 patients with less than 5% positive tumor cells. Of the 91 positive patients, there were 11 patients with more than 50% positive tumor cells. The relation between PDPK FA and clinicopathologic factors was examined. Table 1 showed that PDPK FA expression was associated with sex (P = .014), tumor size (P = .032), tumor multiplicity (P = .006), microstatellite nodules (P < .001), tumor differentiation (P = .022), and venous invasion (P = .001).
Univariate analysis of prognostic significance of the PDPK FA expression was performed for disease-free survival and overall survival by the Kaplan-Meier method. Figure 2 illustrates patient survival over time according to PDPK FA expression and reveals that the patients with PDPK FA-positive HCC were associated with very poor outcome (P < .001). The 5-year disease-free survival for the patients with positive PDPK FA was 5.5% versus 53.5% for those patients with negative PDPK FA (P < .001; Fig 2A; Table 2), and the 5-year overall survival for the patients with positive PDPK FA was 27.5% versus 74.4% for the negative patients (P < .001; Fig 2B; Table 2). Of the other prognosticators investigated, univariate analysis (Table 2) revealed that tumor multiplicity, AFP, GOT, differentiation, tumor stage, microsatellite nodules, and venous invasion adversely affected the 5-year disease-free survival as well as the 5-year overall survival (P < .05). In addition, tumor size and hepatic function assessed by Child-Pugh classification adversely affected the overall survival (P < .05) but not the disease-free survival (Table 2).
To evaluate the robustness of the prognostic value of PDPK FA expression, Cox multivariate proportional hazards regression analysis was performed to derive risk estimates related to disease-free survival and overall survival with all the variables to control for confounders. Multivariate analysis (Table 3) showed that PDPK FA (P < .001) and venous invasion (P < .001) were independent prognostic factors for the disease-free survival. For the overall survival, PDPK FA (P < .001) and venous invasion (P < .001) were also the only two independent prognostic factors (Table 3). PDPK FA expression in HCC was further identified as a very powerful prognostic indicator for disease-free survival (hazard ratio [HR], 2.878; 95% CI, 1.634 to 5.067; P < .001) as well as for overall survival (HR, 5.035; 95% CI, 2.137 to 11.866; P < .001). PDPK FA was found to be the strongest independent prognostic predictor for progression and patient survival of HCC.
The combination analysis on the survival data further revealed that of 55 HCC patients with presence of microsatellite nodules, 47 patients (85.5%) also exhibited positive PDPK FA and had an unfavorable outcome (Fig 3). In sharp contrast, of 79 HCC patients with absence of microsatellite nodules, 44 patients (55.7%) whose tumors exhibited positive PDPK FA failed to have a favorable outcome (Fig 3). In similarity, of 106 patients with solitary tumor, 66 (62.3%) patients whose tumors exhibited positive PDPK FA also failed to have a favorable outcome (Fig 4). Moreover, it is interesting to note that of 59 HCC patients with presence of venous invasion, 49 patients (83.1%) also exhibited positive PDPK FA and had a poor outcome (Fig 5). In sharp contrast, of 75 patients with absence of venous invasion, 42 patients (56%) whose tumors exhibited positive PDPK FA failed to have a favorable outcome (Fig 5).
This is the first report to establish the multisubstrate/multifunctional signal transducing PDPK FA as an independent and powerful prognostic predictor for progression and patient survival of surgically resected primary HCC. Patients characteristics, including sex, age, and 5-year survival, in this series were similar to those of the previous reports,37-47 indicating that the results obtained from these cases are applicable to HCC worldwide. It was therefore decided to use this representative study population to evaluate the prognostic role of PDPK FA in HCC. Approximately 68% (91 of 134) of the HCC patients exhibited positive PDPK FA expression. The HCC patients whose primary tumors exhibited negative expression of PDPK FA apparently had much better survival probabilities, and the patients with a PDPK FA-positive cancer predominantly had an evidently worse prognosis. Compared with patients with negative PDPK FA expression in HCC tissues, the HR for poor disease-free survival for patients with positive PDPK FA was 2.878, and that for patients with poor overall survival was 5.035. The expression of PDPK FA was associated with sex, tumor size, tumor multiplicity, microsatellite nodules, differentiation, and venous invasion (Table 1). The reason that PDPK FA expression can be associated with these potential prognostic factors may be due to its multisubstrate/multifunctional signal-transducing PDPK nature.31 The correlations of PDPK FA expression with tumor multiplicity and microsatellite nodules in HCC are intriguing. A more comprehensive analysis on the survival data further revealed that among the patients with presence of microsatellite nodules or tumor multiplicity, the majority of the patients also exhibited positive PDPK FA and had an unfavorable outcome (Figs 3 and 4). In sharp contrast, a large population of the patients with absence of microsatellite nodules or tumor multiplicity but with positive PDPK FA still failed to have a favorable outcome (Figs 3 and 4). The results further indicate that combination of PDPK FA expression with the current clinicopathologic prognosticators may accurately predict prognosis of the HCC patients after hepatic resection. The rapid invasion of HCC into the portal venous system has been considered to be one of the important factors adversely affecting survival.1-10,48-50 Consistent with other studies, the present study also showed that venous invasion was an independent and powerful prognosticator for disease-free survival and overall survival in the Cox multivariate regression analysis (Table 3). However, the HR for overall survival was much higher for PDPK FA than for venous invasion (Table 3). Moreover, it is interesting to note that the group of patients with presence of venous invasion nearly matched those whose tumors exhibited positive PDPK FA (Fig 5). More importantly, the HCC patients with absence of venous invasion if associated with positive PDPK FA failed to have a favorable outcome. All the results put together establish PDPK FA as a more sensitive and powerful prognosticator to predict relapse and poor outcome of the patients with HCC. Consistent with its multisubstrate/multifunctional signal-transducing PDPK nature essential for the development of highly malignant phenotypes,31 the prognostic uncertainties of the HCC patients with absence of tumor multiplicity, microsatillite nodules and venous invasion may possibly be resolved by combination of the PDPK FA expression (Figs 3, 4, and 5). As presented in this study, PDPK FA may therefore play an instructional and determinant role to work synergistically with the current clinicopathologic factors to accurately predict progression and patient survival of HCC to help physicians make the clinical decisions after hepatic resection. This study is limited by its retrospective nature and the inclusion only of patients with resectable tumors. It is possible, for example, that the findings pertain to only those who undergo resection. Larger population prospective studies of PDPK FA are needed to further validate the usefulness of this system. Despite this limitation, our study is robust in its results. Taken together with the previous molecular, cellular, and animal studies that showed that suppression of overexpressed PDPK FA is able to inhibit the invasive and metastatic potential of cancer cells,31 this study further establishes PDPK FA as a new, modifiable signal-transducing target for prognostic prediction, prevention, and treatment of invasive progression of HCC. The suppression of overexpressed PDPK FA may possibly prevent invasive progression and metastatic relapse to improve prognosis and quality of life for HCC patients after hepatic resection. The PDPK FA system therefore opens a new way to explore more efficacious treatments for particularly aggressive HCC.
The authors indicated no potential conflicts of interest.
published online ahead of print at www.jco.org on July 5, 2006. Supported by Grant No. NSC 93-2314-B-007-001 from the National Science Council of Taiwan. Y.C.H. and H.H.F. contributed equally to this work. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.
1. Thomas MB, Zhu AX: Hepatocellular carcinoma: The need for progress. J Clin Oncol 23:2892-2899, 2005 2. Llovet JM: Updated treatment approach to hepatocellular carcinoma. J Gastroenterol 40:225-235, 2005[CrossRef][Medline] 3. Bruix J, Boix L, Sala M, et al: Focus on hepatocellular carcinoma. Cancer Cell 5:215-219, 2004[CrossRef][Medline] 4. Cusnir M, Patt YZ: Novel systemic therapy options for hepatocellular carcinoma. Cancer J 10:97-103, 2004[Medline] 5. Ganne-Carrie N, Trinchet JC: Systemic treatment of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 16:275-281, 2004[CrossRef][Medline] 6. Van Deusen MA, Abdalla EK, Vauthey JN, et al: Staging classifications for hepatocellular carcinoma. Expert Rev Mol Diagn 5:377-383, 2005[CrossRef][Medline] 7. Suriawinata A, Xu R: An update on the molecular genetics of hepatocellular carcinoma. Semin Liver Dis 24:77-88, 2004[Medline] 8. Qin LX, Tang ZY: Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: A review of the literature. J Cancer Res Clin Oncol 130:497-513, 2004[Medline] 9. Chen PJ, Chen DS: Hepatitis B virus infection and hepatocellular carcinoma: Molecular genetics and clinical perspectives. Semin Liver Dis 19:253-262, 1999[Medline] 10. Bergsland EK: Molecular mechanisms underlying the development of hepatocellular carcinoma. Semin Oncol 28:521-531, 2001[CrossRef][Medline] 11. Yang SD, Vandenheede JR, Goris J, et al: ATP · Mg-dependent protein phosphatase from rabbit skeletal muscle: I, Purification of the enzyme and its regulation by the interaction with an activating protein factor J Biol Chem 255:11759-11767, 1980 12. Vandenheede JR, Yang SD, Goris J, et al: ATP · Mg-dependent protein phosphatase from rabbit skeletal muscle: II, Purification of the activating factor and its characterization as a bifunctional protein also displaying synthase kinase activity J Biol Chem 255:11768-11774, 1980 13. Yang SD: Identification of the ATP · Mg-dependent protein phosphatase activator (FA) as a myelin basic protein kinase in the brain. J Biol Chem 261:11786-11791, 1986 14. Yang SD, Song JS, Yu JS, et al: Protein kinase FA phosphorylates tau on Ser235-Pro and Ser404-Pro that are abnormally phosphorylated in Alzheimer’s disease brain. J Neurochem 61:1742-1747, 1993[Medline] 15. Yang SD, Yu JS, Shiah SG, et al: Protein kinase FA after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer’s disease brain. J Neurochem 63:1416-1425, 1994[Medline] 16. Yu JS, Yang SD: Protein kinase FA predominantly phosphorylates the in vivo site Thr97-Pro in brain myelin basic protein: Evidence for Thr-Pro and Ser-Arg-X-X-Ser as consensus sequence motifs. J Neurochem 62:1596-1603, 1994[Medline] 17. Yang SD, Huang JJ, Huang TJ: Protein kinase FA predominantly phosphorylates the in vivo sites of Ser502, Ser506, Ser603, and Ser666 in neurofilament. J Neurochem 64:1848-1854, 1995[Medline] 18. Yang SD: Characteristics and regulation of the ATP · Mg-dependent protein phosphatase activating factor (protein kinase FA). Adv Prot Phosphatase 6:133-157, 1991 19. Yang SD: Signal transduction and biological functions of protein phosphatase activating factor (protein kinase FA). J Chin Biochem Soc 23:123-134, 1994 20. Hsu CP, Hsueh SF, Yang CC, et al: Suppression of proline-directed protein kinase FA expression inhibits the growth of human chronic myeloid leukaemia cells. Br J Cancer 82:1480-1484, 2000[Medline] 21. Hsu CP, Yang CC, Yang SD: Suppression of proline-directed protein kinase FA expression potentiates erythroid differentiation of human myeloid leukemia cells. Cancer 89:1004-1011, 2000[CrossRef][Medline] 22. Lee TT, Ho YS, Yu JS, et al: Overexpression of cellular activity and protein level of protein kinase FA correlates with human thyroid tumor cell dedifferentiation. J Cell Biochem 58:474-480, 1995[CrossRef][Medline] 23. Yang SD, Yu JS, Lee TT, et al: Association of protein kinase FA (a proline-directed kinase and a regulator of protooncogenes) with human cervical carcinoma dedifferentiation/progression. J Cell Biochem 59:143-150, 1995[CrossRef][Medline] 24. Yang SD, Yu JS, Yang CC, et al: Overexpression of protein kinase FA (a proline-directed protein kinase) correlates with human hepatoma dedifferentiation/progression. J Cell Biochem 61:238-245, 1996[CrossRef][Medline] 25. Yang CC, Hsu CP, Yang SD: Antisense suppression of proline-directed protein kinase FA enhances chemosensitivity in human prostate cancer cells. Clin Cancer Res 6:1024-1030, 2000 26. Hsu CP, Yang CC, Hsueh SF, et al: Suppression of proline-directed protein kinase FA potentiates apoptotic induction and greatly enhances chemosensitivity in human acute lymphoblastic leukemia cells. Cancer 92:1753-1758, 2001[CrossRef][Medline] 27. Hsu CP, Yang CC, Yang SD: Suppression of proline-directed protein kinase FA systemically inhibits the growth of human acute leukemia cells. Int J Cancer 91:650-653, 2001[CrossRef][Medline] 28. Chung YC, Chang KJ, Yang CC, et al: Association of proline-directed protein kinase FA with tumorigenesis, invasion, and poor prognosis of human colon carcinoma. Cancer 95:1840-1847, 2002[CrossRef][Medline] 29. Hsueh SF, Lai MT, Yang CC, et al: Association of overexpressed proline-directed protein kinase FA with chemoresistance, invasion, and recurrence in patients with bladder carcinoma. Cancer 95:775-783, 2002[CrossRef][Medline] 30. Fu HH, Yang SD: Suppression of proline-directed protein kinase FA inhibits the malignant growth of human pancreatic ductal adenocarcinoma. Anticancer Res 24:1489-1494, 2004[Medline] 31. Yang SD: Proline-directed protein kinase FA as a potential target for diagnosis and therapy of human cancers. Curr Cancer Drug Targets 4:591-596, 2004[CrossRef][Medline] 32. Edmonson HA, Steiner PE: Primary carcinoma of the liver: A study of 100 among 489,000 necropsies. Cancer (Phila) 7:462-503, 1954[CrossRef] 33. Hsu HC, Jeng YM, Mao TL, et al: Beta-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol 157:763-770, 2000 34. Liu SH, Lin CY, Peng SY, et al: Down-regulation of annexin A10 in hepatocellular carcinoma is associated with vascular invasion, early recurrence, and poor prognosis in synergy with p53 mutation. Am J Pathol 160:1831-1837, 2002 35. Jeng YM, Peng SY, Lin CY, et al: Overexpression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 10:2065-2071, 2004 36. Reichlin M: Use of glutaraldehyde as a coupling agent for proteins and peptides. Methods Enzymol 70:159-165, 1980[Medline] 37. The Liver Cancer Study Group of Japan: Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma in Japan. Cancer 74:2772-2780, 1994[CrossRef][Medline] 38. Fong Y, Sun RL, Jarnagin W, et al: An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 229:790-800, 1999[CrossRef][Medline] 39. Jaeck D, Bachellier P, Oussoultzoglou E, et al: Surgical resection of hepatocellular carcinoma. Post-operative outcome and long-term results in Europe: An overview. Liver Transpl 10:S58-S63, 2004[CrossRef][Medline] 40. Poon RT, Fan ST: Hepatectomy for hepatocellular carcinoma: Patient selection and postoperative outcome. Liver Transpl 10:S39-S45, 2004[Medline] 41. Schoniger-Hekele M, Hanel S, Wrba F, et al: Hepatocellular carcinoma–survival and clinical characteristics in relation to various histologic molecular markers in Western patients. Liver Int 25:62-69, 2005[CrossRef][Medline] 42. Yamamoto S, Tomita Y, Nakamori S, et al: Elevated expression of valosin-containing protein (p97) in hepatocellular carcinoma is correlated with increased incidence of tumor recurrence. J Clin Oncol 21:447-452, 2003 43. Chen WT, Chau GY, Lui WY, et al: Recurrent hepatocellular carcinoma after hepatic resection: Prognostic factors and long-term outcome. Eur J Surg Oncol 30:414-420, 2004[CrossRef][Medline] 44. Lin SM, Lin CJ, Hsu CW, et al: Prospective randomized controlled study of interferon-alpha in preventing hepatocellular carcinoma recurrence after medical ablation therapy for primary tumors. Cancer 100:376-382, 2004[CrossRef][Medline] 45. Hu TH, Huang CC, Liu LF, et al: Expression of hepatoma-derived growth factor in hepatocellular carcinoma. Cancer 98:1444-1456, 2003[CrossRef][Medline] 46. Lee WC, Jeng LB, Chen MF: Estimation of prognosis after hepatectomy for hepatocellular carcinoma. Br J Surg 89:311-316, 2002[CrossRef][Medline] 47. King KL, Li AF, Chau GY, et al: Prognostic significance of heat shock protein-27 expression in hepatocellular carcinoma and its relation to histologic grading and survival. Cancer 88:2464-2470, 2000[CrossRef][Medline] 48. Varela M, Sala M, Llovet JM, et al: Treatment of hepatocellular carcinoma: Is there an optimal strategy? Cancer Treat Rev 29:99-104, 2003[CrossRef][Medline] 49. Qin LX, Tang ZY: The prognostic significance of clinical and pathological features in hepatocellular carcinoma. World J Gastroenterol 8:193-199, 2002[Medline] 50. Poon RT, Fan ST, Wong J: Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 232:10-24, 2000[CrossRef][Medline] Submitted August 23, 2005; accepted March 14, 2006.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test for categoric variables. Overall survival was calculated from the date of diagnosis to the date of death or last follow-up. Disease-free survival was measured from the date of diagnosis to the date of recurrence, metastasis, death or last follow-up. The Kaplan-Meier method was used to determine the survival probability, and the log-rank test was used to compare the survival curves between groups. Independent prognostic factors were analyzed by the Cox multivariate proportional hazards regression model with stepwise manner. P < .05 was considered statistically significant. 
