Efficacy of a sepsis clinical decision support system in identifying patients with sepsis in the emergency department.

BACKGROUND: Early prediction of sepsis onset is crucial for reducing mortality and the overall cost burden of sepsis treatment. Currently, few effective and accurate prediction tools are available for sepsis. Hence, in this study, we developed an effective sepsis clinical decision support system (S-CDSS) to assist emergency physicians to predict sepsis. METHODS: This study included patients who had visited the emergency department (ED) of Taipei Tzu Chi Hospital, Taiwan, between January 1, 2020, and June 31, 2022. The patients were divided into a derivation cohort (n = 70,758) and a validation cohort (n = 27,545). The derivation cohort was subjected to sixfold stratified cross-validation, reserving 20% of the data (n = 11,793) for model testing. The primary study outcome was a sepsis prediction (International Classification of Diseases, Tenth Revision, Clinical Modification) before discharge from the ED. The S-CDSS incorporated the LightGBM algorithm to ensure timely and accurate prediction of sepsis. The validation cohort was subjected to multivariate logistic regression to identify the associations of S-CDSS-based high- and medium-risk alerts with clinical outcomes in the overall patient cohort. For each clinical outcome in high- and medium-risk patients, we calculated the sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and accuracy of S-CDSS-based predictions. RESULTS: The S-CDSS was integrated into our hospital information system. The system featured three risk warning labels (red, yellow, and white, indicating high, medium, and low risks, respectively) to alert emergency physicians. The sensitivity and specificity of the S-CDSS in the derivation cohort were 86.9% and 92.5%, respectively. In the validation cohort, high- and medium-risk alerts were significantly associated with all clinical outcomes, exhibiting high prediction specificity for intubation, general ward admission, intensive care unit admission, ED mortality, and in-hospital mortality (93.29%, 97.32%, 94.03%, 93.04%, and 93.97%, respectively). CONCLUSION: Our findings suggest that the S-CDSS can effectively identify patients with suspected sepsis in the ED. Furthermore, S-CDSS-based predictions appear to be strongly associated with clinical outcomes in patients with sepsis.

The theoretical systems of OFDI location determinants in global north and global south economies.

With economic transformation and industrial development, Outward Foreign Direct Investment (OFDI) from southern countries has increased rapidly. The theoretical system established by global north countries with their dominant position in the international investment market has been impacted by global south countries. The existing OFDI theory has always been based on developed countries and can only explain some international investment behavior of southern countries. The Vector Error Correction Model (VECM) is applied to conduct empirical analysis for the impact of the target country's investment climate on the location determinants of OFDI, by applying China and the United States as example which is focusing on 172 countries from 2005 to 2019. The results reveal significant differences in the theoretical system of foreign investment between China and the United States. For China, investment climate factors such as energy, logistics infrastructure, and politics are discover as the main drivers of China's OFDI. However, USA's OFDI is a corporate behavior aimed at economic interests. The differences in OFDI theoretical systems and provides policy advice for northern and southern countries and departments is the major contribution of this research.

Tumor size is a major determinant of prognosis of resected stage I hepatocellular carcinoma.

PURPOSE: The current American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC) includes all solitary tumors without vascular invasion as stage I, regardless of tumor size. The aim of this study is to determine the prognostic significance of tumor size in stage I HCC patients. METHODS: A total of 230 stage I primary HCCs were selected retrospectively. Based on univariate and multivariate analyses, clinical and pathological factors correlated with 5-year disease-free survival (DFS) and 5-year overall survival (OS) were determined. RESULTS: Univariate and multivariate analyses showed significant correlations of low serum α-fetoprotein levels (≤20 ng/ml), small tumor size (≤3 cm), wide resection margin (≥ 1 cm), and absence of cirrhotic liver with better DFS, while smaller tumor size, and wide resection margin with better OS. Of all the parameters, tumor size is the most statistically significant markers for DFS and OS. Interestingly, liver cirrhosis exerted prognostic significance in patients with small-size tumors, while resection margin exerted prognostic significance in patients with large-size tumors. CONCLUSIONS: Our results indicated that tumor size is the most important determinant of DFS and OS in resected primary stage I HCC patients. Therefore, we advocate redefining solitary tumors of ≤3 cm as T1a disease and tumors >3 cm as T1b disease. This stratification of stage I HCC patients could aid in the determination of prognosis and the development of superior protocols for patient management. However, further analysis of big registry cohorts is needed to establish a common consensus.

Expression of hypoxic marker carbonic anhydrase IX predicts poor prognosis in resectable hepatocellular carcinoma.

Carbonic anhydrase IX (CA-IX), a hypoxia marker, correlates with tumor progression in a variety of human cancers. However, the role of CA-IX in hepatocellular carcinomas (HCCs) remains largely unknown. We examined the expression of 277 unifocal, resectable, primary HCC tumors using immunohistochemistry. The CA-IX protein was expressed in 110 of the 227 (48.5%) HCC tumors. The expression of CA-IX correlated with younger age (P = 0.0446), female sex (P = 0.0049), high serum α-fetoprotein levels (P<1x10-6), larger tumor size (P = 0.0031), high tumor grade P<1x10-6) and high tumor stage (P = 1.5x10-6). Patients with HCC tumors that expressed CA-IX were more likely to have lower 5-year disease-free survival (DFS; P = 0.0001) and 5-year overall survival (OS; P<1x10-6). The multivariate analysis indicated that CA-IX expression was an independent predictor for high tumor stage (P = 0.0047) and DFS (P = 0.0456), and a borderline predictor for OS (P = 0.0762). Furthermore, CA-IX expression predicted poor DFS and OS in patients with high tumor stage (P = 0.0004 and P<1x10-6, respectively). Interestingly, CA-IX expression might contribute to the worse prognosis of female patients with advanced HCCs. Our study indicates the expression of the CA-IX protein is a crucial predictor of poor prognosis in resectable HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage.

Expression of bile duct transcription factor HNF1ß predicts early tumor recurrence and is a stage-independent prognostic factor in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) frequently exhibits biliary differentiation, which is typically overlooked. Hepatocyte nuclear factor 1ß (HNF1ß), a bile duct-specific transcription factor expressed in bile ducts but not in the normal hepatocytes, is also expressed in HCC. MATERIALS AND METHODS: The expression of HNF1ß and the biliary differentiation marker cytokeratin 19 (CK19) were retrospectively evaluated using immunohistochemistry in 159 surgically resected primary HCCs. RESULTS: A significant correlation was observed between HNF1ß protein expression and younger age (p = 0.0293), high serum α-fetoprotein levels (p = 6 × 10(-4)), and high tumor grade (p = 0.0255). However, HNF1ß expression exhibited no correlation with tumor stage. Patients with HCCs and HNF1ß expression were more likely to exhibit early tumor recurrence (ETR; p = 0.0048) and a lower 5-year survival rate (p = 0.0001). A multivariate analysis indicated HNF1ß expression as an independent prognostic factor in HCC (p = 0.0048). A combinatorial analysis revealed additive adverse effects of HNF1ß when concomitant with CK19 expression and p53 mutation. Furthermore, HNF1ß expression can predict poor prognosis in patients with ETR. CONCLUSION: Our results indicated that HNF1ß expression is a crucial predictor of poor prognosis in HCC and is independent of tumor stage. Moreover, concomitant HNF1ß and CK19 expressions exhibited additive adverse effects in HCC, confirming that HCC with biliary differentiation has a poor prognosis.

TERT promoter mutation in resectable hepatocellular carcinomas: a strong association with hepatitis C infection and absence of hepatitis B infection.

INTRODUCTION: Mutation in the core promoter of the telomerase reverse transcriptase (TERT) gene was determined to be a frequent event in malignant melanoma and other cancers. However, the role of TERT promoter mutation in hepatocellular carcinomas (HCCs) remains largely unknown. METHODS: Genomic DNA samples from the tumor tissue of 195 HCCs were analyzed for TERT promoter mutation at 2 hotspots (-124 and -146 bp from the ATG start site, g.1,295,228 and g.1,295,250, respectively) through direct sequencing. RESULTS: The TERT promoter mutation was identified in 57 of the 195 HCCs (29.2%) and was associated with old age (P = 0.0122), presence of anti-hepatitis C (HCV; P = 0.0048), and absence of hepatitis B surface antigen (HBsAg; P = 0.0007). However, the TERT promoter mutation did not correlate with serum α-fetoprotein levels, liver cirrhosis, tumor size, tumor grade, tumor stage, early tumor recurrence, ß-catenin mutation or p53 mutation. A multivariate analysis confirmed that the absence of hepatitis B infection is an independent factor associated with TERT promoter mutation. Furthermore, among HCC patients infected with hepatitis C, those with concomitant hepatitis B infection exhibited infrequent TERT promoter mutation (P = 0.0435). Remarkably, patients presenting with TERT promoter mutation-positive and -negative HCCs exhibited similar disease-free and overall survival rates. CONCLUSIONS: Our study indicated that the TERT promoter mutation frequently occurred in HCV-associated HCCs. The absence of Hepatitis B infection was significantly associated with the TERT promoter mutation. These findings suggest that various etiological factors may be involved in differing mechanisms to preserve telomeres during the carcinogenesis of HCCs.

S100P expression is a novel prognostic factor in hepatocellular carcinoma and predicts survival in patients with high tumor stage or early recurrent tumors.

The calcium-binding protein S100P is expressed in a variety of human cancer cells and is important in cancer cell growth and invasion. Using differential display, we found S100P is overexpressed in human hepatocellular carcinoma (HCC). We examined the expression of 305 unifocal, primary HCC tumors using immunohistochemistry. The S100P protein was expressed in 173 of the 305 (56.7%) HCC tumors. The expression of S100P correlated with female sex (P = 0.0162), high serum α-fetoprotein level (P = 0.0001), high tumor grade (P = 0.0029), high tumor stage (P = 0.0319), the presence of the p53 mutation (P = 0.0032), and the absence of the ß-catenin mutation (P = 0.0489). Patients with HCC tumors that expressed S100P were more likely to have early tumor recurrence (ETR) (P = 0.0189) and lower 5-year survival (P = 0.0023). The multivariate analysis confirmed that S100P expression was an independent prognostic factor in HCC. The combinatorial analysis showed an additive unfavorable prognostic interaction between S100P expression and the p53 mutation. In contrast, the ß-catenin mutation was associated with better prognosis in both S100P-positive and -negative HCCs. Furthermore, S100P expression was a predictor of survival in HCC patients with high tumor stage or ETR (P = 0.0026 and P = 0.0002, respectively). Our study indicates the expression of the S100P protein is a novel independent predictor for poor prognosis in HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage or ETR.

Expression of insulin-like growth factor II mRNA-binding protein 3 predicts early recurrence and poor prognosis in intrahepatic cholangiocarcinoma.

INTRODUCTION: Insulin-like growth factor-II mRNA-binding protein 3 (IMP3), a newly identified oncofetal RNA-binding protein, plays a pivotal role in the regulation of cell growth and migration during early stages of embryogenesis, and is found to be expressed in various human cancers. In this study, we elucidated the clinicopathological significance of IMP3 expression in intrahepatic cholangiocarcinoma (ICC). METHODS: From March 1995 to December 2003, 61 surgically resected, unifocal primary ICCs were studied. IMP3 protein expression was detected by immunohistochemical staining. RESULTS: IMP3 protein was expressed in 25 of 61 ICCs (41.0%). In addition to correlating with tumor grade (p = 0.0276), tumor stage (p = 0.0059), lymphovascular invasion (p = 0.0198), serum carbohydrate antigen 19-9 level (p = 0.0146), IMP3 expression predicted early tumor recurrence (ETR) (p = 0.0059) and was a strong indicator of worse disease-free survival (p = 0.0001) and overall survival (p = 0.0007). Even though we did not find that IMP3 expression exerted prognostic impact independent of tumor stage, multivariate analysis confirmed that IMP3 expression was an independent risk factor of high-stage tumor and ETR (p = 0.0170, and p = 0.0052, respectively), and thus it contributed to poor prognosis in ICC patients. CONCLUSIONS: IMP3 expression can serve as a novel maker for ETR and prognostic prediction, and may be a target for adjuvant therapy of patients with ICC after tumor resection.

Expression and prognostic significance of gastric-specific annexin A10 in diffuse- and intestinal-type gastric carcinoma.

BACKGROUND AND AIMS: Annexin A10 (ANXA10) and its liver-specific short isoform (ANXA10S) had tissue-restricted expression. The downregulation of ANXA10S is correlated with tumor progression and poor prognosis in hepatocellular carcinoma. The aim of the present study was to validate the tissue distribution and explore the role of the ANXA10 protein expression in gastric carcinoma. METHODS: We examined the ANXA10 protein expression in human and animal tissues and 356 resected primary gastric carcinomas, using specific mouse and rabbit polyclonal antibodies, by immunohistochemical staining. RESULTS: The ANXA10 protein is a nuclear protein specifically expressed in fetal and adult gastric mucosa and Brunner's gland across species, including humans, minipigs, woodchucks, and mice, and is commonly lost in gastric mucosa with intestinal metaplasia. The ANXA10 protein was expressed in 43.5% (155 cases) of gastric carcinomas; 74.2% (98/132) in the diffuse-type gastric carcinoma (DGC), 73.7% (28/38) in the mixed-type gastric carcinoma, and significantly lower in the intestinal-type gastric carcinoma (IGC) and indeterminate groups, 16.8% (28/167) and 5.3% (1/19), respectively (P<1×10(-8)). IGC with ANXA10 expression was correlated with a higher stage (P=0.049), particularly higher in stage IIIA/IIIB/IV IGC than lower-stage (IA/IB/II) tumors (P=0.005), but was not correlated with age, sex, and nodal status. In contrast, DGC with ANXA10 expression was associated with younger age, female patients, and importantly, lower tumor stage and lymph node metastasis (P=0.007, P=0.065, P=0.024, and P=0.0014, respectively). Moreover, DGC with ANXA10 expression had a better 5-year patient survival (P=0.0048), whereas IGC with ANXA10 expression had a lower 5-year survival (P=0.034). CONCLUSIONS: The ANXA10 protein expression is a novel marker of gastric differentiation, and is differentially expressed in IGC and DGC, with opposite prognostic significance.

Role of p53 and ß-catenin mutations in conjunction with CK19 expression on early tumor recurrence and prognosis of hepatocellular carcinoma.

BACKGROUND: Cytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and ß-catenin mutations, remained largely unknown. MATERIALS AND METHODS: From January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and ß-catenin genes were detected by direct DNA sequencing. RESULTS: CK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and ß-catenin mutation in 14.5% (27/186). The tumor size (p=0.0023), grade (p = 0.00093), tumor stage (p = 4 x 10-7), high α-fetoprotein (p=0.0004), p53 mutation (p = 0.024), absence of ß-catenin mutation (p = 0.0013), and CK19 expression (p = 3 x 10-5) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p < 0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and ß-catenin mutation was rare and CK19 expression abolished the suppression effect of ß-catenin mutation on HCC progression. CONCLUSIONS: CK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and ß-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.

Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC.

BACKGROUND: To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC). METHODS: The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and ß-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of ß-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines. RESULTS: Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with ß-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and ß-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis. CONCLUSION: Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment.

ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma.

PURPOSE: Abnormal spindle-like microcephaly associated (ASPM) plays an important role in neurogenesis and cell proliferation. This study is to elucidate its role in hepatocellular carcinoma (HCC), particularly early tumor recurrence (ETR) and prognosis. EXPERIMENTAL DESIGN: We used reverse transcription-PCR assays to measure the ASPM mRNA levels in 247 HCC and correlated with clinicopathologic and molecular features. RESULTS: ASPM mRNA levels were high in fetal tissues but very low in most adult tissues. ASPM mRNA was overexpressed in 162 HCC (66%) but not in benign liver tumors. ASPM overexpression correlated with high alpha-fetoprotein (P = 1 x 10(-8)), high-grade (grade II-IV) HCC (P = 2 x 10(-6)), high-stage (stage IIIA-IV) HCC (P = 1 x 10(-8)), and importantly ETR (P = 1 x 10(-8)). ETR is the most critical unfavorable clinical prognostic factor. Among the various independent histopathologic (tumor size, tumor grade and tumor stage) and molecular factors (p53 mutation, high alpha-fetoprotein, and ASPM overexpression), tumor stage was the most crucial histologic factor (odds ratio, 14.7; 95% confidence interval, 6.65-33.0; P = 1 x 10(-8)), whereas ASPM overexpression (odds ratio, 6.49; P = 1 x 10(-8)) is the most important molecular factor associated with ETR. ASPM overexpression was associated with vascular invasion and ETR in both p53-mutated (all P values = 1 x 10(-8)) and non-p53-mutated HCC (P = 1 x 10(-8) and 0.00088, respectively). Hence, patients with APSM-overexpressing HCC had lower 5-year survival (P = 0.000001) in both p53-mutated (P = 0.00008) and non-p53-mutated HCC (P = 0.0027). In low-stage (stage II) HCC, ASPM overexpression also correlated with higher ETR (P = 0.008). CONCLUSION: ASPM overexpression is a molecular marker predicting enhanced invasive/metastatic potential of HCC, higher risk of ETR regardless of p53 mutation status and tumor stage, and hence poor prognosis.

Aberrant expression of the glycolytic enzymes aldolase B and type II hexokinase in hepatocellular carcinoma are predictive markers for advanced stage, early recurrence and poor prognosis.

Cancer cells with a high glycolytic rate have an advantage in tumor growth. Hepatocellular carcinoma (HCC) often exhibits an aberrant expression of glycolytic enzymes, particularly type II hexokinase (HKII) and aldolase B (ALDOB). This study examined the aberrant expression of HKII and ALDOB in 203 surgically resected HCCs. A dramatic down-regulation of ALDOB was found in 116 HCCs (57%), while 43% of HCCs maintained the expression. HKII mRNA was overexpressed in 70 (35%) primary HCCs. The ALDOB down-regulation and HKII overexpression correlated with high-grade (grade II-IV) HCC (all ps<0.0001), portal vein invasion (stage IIIB-IV) (ps<1x10(-6)), early tumor recurrence (ETR) (p<0.001 and p<0.01, respectively) and a lower 5-year survival (p=0.000001 and p=0.0062, respectively). Notably, in stage II HCC which had no vascular invasion, the ALDOB down-regulation was associated with ETR (p<0.05) and a lower 5-year survival (p=0.015). The down-regulation of ALDOB correlated with a high AFP (p=1x10(-8)), whereas the overexpression of HKII, which has two functional motifs for the mutant p53, correlated with the p53 mutation, p<0.01. The three factors (ALDOB down-regulation, HKII overexpression and p53 mutation) not only correlated with tumor progression, but also interacted with one another, leading to a more aggressive HCC with a portal vein invasion and various extent of intrahepatic metastasis by more than four-fold (ps<1x10(-6)) and frequent ETR by more than two-fold (ps<0.0001) compared with HCCs without the events. In conclusion, the aberrant expression of ALDOB and HKII is associated with advanced disease, ETR and poor prognosis, and ALDOB down-regulation in stage II HCC is a predictive marker of ETR and an unfavorable outcome.

Overexpression of KIAA0101 predicts high stage, early tumor recurrence, and poor prognosis of hepatocellular carcinoma.

PURPOSE: KIAA0101 is a proliferating cell nuclear antigen-associated factor and involved in cell proliferation. This study is to elucidate its role in the progression, early tumor recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: KIAA0101 mRNA was measured by reverse transcription-PCR in 216 resected, unifocal, primary HCCs and its protein in 164 cases by immunohistochemistry. RESULTS: KIAA0101 mRNA was overexpressed in 131 (61%) HCCs, and protein was detected in 105 (64%). KIAA0101 mRNA overexpression correlated with higher tumor grade (P = 0.0001), higher tumor stage with vascular invasion and various extents of intrahepatic spread (P = 1 x 10(-8)), ETR (P = 1.8 x 10(-6)), and lower 5-year survival (P = 0.0026). Multivariate analysis confirmed that KIAA0101 overexpression was an independent risk factor associated with high-grade tumor (P = 0.0001), high-stage tumor (P < 0.0001), and ETR (P = 0.0052) and thus contributed to poor prognosis. KIAA0101 protein-positive tumor cells accumulated at the borders of tumor macro-trabeculae and were more abundant in tumor thrombi than in the main tumors. Hence, KIAA0101 may contribute to growth advantage and resistance to hypoxic insult. In this series, p53 mutation was detected in 93 of 184 (51%) HCCs. In both p53-mutated and non-p53-mutated HCCs, KIAA0101 overexpression correlated with higher vascular invasion (stages IIIA to IV; all Ps < 0.0001) and, accordingly, led to lower 5-year survival rates (P = 0.011 and 0.029, respectively). CONCLUSION: KIAA0101 correlates with enhanced metastatic potential and is a significant prognostic factor of HCC.

Cytoplasmic CD24 expression is a novel prognostic factor in diffuse-type gastric adenocarcinoma.

BACKGROUND: CD24, a mucin like cell surface adhesion molecule and a ligand for P-selectin, has been reported as a prognostic factor in a variety of human cancers. However, the role of CD24 in gastric adenocarcinoma remains largely unknown. METHODS: The expression pattern of CD24 in 103 gastric adenocarcinomas (31 diffuse type, 60 intestinal type, and 12 mixed type) was analyzed by immunohistochemistry. RESULTS: Cytoplasmic CD24 expression occurred in 50% of the gastric adenocarcinoma patients and was associated with high-stage tumor (Stage III-IV, P = .023), serosal invasion (SI, P = .010), lymphovascular invasion (LVI, P = .039), and lower 10-year survival (P = .0238). The CD24 staining pattern was different in intestinal and diffuse-type gastric adenocarcinomas. However, the tumor thrombi in lymphovascular spaces exhibited strong cytoplasmic CD24 expression in both types. Further analysis showed that cytoplasmic CD24 expression was, in fact, correlated with high-stage tumor, SI, LVI, and lower 10-year survival significantly (P = .020, P = .007, P = .018, P = .0285, respectively) in diffuse-type gastric adenocarcinoma. Moreover, multivariate analysis showed that cytoplasmic CD24 expression was an independent risk factor of SI and LVI respectively (P = .0083 and P = .0019), and thus it contributed to high-stage tumor and poor patient survival in diffuse- or mixed-type gastric adenocarcinoma. CONCLUSIONS: Cytoplasmic expression of CD24 was associated with invasiveness and poorer prognosis and can serve as a novel target for prognostic prediction and adjuvant treatment of patients with diffuse-type gastric adenocarcinoma after tumor resection.

Aberrant expressions of annexin A10 short isoform, osteopontin and alpha-fetoprotein at chromosome 4q cooperatively contribute to progression and poor prognosis of hepatocellular carcinoma.

Chromosome 4q exhibits high frequency of allelic loss in hepatocellular carcinoma (HCC). This study aimed to elucidate the interaction of the frequent aberrant mRNA expression of alpha-fetoprotein (AFP), osteopontin (OPN) and a novel short isoform of annexin A10 (ANXA10S) at 4q in the tumor progression among 294 patients who received surgical resection of unifocal primary HCC. AFP overexpression, OPN overexpression and ANXA10S down-regulation correlated with high-grade and high-stage tumors, early tumor recurrence (all P<0.0001), and lower 10-year survival (all P=0.000001). The AFP overexpression correlated with OPN overexpression (P=0.0026) and ANXA10S down-regulation (P=0.00001), while OPN overexpression correlated with ANXA10S down-regulation (P=0.00001). Pair-wise combinations revealed interactive effects between these genetic variants for tumor grade, tumor stage and early recurrence (all P<0.0001). HCCs with more genetic aberrations had more frequent high tumor grade, portal vein invasion (stage IIIB-IV) and early recurrence (all P<0.0001). The 10-year survival rate for HCCs with all three genetic alterations was the lowest (7%), followed by those with two (22%) or one event (29%), and the highest for those without these changes (43%), P=0.000001. The prognostic stratification using these molecular factors was similar to that of histopathological staging. These three genetic alterations also helped to identify different subgroups of patients of stage II HCC but with different prognosis (P=0.015). In conclusion, the aberrant expressions of AFP, OPN and ANXA10S cooperatively contribute to tumor progression and poor prognosis, and are useful for molecular staging of HCC and the subclassification of stage II HCC without vascular invasion.

High alpha-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations.

alpha-Fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC). This study was to elucidate the significance and related factors of AFP elevation in HCC in 781 unifocal HCCs receiving curative hepatectomy. We showed that high AFP (> 200 ng/ml), which was associated with AFP mRNA expression in HCC (p = 0.00001), correlated with major clinicopathologic factors. Younger age (< or = 55 years; p=0.00001), hepatitis B surface antigen (HBsAg) in serum (p=0.00001), p53 mutation (p=0.008), large tumor (p=0.00001), vascular invasion (p=0.00001) and early tumor recurrence (p=0.00001) were significant associates of high AFP, while anti-HCV in serum and beta-catenin mutation in HCC had less frequent high AFP (p=0.013 and < 0.0001, respectively). We also showed that HCC with high AFP had a lower 10-year survival (p < 0.0001), particularly in large HCC (p < 0.0001). At univariate analysis, high AFP (p < 0.0001), HBsAg positivity (p=0.05), p53 mutation (p=0.0004), liver cirrhosis (p=0.0094), large tumor (p=0.0003), vascular invasion (p < 0.0001) and early recurrence (p < 0.0001) were significant unfavorable prognostic factors. In Cox proportional hazards regression analysis, high AFP remained a borderline significance (OR=1.2; CI=1.0-1.4) after adjustment for the effect of tumor size and tumor stage (p=0.0821). Furthermore, the detection of AFP mRNA in the liver of AFP mRNA-positive HCC was associated with more frequent early recurrence (p=0.0026) and might be a useful marker of intrahepatic spread. We therefore conclude that AFP elevation, more than a coincidental epiphenomenon, appears to contribute to vascular invasion and HCC progression and help to identify subsets of HCC patients with increased risk for early recurrence and poor prognosis after hepatectomy.

Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma.

BACKGROUND: Intrahepatic metastasis via portal vein spread is an important feature and a crucial unfavorable prognostic factor of hepatocellular carcinoma (HCC). To identify the molecular factors for tumor progression, the authors used differential display (DD) to analyze aberrant gene expression in HCC. The goal of the current study was to elucidate the clinicopathologic and prognostic significance of osteopontin (OPN) in HCC progression. METHODS: OPN mRNA levels, which were increased preferentially in HCC in a DD assay and verified with Northern blotting, were measured in 240 surgically removed, unifocal, primary HCCs using the reverse transcription-polymerase chain reaction at the exponential phase. OPN mRNA expression was correlated with clinicopathologic features, particularly portal vein invasion, early tumor recurrence, and prognosis. RESULTS: Osteopontin mRNA was overexpressed in 133 tumors (55%). The OPN overexpression was associated closely with alpha-fetoprotein elevation (P = 0.001), p53 mutation (P = 0.021), larger tumors (P = 0.002), high-grade HCC (P < 0.001), late-stage HCC (P < 0.001), early tumor recurrence and/or metastasis (P = 0.003), and a lower 10-year survival rate (P = 0.00013). Multivariate analysis revealed that tumor stage and early tumor recurrence were crucial prognostic factors. In early-stage HCC, which has no vascular invasion and a lower early tumor recurrence than late-stage HCC, OPN mRNA overexpression predicted a higher early recurrence rate (P = 0.003). CONCLUSIONS: OPN mRNA overexpression was correlated closely with high-grade, late-stage, and early tumor recurrence, which lead to poorer prognosis. Osteopontin overexpression might serve as an unfavorable prognostic factor and a useful marker for predicting early recurrence in early-stage HCC.

Down-regulation of annexin A10 in hepatocellular carcinoma is associated with vascular invasion, early recurrence, and poor prognosis in synergy with p53 mutation.

Annexins (ANXs) are a large group of calcium-binding proteins participating in diverse important biological processes. ANXA10 is the least expressed new member of unknown function. We showed that ANXA10 mRNA was expressed in adult liver and hepatocellular carcinoma (HCC), but not in multiple adult and fetal tissues, cholangiocarcinoma, and several other common carcinomas. Of 182 unifocal primary HCCs, ANXA10 mRNA was dramatically reduced in 121 (66%), and the down-regulation correlated with p53 mutation (P = 0.024), early intrahepatic tumor recurrence (P = 0.0007), and lower 4-year survival (P = 0.0014). Down-regulation of ANXA10 was twofold more frequent in large than small HCCs (P = 0.0012), in grade II to III than grade I HCC (P < 0.00001), and in stage IIIA to IV than stage I to II HCC (P < 0.00001). Moreover, ANXA10 down-regulation and p53 mutation acted synergistically toward high-grade (P < 0.00001), high-stage HCC (P < 0.00001), and poorer prognosis (P = 0.0025). Our results indicate that the expression of the tissue- and tumor-restricted ANXA10 is a marker of liver cell differentiation and growth arrest, and its down-regulation associated with malignant phenotype of hepatocytes, vascular invasion, and progression of HCC, leading to poor prognosis. Thus, ANXA10 might serve as a new potential target of gene therapy for HCC.