Characterization of Androgen Receptor Complex Associated Protein (ARCAP) in hepatocellular carcinoma and liver.

BACKGROUND: Hepatocellular carcinoma (HCC) ranks many tasks in clinical oncology due to possibly developing a general tumor in men and, usually lead to malignant to death within years. Researches had reported about major factors for being HCC was male sex and HCC associated with cirrhosis in childhood was found more common in males than females. In certain mouse strains as studied, breeding with testosterone significantly increases the development of HCC. Furthermore, castration of male mice diminished the frequency of the development of liver tumors. Meanwhile male hepatitis B virus transgenic mice have a greater occurrence of HCC than females. METHODS: We apply degenerate priming PCR to observe the expression of various steroid receptors in livers. Yeast-two hybrid screening to search a novel RNA fragment helps to find a new full-length gene by RACE experiment. RT-PCR is applied to detect various expressions in tissues and cell lines. In situ hybridization detects DNA in Chromosome mapping. GFP-constructs transfection proves the gene localization in cells. Immunoprecipitation pulldown assay verifies protein interaction. Gene transfection followed with luciferase assay demonstrates the interaction of genes within cellular signaling. Genomic alignment analysis for observing sequences data perform from NCBI database website (http://www.ncbi.nim.nih.gov/genebank/). RESULTS: The androgen receptor (AR) expression level is found at the highest level among the steroid receptors families detected in liver tumors. By yeast-two hybrid screening, we cloned an Androgen Receptor Complex Associated Protein (ARCAP), of 95 Kd in molecular weight and its cDNA. ARCAP locates at Chromosome 1. Our findings indicate ARCAP is highly expressed in hepatoma cell lines and liver tumors and their adjacent tumors as observed. Yeast two-hybrid assay and in vitro immunoprecipitation assays demonstrated an interaction between AR and ARCAP. CONCLUSION: We aim to search for different types and levels of steroid receptors expressed within human HCCs and in the adjacent liver tissues. To verify possible molecular mechanisms by which AR might affect hepatoma cells, we had characterized a novel protein ARCAP which functions as a coregulator to interact with AR within liver. The ligand-dependent AR with its cofactor, ARCAP, can induce a signal cascade by transactivation.

Pandemic aspect of dexamethasone: Molecular mechanisms and clinical application.

The rapid spread of coronavirus disease (COVID-19) in many countries has caused inconvenience in conducting daily life activities, and even deaths. Dexamethasone is a corticosteroid applied in clinical medicine since 1957, especially in immune therapy fields. Herein, we present the characteristics of Dexamethasone, from molecular mechanisms such as genomic and nongenomic pathways by cellular signal regulations, to clinical applications in various phases of the disease. During COVID-19 pandemic, Dexamethasone given to patients who required oxygen or ventilation therapy showed improved life efficacy.

Factors affecting recurrence in node-negative advanced gastric cancer.

BACKGROUND AND AIM: Prognostic factors of lymph node-negative gastric adenocarcinoma after curative resection have been discussed. Recurrent pattern of advanced lymph node-negative gastric cancer after curative resection has rarely been described. METHODS: Recurrent sites and correlated clinicopathological factors of 372 patients with lymph node-negative advanced gastric adenocarcinoma that underwent R0 resection from 1988 to 2005 were analyzed. RESULTS: Recurrence was noted in 51 (13.7%) patients. Recurrent rates according to site of recurrence were 26 peritoneal seeding (51.0%), 26 locoregional (51.0%), 17 hematogenous (33.3%), and 4 lymph node metastasis (7.8%). Clinicopathological factors to predict peritoneal seeding were serosal exposure, lymphovascular invasion, Lauren's diffuse type differentiation and scirrhous stromal reaction. Serosal exposure, tumor size, microscopic infiltrating growth type predicts locoregional recurrence. Tumor had only lymphovascular invasion predict hematogenous spreading. CONCLUSION: Node-negative advanced gastric cancer has more peritoneal seeding and locoregional recurrence. Aggressive cell behavior predicted the route of tumor cell spreading.

miR-21 microRNA expression in human gastric carcinomas and its clinical association.

BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that have been shown to be aberrantly expressed in many human carcinomas. Of these miRNAs, miR-21 appears to be important in tumorigenesis given its up-regulation in almost all types of human cancer examined. However, its association with the clinicopathological features of human gastric cancer has yet to be addressed. PATIENTS AND METHODS: Cancer tissues and corresponding normal tissues from 37 patients with gastric cancer were examined for the expression level of miR-21 using quantitative PCR and the clinical relevance of miR-21 was statistically analyzed. RESULTS: miR-21 was overexpressed in 92% (34/37) of the gastric cancer samples examined. However, the patients with higher miR-21 expression did not have a worse prognosis. CONCLUSION: miR-21 could serve as an efficient diagnostic marker for gastric cancer, but does not affect the clinical prognosis of gastric cancer patients.

Survival predictors in patients with node-negative gastric carcinoma.

BACKGROUND: Presence or absence of nodal metastasis influences outcome of gastric cancer patients. This study gives insight into survival predictors and clinicopathological features of node-negative gastric adenocarcinoma. METHODS: Between 1988 and 1999, 689 gastric cancer patients without other cancer or gastrectomy for benign disease who underwent curative resection were enrolled in this study. Clinicopathological data in patients with node metastasis were compared with those without. RESULTS: The survival rate at 5 and 10 years for node-negative cases was 91.7% and 89.7%, respectively. On univariate analysis, node-negative patients were characterized by frequent location in the lower two-thirds of the stomach (84.9%), tumor size less than 4 cm (63.5%), grossly superficial type (71.6%), more medullary stromal reaction (50.5%) and intestinal type (67.7%), tumor invasion confined to serosa (78.4%), less poorly differentiated cell type (43.2%), and less lymphovascular invasion (33.4%). Multivariate analysis demonstrated that lymphovascular invasion (relative risk: 5.036) and depth of cancer invasion (relative risk: 4.404) were independent poor prognostic factors. However, lymphovascular invasion and serosal invasion were also correlated (P < 0.001). CONCLUSION: Patients with node-negative gastric adenocarcinoma had less disease progression and a favorable survival. Lymphovascular invasion and depth of cancer invasion were two independent but correlated survival predictors.

Lymph node metastasis as a single predictor in patients with Borrmann type I gastric cancer.

BACKGROUND/AIMS: Borrmann type I gastric cancers are rare. Its clinicopathological features have never been reported. METHODOLOGY: A total of 33 patients with Borrmann type I gastric cancer was evaluated. 570 patients with Borrmann type II, III and IV were used as references. RESULTS: Borrmann type I gastric cancer occurred preferably in upper stomach, and had more T1 and T2 cancer invasion and early TNM stages, but less lymph node metastasis. Histologically, it had more intestinal type and less scirrhous stromal reaction. Five-year disease-free and overall survival rates in patients with Borrmann type I tumors were significantly higher than that of other types (73.3% vs. 45.8%; P = 0.02, and 72.6% vs. 47.8%; P = 0.01, respectively). Analysis of the relation between clinicopathological factors and survival showed that only lymph node metastasis significantly affected on disease-free survival with a relative risk of 8.4. Lymph node metastasis also affected overall survival rate at a marginal level (p = 0.05). CONCLUSIONS: Borrmann type I gastric cancer has higher survival rate. Lymph node metastasis is a single prognostic indicator for survival.

Transpedicle body augmenter in painful osteoporotic compression fractures.

Osteoporotic compression fractures (VCFs) can result in progressive kyphosis and chronic pain. Polymethylmethacrylate has been used for augmentation of VCFs; however, there are cement complications, and long-term fracture healing is unknown. The transpedicle body augmenter (TpBA), a porous titanium spacer, has been reported as an internal support to reconstruct the vertebral body combining short segment fixation in burst fracture. We retrospectively reviewed radiographic and clinical results of TpBA vertebroplasty for single symptomatic VCF in 80 patients. Manual reduction and TpBA vertebroplasty via a paramedian incision with blunt dissection was done. Mean age was 72.3 years (range 51-87 years), and female-male ratio was 66:14. The mean symptom duration was 5 months, and follow-up 44 months. Peri-operative variables and radiographic and clinical results were evaluated. The average operation time was 26.1 min, blood loss 92 cc, and hospitalization 2.3 days. No patient had neurological deterioration. TpBA was found sinking into vertebral body initially, then locked by residual cortex, and finally stabilized within the vertebra. There was no dislodgement of TpBA in the final visit. Sixty-two patients (77.5%) could walk within 3-6 h after operation and the others within 24 h. The anterior vertebral restoration was 8.0 mm initially and 6.1 mm at final follow-up. Wedge angle correction was 11.5 degrees initially and 9.4 degrees at final follow-up. Pain, by the visual analog scale, was 8.6 pre-operatively, 2.5 at day 7 follow-up, and 2.9 at final follow-up. By the questionnaire, 72 of 76 respondents reported a decrease in discomfort after TpBA vertebroplasty, and 63 of 76 patients reported a return to normal activity after operation. The final satisfaction rate was 93.4%. TpBA vertebroplasty led to early and medium-term clinical improvement and anatomic restoration of painful VCFs.

Another option to treat Kümmell's disease with cord compression.

The efficiency of short-segment fixation with transpedicle body augmenter (a titanium spacer with bone-ingrowth porous surface, TpBA) to treat Kümmell's disease with cord compression (stage III) was retrospectively evaluated. No laminectomy or instrumentation reduction was done. Inclusion criteria included Frankel CDE, single-level within T10-L2. FU rate was 88%, i.e. 21 cases were included. Frankel function classification was 6E9D6C. Mean age was 72+/-8 years. F:M was 16:5. FU period was 48 M (range, 30-76 M). The hospitalization was 4.5+/-2.2 days; operation time, 70.4+/-17.2 min; blood loss, 150+/-72 cc. Final Frankel class was 20E1D. Complications included two superficial infection and one pneumonia. Body height and kyphosis were all corrected significantly and well preserved at the final visit. No TpBA dislodgement or implant failure was noted; however, three cases developed new compression fractures. The clinical outcome showed 81% with P1 or P2 by Denis pain scale. This method can decompress spinal canal, maintain kyphosis correction and vertebral restoration, prevent implant failure, and attain good clinical results.

Preliminary report of transpedicle body augmenter vertebroplasty in painful vertebral tumors.

STUDY DESIGN: Transpedicle body augmenter vertebroplasty of painful vertebral tumor was retrospectively evaluated. OBJECTIVE: Transpedicle body augmenter vertebroplasty was designed to treat spinal tumor with intractable pain refractory to conservative management, deformity, biomechanical impairment, and neural deficits. SUMMARY OF BACKGROUND DATA: Chemotherapy, hormonal therapy, and radiation therapy cannot restore spinal stability. Complication rates of major surgery are high. Percutaneous vertebroplasty has a high leakage rate, and tumor tissue may be displaced into the canal. Transpedicle body augmenter vertebroplasty was designed to treat spinal tumor for pain control and stability. METHODS: There were 9 women and 9 men with a mean age of 62.7 +/- 12.6 years included. All patients had vertebral pain. Walking was impossible for 12 patients, and 15 had neurologic deficits. Treatments included manual reduction and transpedicle body augmenter vertebroplasty. RESULTS: Mean follow-up time was 18 months. Mean hospitalization was 7.1 +/- 4.2 days, operating time was 46 +/- 25 minutes, and blood loss was 263 +/- 157 cc. Neither neurologic deterioration nor root irritation was found after transpedicle body augmenter vertebroplasty. No dislodgement of the transpedicle body augmenter was found at the final visit. According to the visual analog scale, pain was 9.3 before surgery, 3.2 at 2-week follow-up, and 2.2 at 3-month follow-up. There were 11 patients (92%) who recovered walking ability. Neurologic status improved in 14 patients (93%). The satisfaction rate was 89%. CONCLUSION: Transpedicle body augmenter vertebroplasty proved to be safe and effective in reducing pain and improving functional status of patients with spinal tumor.

Multiple primary cancers in patients with gastric cancer.

BACKGROUND/AIMS: Some gastric cancer patients have multiple primary cancers (MPC). We evaluate the current status of MPC with gastric cancer. METHODOLOGY: 2,109 gastric cancer patients treated between 1987 and 2002 were analyzed. RESULTS: There were 99 MPC with gastric cancer (4.7%). Second cancer (77.8%) was discovered within 5 years before and after the onset of gastric cancer. 34.3% of patients were discovered within 1 year (synchronous tumor). In the 77 male patients, prostate cancer was the most common occurrence (19.5%), followed by cancers of the colon (18.2%) and liver (14.3%). In the 22 female patients, colon cancer was the most common (31.9%) followed by breast and cervix cancers (22.7%). These cancers were the most common diseases in Taiwan in the same period. Gastric cancer patients with MPC had less stromal reaction and better survival than those without. Patients with metachronous secondary tumors had more peritoneal dissemination and worse survival than those with synchronous primary cancer. CONCLUSIONS: Gastric cancer patients may develop second cancer(s), which is often a current prevalent malignancy. Knowledge of time to development and mode of organ association may allow clinicians to detect potentially curable subsequent cancer(s).

PTPN3 and PTPN4 tyrosine phosphatase expression in human gastric adenocarcinoma.

BACKGROUND: Degenerated PCR primers, designed according to the consensus tyrosine phosphatase catalytic motifs, were used in order to amplify expressed protein-tyrosine phosphatase molecules from human gastric cancer-derived cells. From such profiles, more than twenty different types of tyrosine phosphatase were identified from gastric cancer tissue. A non-receptor tyrosine phosphatase, PTPN4, was found to be expressed in a tumor-tissue profile with only low frequency. The most closely-related gene to tyrosine phosphatase, PTPN3, has been shown to be mutated in cases of human colorectal cancer, but its expression is cases of gastric cancer is not known. MATERIALS AND METHODS: The mRNA expression of PTPN3 and PTPN4 by RT-PCR was investigated, and the protein expression status of PTPN3 was examined, using immunohistochemistry, to elucidate clinicopathological associations of the PTPN3 and PTPN4 family within human stomach cancer. RESULTS: PTPN3 and PTPN4 were expressed in all gastric cancer cell lines and clinical cancer tissue specimens examined. Following the examination of 92 gastric cancer patients' pathological specimens, PTPN3 expression showed no statistical significance with respect to the patients' survival. A statistically significant correlation between PTPN3 staining and the differentiation status of gastric cancer tissue was, however, observed. CONCLUSION: This finding indicates that both PTPN3 and PTPN4 are expressed within human gastric cancer cells and that PTPN3 seems to play an important role in gastric cancer differentiation and the progression of malignancy.

Protein tyrosine-phosphatase expression profiling in gastric cancer tissues.

Protein phosphorylation is an important regulatory mechanism involved in signal transduction and cancers. In comparison to the extensive tyrosine-kinase oncogenesis research, there are only relatively few studies of protein tyrosine-phosphatase expression in cancers. The expression profile for tyrosine-phosphatases was investigated in gastric cancers using RT-PCR and molecular cloning. The present study showed a general PTP expression profile in gastric cancer tissues, with the identification of 22 distinct tyrosine-phosphatases. Following the examination of five PTPs (PTPRA, PTPRB, PTPRD, PTPRG and PTPRZ) using immunohistochemistry, strong association was observed between PTPRA/PTPRZ expression and gastric cancer progression including lymphovascular invasion and liver/peritoneal dissemination.

Effects of COX-2 inhibitor on growth of human gastric cancer cells and its relation to hepatocyte growth factor.

It is known that hepatocyte growth factor binding to its receptor regulates gastric cancer progression and metastasis. HGF was found to up-regulate the expression of cyclooxygenase-2 gene and increases prostaglandin (PG) synthesis in gastric mucosa cells. Overexpression of COX-2 and increased PG secretion have also been found to be involved in the regulation of growth and metastasis of gastric cancer. Results from this study showed that c-Met and COX-2 are expressed in 28 cases (93.3%) and 16 cases (53.3%) of 30 human gastric cancer tissues, respectively. Expressions of c-Met positively correlated with that of COX-2 (r=0.41; P=0.024). Using in vivo and in vitro models to further examine the interaction between c-MET and COX-2, we found that HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. COX-2-specific inhibitor-NS398 inhibited the growth of human gastric cancer SC-M1 cells as well as HGF stimulated the growth of SC-M1 cells in a dose-dependent manner. HGF treatment of SC-M1 cells increased the secretion of PGE2 and this stimulation was blocked by NS398. In vivo SC-M1 tumor model showed that HGF stimulated the tumor growth and NS398 retarded the tumor growth. These results suggest that COX-2-specific inhibitors may play some role on the therapy of gastric cancer patients with high serum HGF level and overexpression of c-Met in tumor.

High CD40 expression in gastric cancer associated with expanding type histology and liver metastasis.

BACKGROUND/AIMS: We have previously reported higher serum TNF-alpha levels in some gastric cancer patients. The status of its receptor (CD40 expression) in gastric cancer tissue and their clinical relevance is worthy of study. METHODOLOGY: The expression of CD40 was examined immunohistochemically in 32 gastric carcinoma specimens and graded as high and low expressions according to the proportion of stained tumor cells. The clinicopathological factors including age, sex, tumor location, size, gross appearance, stromal reaction pattern, degree of cellular differentiation, histological classification, depth of tumor invasion, lymph node status, peritoneal dissemination, liver metastasis and TNM stage were analyzed according to the different expression of CD40. RESULTS: There were 18 patients with low CD40 expression and 14 patients with high CD40 expression. There were more expanding type tumors than infiltrating type by Ming's histological classification (57.1% vs. 16.7%, p=0.027) and liver metastasis (28.6% vs. 0, p=0.028) in the high expression group. The patient survival showed a worse tendency in patients with high CD40 expression, but did not reach statistical difference. There was no correlation between CD40 expression level and other clinicopathological features. CONCLUSIONS: The fact that high CD40 expression existed more in expanding type tumor and had more liver metastasis suggests CD40 may play an important role in local invasion mode and hematogenous spread.

Prognostic implications of the expression of erbB2, topoisomerase II alpha and thymidylate synthase in metastatic gastric cancer after fluorouracil-based therapy.

OBJECTIVE: This retrospective study aimed to ascertain the expression of erbB2 in relation to topoisomerase II alpha (T2 alpha) and thymidylate synthase (TS) markers in 30 consecutive metastatic gastric cancer patients with a specimen available for study. METHODS: All patients had been entered on consecutive chemotherapeutic clinical trials that were all 5-fluorouracil based. The specimens were evaluated by fluorescence in situ hybridization to ascertain erbB2 and T2 alpha gene amplification, and by immunohistochemical staining for T2 alpha and TS protein expression. RESULTS: erbB2 amplification was detected in 16.7% of specimens, with co-amplification of the T2 alpha gene in 40%, and 44% had undetectable TS protein expression. Kaplan-Meier survival curves showed significantly prolonged overall survival in patients with erbB2 and T2 alpha gene amplification, T2 alpha protein overexpression and absence of TS protein expression (P = 0.0011, P = 0.0048, P = 0.0061 and P = 0.0267, respectively, by log rank test). There was a positive correlation between erbB2 amplification and T2 alpha amplification, T2 alpha protein overexpression, and a trend towards absence of TS expression (P = 0.0001, P = 0.003 and P = 0.066 by Fisher's exact test). CONCLUSION: High dose fluorouracil/leucovorin-based chemotherapy may have the potential to reverse the adverse effects resulting from erbB2 gene amplification in gastric cancer.

Arg tyrosine kinase expression in human gastric adenocarcinoma is associated with vessel invasion.

BACKGROUND: Gastric cancer is one of the prevalent cancer types in the Far East region. In order to discover new prognostic and diagnostic biomarkers for gastric cancer progression, we have used degenerated PCR primers designed to amplify all expressed protein tyrosine kinase molecules from human cancer tissues. In previous studies, we have shown the clinical significance of arg tyrosine kinases in a colorectal cancer progression model. MATERIALS AND METHODS: We further investigated the protein expression of arg tyrosine kinase by immunohistochemistry and analyzed the clinicopathological association with human cancers. RESULTS AND CONCLUSION: Specimens from 79 patients were examined and this demonstrated that the expression of arg kinase showed no statistically significant correlation with the patients' overall survival. However, higher levels of arg kinase immunoreactivity did show a statistically significant association with vessel invasion in gastric cancer tissues examined. This indicates a potential involvement of arg in gastric cancer invasion and progression.

Incidence and factors associated with recurrence patterns after intended curative surgery for gastric cancer.

Recurrence after curative resection for gastric cancer remains high. We examined its incidence and factors related to recurrence pattern, while trying to avoid the interaction of various factors. A total of 611 gastric cancer patients after resection for curative intent (1988-1995) were analyzed. The result showed that 245 patients had recurrence (40.1%). Cumulative recurrence rates were 53.5%, 80%, 89.0%, 94.7%, 96.3%, 98%, and 99.5% at 1, 2, 3, 4, 5, 6, and 7 years, respectively. Over half of patients with recurrence (123; 50.2%) had an initial single recurrence. Taking single and multiple recurrence together, most recurrences (213; 86.9%) were distant metastases, 110 recurrences (44.9%) were local relapses, and 78 recurrences (49.8%) were both local and distant. Among the distant metastases, 131 patients (53.5%) had peritoneal dissemination, 106 patients (43.3%) had hematogenous metastases, and 70 patients (28.6%) had distant lymphatic spread. Scirrhous-type stromal reaction, serosa invasion, and female gender were factors negatively related to peritoneal recurrence. Medullary-type stromal reaction and male gender showed a preference for locoregional recurrence, and expanding growth tumor commonly led to hematogenous metastasis. Patients who had paraaortic lymph node metastasis were at high risk of developing distant lymphatic recurrence. It is conceivable that the patterns of recurrence and the times to recurrence provide a biological basis for clinical monitoring of patients with the aim of modifying therapeutic modalities.

Clinical significance of AXL kinase family in gastric cancer.

BACKGROUND: We have used degenerated PCR primers designed according to the consensus kinase motifs in order to amplify expressed protein tyrosine kinase molecules from human gastric cancers. From such kinase expression profiles, we have identified more than fifty different tyrosine and serine/threonine kinases from two matched pairs of gastric cancer tissue and normal mucosa. In previous studies, we have shown the clinical significance of two tyrosine kinases identified in gastric cancer, tie-1 and mkk4. MATERIALS AND METHODS: In this report, we further investigate the protein expression of the whole axl receptor tyrosine-kinase family (axl/ufo, nyk/mer and sky/rse) by immunohistochemistry and their clinicopathological associations. RESULTS: On examination of 96 patients specimens, expression of the axl kinase family alone showed no statistical significance with respect to the patients' survivaL However, the combination of nyk/mer expression with axl/ufo expression correlated inversely with the patients' prognosis result. CONCLUSION: This finding indicates that a co-operative relationship exists between axllufo and nyk/mer protein kinases and this seems to play an important role in gastric cancer progression and metastasis.

Phase II and pharmacokinetic study of GL331 in previously treated Chinese gastric cancer patients.

PURPOSE: A phase II and pharmacokinetic study was designed to assess the efficacy and toxicity profile of an epidophyllotoxin analogue, GL331, in previously treated Chinese gastric cancer patients, with concurrent pharmacokinetic evaluation of the drug's metabolism. MATERIAL AND METHODS: GL331 was given at 200 mg/m(2) as a daily 3-h infusion for 5 days every 4 weeks. RESULTS: Enrolled in the study were 15 patients. One patient died from neutropenic sepsis before evaluation, one patient did not receive the full dose for reasons unrelated to GL331, nine patients had progressive disease with a median survival of 80 days, and five had stable disease with a median survival of 240 days. Grade 3 and 4 myelosuppression occurred in 10 of the 15 patients, with one death from neutropenic sepsis. This patient's peak GL331 concentration was 16.8 microg/ml, which was high compared to the mean peak drug concentration of 6+/-4.1 microg/ml. The mean systemic GL331 clearance was 12.1+/-7.2 l/h per m(2), much lower than 23.3+/-8.2 l/h per m(2) found in the phase I trial. Topoisomerase IIalpha was determined by immunohistochemistry and overexpression was detected in 3 of 11 specimens. CONCLUSIONS: GL331 was ineffective at this dose and schedule in this group of patients in spite of adequate blood levels of the drug.