The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.

Flt-4, a VEGF receptor, is activated by its specific ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis. This report provides evidence that the VEGF-C/Flt-4 axis enhances cancer cell mobility and invasiveness and contributes to the promotion of cancer cell metastasis. VEGF-C/Flt-4-mediated invasion and metastasis of cancer cells were found to require upregulation of the neural cell adhesion molecule contactin-1 through activation of the Src-p38 MAPK-C/EBP-dependent pathway. Examination of tumor tissues from various types of cancers revealed high levels of Flt-4 and VEGF-C expression that correlated closely with clinical metastasis and patient survival. The VEGF-C/Flt-4 axis, through upregulation of contactin-1, may regulate the invasive capacity in different types of cancer cells.

Intratypic variants of human papillomavirus type 16 and risk of cervical neoplasia in Taiwan.

The associations between variants of human papillomavirus (HPV) 16 and risk of cervical neoplasia have been reported, but nucleotide variations of HPV 16 in Asian populations and their association with cervical neoplasia have not been evaluated extensively. During 1991-1992, 11,923 women from seven townships in Taiwan were enrolled. The HPV DNA in cervical cells was detected and genotyped using EasyChip HPV blot. Nucleotide variations in the long control region (LCR), E6, and E7 genes were determined using DNA sequencing for 170 HPV 16-positive cervical samples. The Asian variant was the most prevalent variant (81.8%) of HPV 16 in Taiwan, and was also associated with increased prevalence of histologically confirmed cervical intraepithelial neoplasia grade 3 or worse, showing an age-adjusted odds ratio (exact confidence limits) of 10.70 (1.62-451.05; P = 0.0049) compared to the HPV 16 European variant. Similar significant associations with cervical intraepithelial neoplasia grade 3 or worse were also observed for distinct nucleotide substitutions, including T178A/G, A647G, A7730C/G, T7781C, G7842A, and C24T/G. These results demonstrate that non-European variants (non-E) of HPV 16, predominantly Asian variants, are associated with increased risk for severe cervical neoplasia, compared with European variants. Molecular mechanisms accounting for varied cervical neoplasia risk among different HPV 16 variants warrant further investigation.

Associations of human leukocyte antigen class II genotypes with human papillomavirus 18 infection and cervical intraepithelial neoplasia risk.

BACKGROUND: Only a small proportion of women infected with human papillomavirus type 18 (HPV18) may progress to persistent infection and cervical neoplasia. This community-based cohort study aimed to assess associations with human leukocyte antigen (HLA) class II genotypes for natural infection of HPV18 and subsequent risk of cervical neoplasia. METHODS: Among 10,190 cytologically normal participants, 125 with HPV18 infection were identified by HPV blot kit. HPV18 viral load at study entry was examined by real-time polymerase chain reaction; persistent infection was defined as HPV18 infection at 2 consecutive examinations. RESULTS: There was a significant association between HLA-DRB1*0403 allele and high HPV18 viral load (>1000 copies in 50 ng of total DNA) at study entry (odds ratio [OR], 7.2; 95% confidence interval [CI], 2.0-25.2). After adjustment for age and viral load at study entry, haplotype HLA-DRB1*0405-DQA1*0301-DQB1*0302 was significantly associated with persistent HPV18 infection (OR, 13.3; 95% CI, 1.7-105.9). HLA-DRB1*0403 allele was also associated with a significantly increased risk of high-grade squamous intraepithelial lesion or cancer, showing a multivariate-adjusted hazard ratio (95% CI) of 18.1 (2.6-128.5). CONCLUSIONS: HLA-DRB1*0403 allele and HLA-DRB1*0405-DQA1*0301-DQB1*0302 haplotype may play important roles in determination of high viral load and persistent infection of HPV18 and subsequent cervical neoplasia risk.

Prevalence of genotype-specific human papillomavirus infection and cervical neoplasia in Taiwan: a community-based survey of 10,602 women.

Human papillomavirus (HPV) causes cervical neoplasia; but limited data are available from Asia. We conducted a large-scale community-based cohort study in Taiwan to estimate prevalence of genotype-specific HPV infection and cervical neoplasia. Following written informed consent, cervical cells for cytology and HPV testing were collected from 11,923 participants (aged 30-65 years old, mean 46.3) in 1991-1992. Genotyping was performed using MY11/GP6+ PCR-based HPV Blot (EasyChip) for 39 HPV types. The overall HPV prevalence was 16.2% for 10,602 eligible participants, and 13.8% for 10,190 cytologically normal participants. The most common carcinogenic types were HPV52 (2.5%), HPV16 (2.0%), HPV56 (1.8%), HPV18 (1.6%), HPV33 (1.2%), HPV58 (1.3%) and HPV39 (1.0%). Among the 56 prevalent invasive and in situ cases, HPV16 (48.2%) was most common, followed by HPV58 (25.0%), HPV52 (19.6%), HPV31 (8.9%), HPV33 (8.9%) and HPV18 (3.6%). HPV16 and HPV58 caused cytological HSIL+ at younger ages than HPV52. Approximately half of the cervical cancer cases and high-grade precursors in Taiwan could be prevented by prophylactic vaccines against HPV16 and HPV18 infection. Up to 40% more could be prevented by targeting HPV58, HPV52, HPV33 and HPV31, arguing for the introduction of vaccines including more types.

Unique variants of human papillomavirus genotypes 52 and 58 and risk of cervical neoplasia.

Human papillomavirus (HPV) 52 and 58 are oncogenic HPV types prevalent in Asia. Our study aims to explore intratypic variants of HPV 52 and 58 in Taiwan. A total of 11,923 women were enrolled from seven townships in 1991-1992. HPV DNA in their cervical cells was detected and typed by EasyChip® HPV blot. Among 424 participants infected with HPV 52 and/or 58, nucleotide variations were determined in cervical cell samples of 406 participants by the polymerase chain reaction sequencing of the long control region, E6 and E7 genes. Nonprototype-like variants including lineages B and C were detected in 278 (99.3%) of 280 HPV 52 samples. The prototype and prototype-like group (lineage A) of HPV58 was found in 132 (98.5%) of 134 HPV 58 samples, with sublineage A1, A2 and A3 variant in 14.2, 27.6 and 56.7%, respectively. Among women infected with single HPV 52 type, the C variant (vs. B variant) was associated with an increased prevalence of cytologically diagnosed high-grade squamous intraepithelial lesion or worse lesions showing an age-adjusted odds ratio (95% confidence interval, CI) of 5.2 (1.0-27.6) and an increased prevalence of histologically confirmed high-grade cervical intraepithelial neoplasia or more severe lesions with an age-adjusted odds ratio (95% CI) of 7.6 (1.3-43.8). It was concluded that frequency distributions of HPV 52 and 58 variants in Taiwan were different from those in European and American populations. The association between C variant of HPV 52 and prevalence of cervical neoplasia needs further validation.

Post-coital vaginal douching is risky for non-regression of low-grade squamous intraepithelial lesion of the cervix.

BACKGROUND: Vaginal douching is a common practice worldwide. Its effect on the natural history of the early lesion of human papillomavirus (HPV) infection, low-grade squamous intraepithelial lesion (LSIL), is unknown. METHODS: In a prospective nation-wide cohort (n=1332), epidemiological variables including habit of vaginal douching after intercourse and outcomes of LSIL were studied. Colposcopy-confirmed LSIL women (n=295) were followed every 3 months. Parameters of HPV infection, sexual behavior, personal hygiene and environmental exposures were compared with the follow-up outcomes. RESULTS: There was a 15% chance of HSIL co-existing with the LSIL cytology result. Eight percent of colposcopy-confirmed LSIL were found with HSIL in 1 year. With a follow-up of up to 36 months, 83% LSIL regressed, 11% progressed and 6% persisted. The mean time (95% CIs) to regression and progression were 5.2 (4.7-5.8) and 8.0 (5.8-10.3) months, respectively. Risk factors of the non-regression of LSIL included HPV prevalence on enrollment, habit of vaginal douching after intercourse with a hygiene product and non-regular Pap screening, with odd ratio of 4.4 (1.9-10.3), 3.14 (1.04-9.49) and 2.12 (1.24-3.62), respectively. HPV prevalence and vaginal douching also conferred a slower regression of LSIL (8.0 vs. 4.1 months, P<.001 and 8.0 vs. 5.6 months, P=0.02, respectively). CONCLUSION: The study disclosed a transient but warning nature of cytological LSIL. Practicing of vaginal douching after intercourse, especially with hygiene products, is associated with non-regression of LSIL.

Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results.

OBJECTIVE: Management of equivocal Papanicolaou smear result remains to be challenging even with the aid of human papillomavirus test. Recently, 3 novel methylation-silenced genes, PAX1, WT1, and PCDH10, have been found to be specifically associated with cervical cancer. We compared the performances of methylation test of these genes with human papillomavirus tests in triage of equivocal Papanicolaou smear result. STUDY DESIGN: Two hundred twenty-two women with Papanicolaou smear results of atypical cells of undetermined significance nested to a multicenter, nation-wide cohort (the T1899 cohort) were studied. Status of cervical neoplasm was diagnosed with colposcopic biopsy. Status of gene methylation was determined by methylation-specific polymerase chain reaction. High-risk human papillomavirus DNA was detected by polymerase chain reaction-reverse line blot hybridization and Hybrid Capture 2. RESULTS: Cervical intraepithelial neoplasm 1, cervical intraepithelial neoplasm 2, cervical intraepithelial neoplasm 3, carcinoma in situ, carcinoma, and normal cervix were diagnosed in 58, 17, 14, 10, 1, and 120 women, respectively. Methylation of PCDH10, WT1, and PAX1 was highly associated with the severity of cervical neoplasm (P < 10⁻9, < 10⁻7, and < 10⁻5, respectively). In comparison with a negative test result, the odds ratio (95% confidence intervals) for cervical intraepithelial neoplasm 3 or more severe neoplasms for women tested positive for methylation of these 3 genes were 26.4 (9.0-77.3), 18.1 (6.9-47.2), and 10.3 (4.1-25.9), respectively; whereas those positive for human papillomavirus polymerase chain reaction and Hybrid Capture 2 were 10.5 (3.5-31.9) and 5.6 (2.3-21.4). In triage for atypical cells of undetermined significance, each methylation test had less colposcopy referral and false-positive rates, but higher false-negative rate than the human papillomavirus tests. With a combination test of PCDH10 or WT1 methylation, a comparable false-negative rate (P = .62) but much less false-positive rate (P = .002) and colposcopy referral rate (P < 10⁻6) were achieved. CONCLUSION: In triage of atypical cells of undetermined significance Papanicolaou smear results, methylation test of WT1 and PCDH10 is superior to human papillomavirus test in this multicenter cohort. Comparing to current human papillomavirus triage, the new test has only one third of false positivity and half of colposcopy referral, with no compromise of the sensitivity in diagnosis of cervical intraepithelial neoplasm 3 or more severe neoplasms.

Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis.

Although cancer vaccines are emerging as innovative methods for cancer treatment, these alone have limited potential for treating measurable tumor burden. Thus, the importance of identifying anticancer strategies with greater potency is necessary. The chimeric DNA vaccine CTGF/E7 (connective tissue growth factor linked to the tumor antigen human papillomavirus 16 E7) generates potent E7-specific immunity and antitumor effects. We tested immune-modulating doses of chemotherapy in combination with the CTGF/E7 DNA vaccine to treat existing tumors in mice. Metronomic low doses of paclitaxel, not the maximal tolerable dose, are synergistic with the antigen-specific DNA vaccine. Paclitaxel, given in metronomic sequence with the CTGF/E7 DNA vaccine enhanced the vaccine's potential to delay tumor growth and decreased metastatic tumors in vivo better than the CTGF/E7 DNA vaccine alone. The two possible mechanisms of metronomic paclitaxel chemotherapy are the depletion of regulatory T cells and the inhibition of tumor angiogenesis rather than direct cancer cell cytolytic effects. Results indicate that combination treatment of metronomic chemotherapy and antigen-specific DNA vaccine can induce more potent antigen-specific immune responses and antitumor effects. This provides an immunologic basis for further testing in cancer patients.

Incidence of cervical cancer and age-specific survival of small cell cervical carcinoma in Taiwan.

OBJECTIVE: To determine the incidence of cervical cancer and the age-specific survival from small cell cervical carcinoma in Taiwan. DESIGN: Retrospective study. Setting. Taiwan. POPULATION: Women diagnosed with cervical cancer from 1991 to 2005. METHODS: Analysis of data from the National Cancer Registration System and National Death Certification System. MAIN OUTCOME MEASURES: Incidence and age at diagnosis of cervical carcinoma and age-specific and overall survival from small cell cervical carcinoma. RESULTS: During the study period, 36 122 women were diagnosed with cervical cancer, and 81.8% had squamous cell carcinoma (SCC). For the periods 1991-1995, 1996-2000 and 2001-2005, the mean age at diagnosis increased from 53.9 ± 13.3 to 55.0 ± 14.9 and then to 56.7 ± 14.7 years, respectively. The incidence of SCC decreased from 1991 to 2005. During the same period, non-significant increases of adenocarcinoma and small cell carcinoma were noted. For SCC, occurrence peaked in 1991-1995 in patients 50-59 years of age. From 1996 to 2005, it peaked in patients 40-49 years of age. For cervical adenocarcinoma, occurrence peaked in patients 40-49 years of age, with a steady increase in this age group from 1991 to 2005. Occurrence of small cell cervical carcinoma peaked in the period 1991-1995 in patients 30-39 years of age. During the 15 years of the study, the overall mortality rate of the 198 patients with small cell cervical carcinoma was 65.7%. CONCLUSIONS: In Taiwan, the incidence of small cell cervical carcinoma and adenocarcinoma tended to increase, but the incidence of squamous cell cervical carcinoma significantly decreased during the period 1991-2005.

Association between human papillomavirus and adenocarcinoma of rectum and recto-sigmoid junction: a cohort study of 10,612 women in Taiwan.

This study aimed at assessing the association between the type-specific human papillomavirus (HPV) infection and the risk of adenocarcinoma of the rectum and recto-sigmoid junction. A total of 10,612 women aged 30-65 years old were enrolled from seven townships in Taiwan. Cervical cells collected at study entry were tested for 39 types of HPV infection by polymerase chain reactions and HPV blot kit. Newly developed adenocarcinomas of rectum and recto-sigmoid junction were ascertained through computerized linkage with national cancer registry profiles. An increased risk of adenocarcinomas of the rectum and recto-sigmoid junction was observed with HPV infection, showing a hazard ratio [HR] (95% confidence interval [CI]) of 1.99 (0.98-4.04) after adjustment for age and body mass index. The adjusted HR (95% CI) for the infection of HPV types other than 6 and 11 was 2.18 (1.04-4.60). Women with cervical infection of HPV types other than 6 and 11 at study entry may have an increased risk of adenocarcinomas of the rectum and recto-sigmoid junction, which deserves further validation by large-scale studies.

Prognostic and predictive values of E-cadherin for patients of ovarian clear cell adenocarcinoma.

OBJECTIVES: The purpose of the study was to analyze negative versus positive immunoexpression of epithelial cadherin (E-cadherin) and p53 in patients with primary advanced ovarian clear cell adenocarcinoma (OCCA) and its significance in relation to clinical features, progression-free survival and overall survival (OS). METHODS AND MATERIALS: Protein expression of E-cadherin and p53 was immunohistochemically evaluated in 61 OCCA patients with stages IIC to IV. The clinical factors studied included stage, age, CA-125, residual tumors, and chemotherapy regimens. RESULTS: Positive p53 immunoexpression was 44.8% (26/58) of OCCAs; in contrast, E-cadherin immunoexpression was observed in 75.9% (44/58) of OCCAs. The expected 5-year OS rate of OCCA treated with paclitaxel-based chemotherapy was significantly better than non-paclitaxel-based chemotherapy (40% vs 0%, P = 0.001). The expected 5-year OS rate of OCCA patients with positive E-cadherin immunoexpression (>10%) was also significantly better than patients with negative E-cadherin immunoexpression (≤10%) (35% vs 0%, P = 0.02). The expected 5-year OS rate of those receiving paclitaxel-platinum chemotherapy was not significantly different from platinum-based chemotherapy for those with negative E-cadherin immunoexpression (P = 0.11). The expected 5-year OS rate of those receiving paclitaxel-based chemotherapy was better than non-paclitaxel-based chemotherapy for those with positive E-cadherin immunoexpression (43% vs 0%, P = 0.01). Paclitaxel-based chemotherapy and positive E-cadherin immunoexpression were 2 independent prognostic factors in OS of patients with OCCA (P = 0.01 and 0.04, respectively). CONCLUSIONS: E-cadherin is a useful prognostic marker for OCCA patients, and paclitaxel-based chemotherapy can improve survival among patients with positive E-cadherin immunoreactivity.

Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway.

Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9+/-0.4 in the resistant group and 34.3+/-0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs.

Costs of cervical cancer and precancerous lesions treatment in a publicly financed health care system.

PURPOSE: Although cervical cancer is the most frequent cancer for women in Taiwan, no examination of its treatment costs has yet been undertaken. This study aimed to investigate the costs of cervical cancer and precancerous lesion treatment in Taiwan. METHODS: A total of 7,398 cases of cervical intraepithelial neoplasia (CIN) lesions were identified from the Taiwan Cervical Cancer Screening Registration System in 2003. A further 1,469 cases of invasive cervical cancer (ICC) were also identified from a survey on cervical cancer staging information conducted by the Taiwan Cancer Registration Task Force. Resource usage covering the first 6 months after CIN diagnosis and the 5 years after ICC diagnosis were extracted from the National Health Insurance claims database. The duration of each visit and the transportation costs were collected by means of personal interviews with CIN/ICC patients. The mean and standard deviation of the treatment and indirect costs were estimated. RESULTS: The average total costs for CIN patients were NT$4,201 for CIN1, NT$8,623 for CIN2 and NT$14,406 for CIN3, with the indirect costs accounting for 25-33% of the total. The total costs for ICC patients were NT$210,230 for Stage 1, NT$392,387 for Stage 2, NT$433,969 for Stage 3 and NT$464,701 for Stage 4, with the indirect costs accounting for about 14-17% of the total. CONCLUSIONS: CIN and ICC treatment resulted in considerable costs to the healthcare system in Taiwan. Indirect costs associated with such treatment were also substantial and cannot be ignored.

Phase II study of capecitabine (Ro 09-1978) in patients who have failed first line treatment for locally advanced and/or metastatic cervical cancer.

PURPOSE: The objective of this study is to evaluate the efficacy and safety of capecitabine in cervical cancer patients who have locoregional failure and/or distant metastasis and failed first line therapy. The efficacy of capecitabine is determined by the overall response rate (ORR) according to WHO criteria for response and the safety by adverse event (AE) and tolerability profiles according to NCI CTC version 2.0. PATIENTS AND METHODS: Patients with loco-regional failure and/or metastatic cervical cancer who have failed first line therapy were enrolled into the study. The patient received capecitabine 1, 250 mg/m2 twice daily for 14 consecutive days with 7 days rest (21-day cycle). The treatment was continued for up to six cycles. RESULTS: Forty-five patients previously treated by single or combination of surgery, or chemotherapy or radiotherapy were enrolled for study. Thirty-seven of 45 patients (82%) received at least 2 cycles of treatment and they were evaluated for response. The intention to treat analyses revealed 6/45(13%) ORR, 1/45 (2%) CR and 5/45 (11%) PR. Twenty-four patients (53%) had stable disease and 20% had progression of the disease. The median time to progression was 4. 1 months and the median overall survival was 9.3 months. CONCLUSION: Capecitabine as a monotherapy has a modest response in locoregional failure and/or metastatic cervical cancer who have failed first line therapy.

Phase II trial of carboplatin and distearoylphosphatidylcholine pegylated liposomal doxorubicin (Lipo-Dox) in recurrent platinum-sensitive ovarian cancer following front-line therapy with paclitaxel and platinum.

OBJECTIVE: To evaluate the effectiveness and toxicity of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer. METHODS: A phase II study of carboplatin/DPLD treatment for platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer was initiated in July 2002. As of March 2008, a total of 32 patients were enrolled. RESULTS: Of the 32 patients, one achieved a complete response; 19 (59%) achieved a partial response. The overall objective response rate was 62% (95% confidence interval [CI], 45%-80%). The median progression-free survival and overall survival for all 32 patients was 9.1 months (95% CI, 6.4-10.4 months) and 27.9 months (95% CI, 13.9-38.6 months), respectively. Toxicity was tolerable. The most common grade 3 or 4 toxicities were anemia (n=3) and nausea/vomiting (n=3). Grade 3/4 leukopenia (n=2), grade 3/4 thrombocytopenia (n=2) and grade 4 hepatitis (n=1) occurred in five patients. CONCLUSION: Carboplatin/DPLD appears to be an effective regimen with low toxicity for treatment of patients with platinum-sensitive, paclitaxel-pretreated, recurrent, epithelial ovarian cancer.

Prognostic factors in women with early stage small cell carcinoma of the uterine cervix.

Small cell carcinoma of the uterine cervix (SCCUC) is an uncommon, aggressive disease accounting for less than 5% of all cervical cancers. Due to its rarity, definitive treatment strategies have not been developed. Our aim was to analyze the clinical factors, treatment modalities, sites of relapse, and overall survival of women with early stage SCCUC and thus determine prognostic factors. The clinical records of 18 women diagnosed with stage IB1 to IIA SCCUC were reviewed, and patient characteristics and treatment modalities were analyzed to determine the prognostic factors for disease-free survival (DFS) and overall survival (OS). DFS and OS were 39% and 44% at 2 years. Lymph node metastasis was a significant prognostic factor of DFS. International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis were significant prognostic factors of OS as determined by multivariate analysis (p < 0.05). Radical hysterectomy followed by adjuvant chemotherapy resulted in higher 2-year survival rates compared to radical hysterectomy followed by adjuvant radiotherapy (62.5% vs. 16.7%); however, the difference was not statistically significant due to the small sample size. FIGO stage and lymph node metastasis are significant indicators of OS in patients with early stage SCCUC. Further larger scale analysis is warranted to determine whether adjuvant chemotherapy may facilitate a better prognosis than adjuvant radiotherapy.

Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways.

Morphine has been widely used for pain management. Other than analgesia, it has effects on vascular endothelial cells, including angiogenesis and apoptosis. An in vitro model of human umbilical vein endothelial cells (HUVECs) was made to investigate the effects and comprehensive mechanisms of morphine on vascular endothelial cells. Morphine enhanced apoptosis of HUVECs, increased intracellular reactive oxygen species (ROS), and reduced mitochondrial membrane potentials (MMPs). It also induced the release of NO and activated NF-kappaB in HUVECs. Naloxone, the opioid receptor antagonist, could reverse cell apoptosis and ROS generation, NO production, and MMP loss. Expression levels of Bak and Bax, and the activation of caspases 3 and 7 in HUVECs significantly increased when treated with morphine. Inhibition of NO production by NO synthase inhibitor reduced morphine-induced apoptosis. Morphine could induce apoptosis of HUVECs through both the NO and ROS pathways. Thus, inhibiting NO or ROS may be a potential target in blocking morphine-induced apoptosis of endothelial cells.

Concurrent endometrial carcinoma in patients with a curettage diagnosis of endometrial hyperplasia.

BACKGROUND/PURPOSE: Endometrial hyperplasia is considered a precursor of endometrial carcinoma, but concurrent endometrial carcinoma in patients with endometrial hyperplasia is seen frequently. Our aim was to examine the risk factors for coexisting endometrial carcinoma in patients with endometrial hyperplasia. METHODS: Between January 1996 and September 2006, 77 patients who underwent hysterectomy for endometrial hyperplasia were enrolled retrospectively. We divided the patients into non-endometrial carcinoma and endometrial carcinoma groups, depending on the final pathology of hysterectomy and analyzed the clinical variables of these patients. RESULTS: The prevalence rate of concurrent endometrial carcinoma in patients with endometrial hyperplasia was 26%. Those with atypical endometrial hyperplasia had a higher rate of coexisting endometrial carcinoma (54%). In addition to cytologic atypia, body mass index (BMI) was another risk factor. All the patients with concomitant endometrial carcinoma had at least one risk factor, but almost 50% of the cases in the non-endometrial group had no risk factors. Half of the women with cytological atypia and BMI > 25 had coexisting endometrial carcinoma. CONCLUSION: When patients are diagnosed with endometrial hyperplasia, surgical intervention should be performed in those with cytological atypia and higher BMI because of the possibility of coexisting endometrial carcinoma.

Lysophosphatidic acid induces ovarian cancer cell dispersal by activating Fyn kinase associated with p120-catenin.

Lysophosphatidic acid (LPA), known as the "ovarian cancer activating factor," is a natural phospholipid involved in important biological functions, such as cell proliferation, wound healing and neurite retraction. LPA causes colony dispersal in various carcinoma cell lines by inducing morphological changes, including membrane ruffling, lamellipodia formation, cell-cell dissociation and single cell migration. However, its effects on cell-cell dissociation and cell-cell adhesion of ovarian cancer cells have not been studied. In our study, we showed that LPA induced sequential events of intercellular junction dispersal and "half-junction" formation in ovarian cancer SKOV3 cells and that Src-family kinases were involved in both processes, since the effects were abolished by the selective tyrosine kinase inhibitor PP2. LPA induced rapid and transient activation of Src family kinases, which were recruited to cell-cell junctions by increasing the association with the adherens junction protein p120-catenin. We identified the Src family kinase, Fyn, as the key component associated with p120-catenin after LPA stimulation in SKOV3 cells. Our study provides evidence that LPA induces junction dispersal in ovarian cancer SKOV3 cells by activating the Src family kinase Fyn and increasing its association with p120-catenin at the cell-cell junction.

Weekly cisplatin, infusional high-dose 5-fluorouracil and leucovorin for advanced, recurrent and metastatic cervical carcinoma.

BACKGROUND: To evaluate the effectiveness and toxicity of infusional cisplatin and weekly 24-hour infusion of high-dose fluorouracil plus leucovorin (P-HDFL) for the treatment of patients with stage IVB, recurrent and metastatic carcinoma of the cervix. PATIENTS AND METHODS: A phase II study of P-HDFL in stage IVB, recurrent and metastatic carcinoma of cervix was initiated in January 2001. As of March 2007, a total of 21 patients were enrolled. Of these, 16 were evaluable for response. RESULTS: The overall objective response rate was 25% [95% confidence interval (CI), 1.2-48.8%] with none achieving complete response. The median progression-free survival and overall survival for all 21 patients was 2.3 months (95% CI, 1.2-4.3 months) and 10.5 months (95% CI, 4.6-17.4 months), respectively. Toxicity was tolerable. The main problems were nausea/vomiting and anemia. CONCLUSION: P-HDFL appears to be a moderately effective regimen with low toxicity for treating patients with advanced, recurrent and metastatic cervical cancer.