Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer

Strong expression of many matrix metalloproteinases (MMPs) has been related to poor survival of colorectal cancer (CRC) patients. The expression of tissue inhibitors of metalloproteinases (TIMPs) has been associated with both a beneficial and a poor outcome and there is thus a need to further clarify the significance of MMPs and TIMPs in CRC. The prognostic significance of 4 MMPs and TIMPs in CRC was evaluated. Formalin-fixed, paraffin-embedded tissue arrayed samples of 351 patients with primary colon or rectal cancer of Dukes' stages A-D were selected for immunohistochemical staining of MMP-1, -2, -7 and -13, and TIMP-1, -2, -3 and -4. High expression of MMP-2 in the malignant epithelium as well as in the surrounding stroma was associated with reduced survival of colon cancer patients. Strong epithelial and stromal cytoplasmic staining of TIMP-3 was associated with a longer survival in rectal cancer patients, and here the interobserver variation for evaluating the degree of staining was lower than for epithelial staining. Strong stromal cytoplasmic staining of TIMP-4 predicted longer survival of rectal cancer patients. Multivariate analysis showed that stromal cytoplasmic TIMP-3 staining was the only marker of independent prognostic value. MMP-2 might be a useful prognostic marker in colon cancer, and TIMP-3 and TIMP-4 in rectal cancer, but the findings associated with stromal staining should be interpreted with some caution. Different biologic behavior or different genetic development may explain the differences between colon and rectal cancers regarding the expression of MMP-2, TIMP-3 and TIMP-4.     

紧密连接相关蛋白在胃腺癌中的联合表达及预后意义

  目的  探讨紧密连接蛋白(Claudin-1、-3、-4和-7)在胃腺癌纵向侵袭转移中的表达变化及预后意义。  方法  应用组织芯片和免疫组化SP法检测139例胃腺癌患者黏膜腺上皮(含肠化生上皮), 黏膜层, 肿瘤中心, 侵袭前沿及淋巴结转移灶胃癌组织Claudin-1、-3、-4、-7的表达水平, 分析其与胃腺癌侵袭转移及预后关系。  结果  Claudin-1、-3、-4和-7在肠化生上皮的总体表达水平高于胃黏膜腺上皮(P < 0.05);从黏膜层→肿瘤中心→侵袭前沿→淋巴结转移灶, 胃癌组织Claudin-1、-3、-4和-7的表达呈抛物线样趋势, 肿瘤中心表达最高(χ2=111.84, 52.35, 33.71和111.91, P < 0.05);肿瘤中心Claudin-1和-3表达降低, 患者预后不良(χ2=5.530和χ2=9.846, P < 0.05), Cox多因素生存分析发现仅Claudin-3和临床分期可作为胃癌患者的预后独立预测因素。  结论  Claudin-1、-3、-4和-7在胃癌纵向侵袭转移中的表达变化可能与胃黏膜的肠上皮化生、肿瘤增殖及侵袭转移中的上皮-间质转化有关。      

Expression of matrix metalloproteinases-2, -8, -13, -26, and tissue inhibitors of metalloproteinase-1 in human osteosarcoma

Osteosarcoma (OS) is among most common malignant tumour of bone. Matrix metalloproteinases (MMPs) are predominantly associated with poor prognosis of several cancers, although some of them, like MMP-8, seem to have a protective role in some cancers. We analyzed the distribution patterns of MMP-2, -8, -13, -26, and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in 25 OS patients. MMP-2, -8, -13, -26 and TIMP-1 were mostly detected in sarcoma cells. Response to chemotherapy affected the amount of MMP-2, -8, and -13 in resection sections when compared to biopsies: patients with excellent or good response had less positivity to MMP-2 in chemotherapy samples than those with moderate or poor response. We conclude that MMP-2, -8, -13, -26, and TIMP-1 are expressed in OS tissue, and all, except protective MMP-8, were also found in metastases indicating that MMPs and TIMP-1 can participate in the OS progression.     

Cleavage of caspases-1, -3, -6, -8 and -9 substrates by proteases in skeletal muscles from mice undergoing cancer cachexia

A prominent feature of several type of cancer is cachexia. This syndrome causes a marked loss of lean body mass and muscle wasting, and appears to be mediated by cytokines and tumour products. There are several proteases and proteolytic pathways that could be responsible for the protein breakdown. In the present study, we investigated whether caspases are involved in the proteolytic process of skeletal muscle catabolism observed in a murine model of cancer cachexia (MAC16), in comparison with a related tumour (MAC13), which does not induce cachexia. Using specific peptide substrates, there was an increase of 54% in the proteolytic activity of caspase-1, 84% of caspase-8, 98% of caspase-3 151% to caspase-6 and 177% of caspase-9, in the gastrocnemius muscle of animals bearing the MAC16 tumour (up to 25% weight loss), in relation to muscle from animals bearing the MAC13 tumour (1-5% weight loss). The dual pattern of 89 kDa and 25 kDa fragmentation of poly (ADP-ribose) polymerase (PARP) occurred in the muscle samples from animals bearing the MAC16 tumour and with a high amount of caspase-like activity. Cytochrome c was present in the cytosolic fractions of gastrocnemius muscles from both groups of animals, suggesting that cytochrome c release from mitochondria may be involved in caspase activation. There was no evidence for DNA fragmentation into a nucleosomal ladder typical of apoptosis in the muscles of either group of mice. This data supports a role for caspases in the catabolic events in muscle involved in the cancer cachexia syndrome.     

Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10000 women in Costa Rica

Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n=9949), HPV-18 (n=9928), HPV-31 (n=9932), and HPV-45 (n=3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n=573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for HPV-16, -18, -31, or -45, seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA- and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.     

Expression of Ret/PTC1, -2, -3, -delta3 and -4 in German papillary thyroid carcinoma.

Ret/PTC oncogene has been described with a frequency of 2.5-30% in papillary thyroid carcinomas. We examined the expression of ret/PTC in 99 German papillary thyroid carcinomas, including two recently described new variants of ret/PTC3 and identified eight ret/PTC-positive tumours (8%) but none with the new variants.     

Diagnostic value of CEA, CA 15-3, CA 19-9, CYFRA 21-1, NSE and TSA assay in pleural effusions

The aim of this study was to evaluate the individual and combined diagnostic utility of six tumor markers in patients with pleural effusion. Pleural and serum levels of carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA 15-3), carbohydrate antigen 19-9 (CA 19-9), cytokeratin fragment 19 (CYFRA 21-1), neuron-specific enolase (NSE) and total sialic acid (TSA) were assayed in 74 patients with pleural effusions (44 malignant and 30 benign). All tumor markers except TSA and NSE were increased in both serum and pleural fluid of patients with malignant diseases. Using the cut-off values 3 ng/ml, 14 U/ml, 5 U/ml, 8 ng/ml and 70 mg/dl for pleural fluid CEA, CA 15-3, CA 19-9, CYFRA 21-1 and TSA, respectively, the sensitivity (%) and specificity (%) of these tumor markers were as follows: CEA; 52/77, CA 15-3; 80/93, CA 19-9; 36/83, CYFRA 21-1; 91/90, TSA; 80/67, for differentiating malignant effusions from benign. When CA 15-3 and CYFRA 21-1 combined, the sensitivity and specificity were increased (100 and 83%, respectively). Classifying the malignant effusions as bronchial carcinoma and malignant pleural mesothelioma, CEA was shown to have the highest sensitivity and specificity (88 and 90%, respectively) while the combination of CEA with other tumor markers increased sensitivity but decreased specificity. According to our results, tumor markers are not suitable for the differential diagnosis of malignancy.     

Gestational choriocarcinoma in norway, 1953-92 - an epidemiologic report

The objective of this study was to evaluate changes in incidence and survival rates in patients with gestational choriocarcinoma, and to examine the prognostic importance of clinical stage and age. A population based analysis (retrospective study) of all patients with gestational choriocarcinoma reported to the Cancer Registry of Norway in the 40-year period 1953-92. One hundred and fifteen patients with gestational choriocarcinoma were examined. The main outcome measures the incidence rates per 1,000 live births, clinical stage distribution (FIGO classification), 5-year survival rates (Kaplan-Meier plot) and relative rates (RR). The incidence rates ranged from 0.028 to 0.096, but no temporal trend was observed. Most cases were classified into the clinical stages I (53.9%) and III (24.3%). A more favourable stage distribution was seen in the diagnostic period 1973-92 compared to 1953-72 (p<0.01). The 5-year survival rate (Kaplan-Meier plot) rose from 57.9% in the first period to 94.8% in the last period (p<0.001). The survival rate declined gradually with advancing stage of the disease. The 5-year survival rates (1953-92) in the succeeding stages I, II, III and IV were 93.5%, 80.0%, 64.1% and 26.7%, respectively. The multivariate analysis (GLIM) revealed that stage was an important prognostic factor (p=0.00), whereas age did not reach the significant level as prognostic factor (p=0.72).     

Cancer in Appalachia, 2001-2003

BACKGROUND: Researchers have not been able to examine cancer incidence rates in Appalachia because high-quality data have not been uniformly available across the region. This study is the first to report cancer incidence rates for a large proportion of the Appalachian population and describe the differences in incidence rates between Northern, Central, and Southern Appalachia. METHODS: Forty-four states and the District of Columbia provided information for the diagnosis years 2001 through 2003 from cancer registries that met high-quality data criteria. Eleven of 13 states with counties in Appalachia, covering 88% of the Appalachian population, met these criteria; Virginia and Mississippi were included for 2003 only. SEER(*)Stat was used to calculate age-adjusted rates per 100,000 population and 95% gamma confidence limits. RESULTS: Overall, cancer incidence rates were higher in Appalachia than in the rest of the US; the rates for lung, colon/rectum, and other tobacco-related cancers were particularly high. Central Appalachia had the highest rates of lung (men: 143.8; women: 75.2) and cervical cancer (11.2)-higher than the other 2 regions and the rest of the US. Northern Appalachia had the highest rates for prostate, female breast, and selected other sites, and Southern Appalachia had the lowest overall cancer incidence rates. CONCLUSIONS: Cancer incidence rates in Appalachia are higher than in the rest of the US, and they vary substantially between regions. Additional studies are needed to understand how these variations within Appalachia are associated with lifestyle, socioeconomic factors, urban/rural residence, and access to care.     

Expression of IGF-II,IGFBP-2, -5, and -6 in meningiomas with different brain invasiveness

Meningiomas show clinical characteristics that vary from very benign to clearly malignant with rapid invasive growth and metastases. This study was undertaken to analyze the expression of members in the insulin-like growth factor (IGF) system in meningiomas showing different degrees of brain invasion. Tissue samples from 16 meningiomas were analyzed for members in the IGF family by mRNA in situ hybridization. The meningiomas comprised three groups: I. Benign meningiomas that did not interfere with the arachnoid plane and showed no edema. II. Benign meningiomas that did not respect the arachnoid plane and tumors that caused edema. III. Aggressive and malignant meningiomas that caused edema and showed brain invasion.IGF-II mRNA was identified in all tumors analyzed, and with a clear increase in expression observed in group III tumors. IGFBP-2 mRNA was detected in equal levels in all tumors. IGFBP-5 mRNA levels were highest in the benign group without edema (I) of meningiomas whereas IGFBP-6 mRNA levels were highest in the group with brain invasion (III). Brain invasiveness in degrees from respect of the arachnoid membrane progressing to frank brain invasion correlated with increases in IGF-II and IGFBP-6 expression. High levels of IGFBP-6 may not inhibit IGF-II actions, which is known to be growth promoting in tumors. Instead, IGFBP-6 appears to have an importance for the characteristics of edema and brain invasion in meningiomas.     

Smoking in Italy, 1986-1987

Smoking trends and patterns in Italy were evaluated using data from the 1986-87 Italian National Health Survey, based on a sample of 30,096 males and 32,176 females aged 15 or over, randomly selected within strata of geographical areas and sizes of the place of residence and of the household in order to be representative of the whole Italian population: 40.8% of Italian males and 17.3% of females described themselves as current smokers (overall estimated prevalence, 28.6%). In comparison with previous survey-based data, self-reported smoking prevalence in males has been steadily decreasing over the last three decades, whereas rates in females have been increasing up to the early 1980s, and have shown a levelling off only in more recent years. The apparent declines in self-reported smoking, however, were not reflected in official sales figures. In fact, in the mid 1980s, there were simultaneously the lowest overall prevalence of the last three decades and the highest sales figures ever reported. The inter-sex differences in smoking prevalence were smaller at younger ages. Education, but not occupation as a measure of social class, was inversely related to smoking prevalence in males. Furthermore, rates for males were lower in the northern (and richer) part of the country. The pattern was totally different in females, since smoking prevalence was higher in more educated women, of higher social class, living in North Italy. This suggests that, in the absence of adequate measures, smoking prevalence is likely to rise among Italian women in the near future. Continued monitoring of smoking patterns gives important information with which to identify the most likely future patterns in smoking and smoking-related diseases, besides providing data for targeting intervention programs.     

Cancer in Mali, 1987-1988

Results from the population cancer registry in Bamako, Mali, for the years 1987 and 1988, are presented. The age-standardized incidence for all cancers is high compared with rates reported elsewhere in West Africa (119.6 per 10(5) in males and 88.3 per 10(5) in females), but the leading cancers in each sex are the same (liver cancer in males, cervix cancer in females). The incidence of stomach cancer is the highest recorded in Africa, while rates for lung cancer, although low, exceed those in earlier series from registries in the region.     

Metabolism and tumorigenicity of 7-, 8-, 9-, and 10-fluorobenzo(a)pyrenes

The skin tumor-initiating activities of 7-, 8-, 9-, and 10-fluorobenzo(a)pyrenes have been compared to that of benzo(a)pyrene in female Sencar mice after 16 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Single initiating doses of 200 or 400 nmol of each hydrocarbon were tested, and the mice were treated twice weekly with 3.2 nmol of the promoter. Under these conditions, benzo(a)pyrene caused an average of 2.9 and 5.7 papillomas/mouse, respectively, whereas none of the four fluorinated hydrocarbons had significant tumor-initiating activity. Examination of the hepatic metabolism of 7- and 8-fluorobenzo(a)pyrene revealed that a 7,8-dihydrodiol was not detected as a metabolite; thus, the bay-region diol-epoxide pathway known to be responsible for the tumorigenic activity of benzo(a)pyrene is blocked. Although 7,8-dihydrodiols are formed from 9- and 10-fluorobenzo(a)pyrene, these dihydrodiols with fluorine substituted on the 9,10-double bond may not be converted to diol-epoxides by the cytochrome P-450 system, or such fluorinated 7,8-diol-9,10-epoxides may not be tumorigenic.     

Cancer survival in Songkhla, Thailand, 1990-1999

The Songkhla registry, besides being hospital-based, has population-based cancer registration data available since 1990. Cancer registration is done by active methods. The registry is contributing data on survival for 36 cancer sites or types registered during 1990-1999. Follow-up has been carried out by passive and active methods with median follow-up ranging from 3-71 months for different cancers. The proportion with histologically verified diagnosis for various cancers ranged between 52-100%; death certificate only (DCO) cases comprised 0-34%; 54-93% of total registered cases were included for survival analysis. Complete followup at five years ranged from 50-85% for different cancers. Five-year age-standardized relative survival rates of common cancers were cervix (59%), lung (7%), breast (59%), thyroid (86%), oesophagus (11%), liver (2%), nonmelanoma skin (75%), colon (45%) and oral cavity (33%). Five-year relative survival by age group did not reveal any pattern or trend and was fluctuating. A majority were diagnosed with regional spread of disease, and survival decreased with increasing clinical extent of disease.     

Cancer survival in Lampang, Thailand, 1990-2000

The Lampang cancer registry was established in 1995, with retrospective data collection since 1988. Cancer registration is currently done by passive methods. The registry is contributing data on survival for 40 cancer sites or types registered during 1990-2000. Follow-up has been carried out by passive and active methods with median follow-up ranging from 1-74 months for different cancers. The proportion having a histologically verified diagnosis for various cancers ranged between 30-100%; death certificate only (DCO) cases comprised 0-33%; 67-100% of total registered cases were included for survival analysis. Complete follow-up at five years ranged from 96-100% for different cancers. The 5-year age-standardized relative survival rate was the highest for skin non-melanoma (85%) followed by lip (81%), thyroid (74%), corpus uteri (71%) and penis (71%). The 5-year relative survival by age group showed a fluctuating trend. An overwhelmingly high proportion of cases were diagnosed with a regional spread of disease, ranging from 35-68% for different cancers, and survival was decreasing with increasing extent of disease for most cancers studied.     

Cancer survival in Qidong, China, 1992-2000

The Qidong cancer registry was established in 1972, and registration of cases is done by active and passive methods. The registry contributed data on 33 cancer sites or types registered during 1992-2000 for this survival study. Data on 22 cancers registered during 1972-2000 were utilized to elicit the survival trend by period and cohort approaches. Follow-up was done by a mixture of active and passive methods, with median follow-up ranging from 2-25 months. The proportion of cases with histologically verified cancer diagnosis ranged from 9-100%, and 87-100% of total registered cases were included for survival analysis. The top-ranking cancers on 5-year age-standardized relative survival (%) were thyroid (78%), breast (58%), corpus uteri (54%), larynx (51%) and urinary bladder (42%). The corresponding survival rates for common cancers were liver (6%), lung (7%) and stomach (18%). The 5-year relative survival by age group fluctuated and showed no distinct pattern or trend. The comparison of 5-year relative survival trend by cohort and period approaches revealed that period survival closely predicted the survival experience of cancer cases diagnosed in that period for most cancers.