PRL-3 overexpression in epithelial cells is induced by surrounding stromal fibroblasts

We isolate and culture carcinoma-associated fibroblasts (CAFs) from primary tumour (CAFpt), CAFs from corresponding synchronous liver metastasis (CAFlm) as well as normal colonic fibroblasts (NCF) from the same patient. From these cultures, conditioned media (CM) was obtained. Culture of a wide panel of colorectal and pancreatic cell lines in CM from CAFlm resulted in overexpression of mRNA PRL-3 and higher overexpression in CAFs than in non-activated fibroblasts. Moreover PRL-3 mRNA expression correlates with expression of α-SMA and deposition of collagen fibrils in the stroma. We demonstrate that products secreted by CAFs trigger PRL-3 overexpression in cancer cells. Identification of these factors may contribute to new stroma-targeted therapies for desmoplastic tumours.     

Process performance of cervical screening programmes in Europe

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition.Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries.These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.     

Dietary patterns and risk of cancer: A factor analysis in Uruguay

A multisite case–control study on factor analysis and several cancer sites (mouth and pharynx, esophagus, stomach, colon, rectum, larynx, lung, breast, prostate, bladder, kidney) was conducted in Uruguay. The study included 3,528 cases and 2,532 controls. Factor analysis (principal components) was modeled among controls. This patterning method retained 4 factors per sex, labeled as prudent, drinker, traditional and Western. Odds ratios for these cancer sites, stratified by sex, were estimated using polytomous regression. Whereas the prudent pattern was mainly negatively associated with cancers of the upper aerodigestive tract, the Western pattern showed a strong increase in breast, lung and colon cancers. The study allowed for the reproducibility of the prudent, drinker and Western patterns, whereas the traditional pattern appears to be country specific. © 2008 Wiley‐Liss, Inc.     

Glucose avidity of carcinomas

The cancer cell phenotype has been summarized in six hallmarks [D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (1) (2000) 57-70]. Following the conceptual trait established in that review towards the comprehension of cancer, herein we summarize the basis of an underlying principle that is fulfilled by cancer cells and tumors: its avidity for glucose. Our purpose is to push forward that the metabolic reprogramming that operates in the cancer cell represents a seventh hallmark of the phenotype that offers a vast array of possibilities for the future treatment of the disease. We summarize the metabolic pathways that extract matter and energy from glucose, paying special attention to the concerted regulation of these pathways by the ATP mass-action ratio. The molecular and functional evidences that support the high glucose uptake and the "abnormal" aerobic glycolysis of the carcinomas are detailed discussing also the role that some oncogenes and tumor suppressors have in these pathways. We overview past and present evidences that sustain that mitochondria of the cancer cell are impaired, supporting the original Warburg's formulation that ascribed the high glucose uptake of cancer cells to a defective mitochondria. A simple proteomic approach designed to assess the metabolic phenotype of cancer, i.e., its bioenergetic signature, molecularly and functionally supports Warburg's hypothesis. Furthermore, we discuss the clinical utility that the bioenergetic signature might provide. Glycolysis is presented as the "selfish" pathway used for cellular proliferation, providing both the metabolic precursors and the energy required for biosynthetic purposes, in the context of a plethora of substrates. The glucose avidity of carcinomas is thus presented as the result of both the installment of glycolysis for cellular proliferation and of the impairment of mitochondrial activity in the cancer cell. At the end, the repression of mitochondrial activity affords the cancer cell with a cell-death resistant phenotype making them prone to malignant growth.     

Do women ?50 years of age need as much screening as women <50 years after they have had negative screening results?

To assess the adequacy of a routine screening to identify cervical intraepithelial neoplasia 2 or worse (CIN2+) in women over 50 years of age, a retrospective cohort was set in six Italian organised population-based screening programmes. In all, 287 330 women (1 714 550 person-years of observation, 1110 cases) screened at age 25-64, with at least two cytological screening tests, the first negative, were followed from their first negative smear until a biopsy proven CIN2+ lesion or their last negative smear. For women aged 25-49 and 50-64 years, crude and age-standardised detection rate (DR), cumulative risk (CR), adjusted hazard risk for number of previous negative screens, probability of false-positive CIN2+ after two or more smear tests were calculated. Detection rate is significantly lower over 50 years of age. Multivariable analysis shows a significant protective effect from four screening episodes (DR=0.70, 95% CI: 0.51-0.97); the effect of age >or=50 is 0.29 (95% CI: 0.24-0.35). The CR of CIN2+ is at least eightfold higher in women <50 (CR=2.06, 95% CI: 1.88-2.23) after one previous negative test than in women >or=50 years with four screens (CR=0.23, 95% CI: 0.00-0.46). Over 50 years of age, after four tests at least three false-positive cases are diagnosed for every true positive. Benefits arising from cytological screening is uncertain in well-screened older women.     

A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma

BACKGROUND: The use of adjuvant chemotherapy to treat adults with localized resectable soft-tissue sarcoma remains controversial. The objective of this systematic review was to update the 1997 meta-analysis of randomized controlled trials (RCTs) to reassess the efficacy of doxorubicin-based chemotherapy with respect to recurrence and survival. METHODS: A comprehensive literature search was performed to identify RCTs of adjuvant chemotherapy for adult patients diagnosed with localized resectable soft-tissue sarcoma. Two reviewers independently assessed eligibility and quality of the studies using a modified version of the Detsky Quality Scale. The outcome measures were local, distant, and overall recurrence and survival calculated through the fixed effect or random effect model. RESULTS: Four new eligible trials were identified allowing for a total of 18 trials representing 1953 patients to be included in the analysis. The odds ratios (OR) for local recurrence was 0.73 (95% confidence interval [CI] 0.56-0.94; P = .02) in favor of chemotherapy. For distant and overall recurrence the OR was 0.67 (95% CI 0.56-0.82; P = .0001) in favor of chemotherapy. In terms of survival, doxorubicin alone had an OR of 0.84 (95% CI, 0.68-1.03; P = .09), which as not statistically significant. However, the OR for doxorubicin combined with ifosfamide was 0.56 (95% CI, 0.36-0.85; P = .01) in favor of chemotherapy. CONCLUSIONS: This updated meta-analysis confirms the marginal efficacy of chemotherapy in localized resectable soft-tissue sarcoma with respect to local recurrence, distant recurrence, overall recurrence, and overall survival. These benefits are further improved with the addition of ifosfamide to doxorubicin-based regimens, but must be weighed against associated toxicities.