The combined use of VIGl@ct (R) (bioMerieux) and fluorescent amplified length fragment polymorphisms in the investigation of potential outbreaks

Even with good surveillance programmes, hospital-acquired infections (HAls) are not always recognized and this may lead to an outbreak. In order to reduce this risk, we propose a model for prompt detection of HAls, based on the use of a real-time epidemiological information system called VIGI@ct (R) (bioMerieux, Las Balmas, France) and on the rapid confirmation or exclusion of the genetic relationship among pathogens using fluorescent amplified length fragment polymorphism (f-AFLP) microbial fingerprinting. We present the results of one year's experience with the system, which identified a total, of 306 suspicious HAls. Of these, 281 (92%) were 'confirmed' by clinical evidence, 16 (5%) were considered to be simple colonization and the tatter nine (3%) were archived as 'not answered' because of the absence of the physician's cooperation. There were seven suspected outbreaks; of these, f-AFLP analysis confirmed the clonal relationship among the isolates in four cases: outbreak 1 (four isolates of Pseudomonas aeruginosa), outbreak 2 (three Escherichia coli isolates), outbreak 6 (two Candida parapsilosis isolates) and outbreak 7 (30 ESPL-producing Klebsiella pneumoniae subsp. pneumoniae). Based on our results, we conclude that the combination of VIGI@ct (R) and f-AFLP is useful in the rapid assessment of an outbreak due to Gram-positive or Gramnegative bacteria and yeasts. (C) 2007 The Hospital Infection Society. Published by Elsevier Ltd. All rights reserved

YAP activation is an early event and a potential therapeutic target in liver cancer development

Background and Aims: Although the growth suppressor Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in early rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. Methods: The experimental model used is the Resistant-Hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. Results All foci of preneoplastic hepatocytes generated in rats 4 weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the β-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by up-regulation of its target genes. Increased YAP expression was also observed in early dysplastic nodules and adenomas in humans. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP–TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. Conclusions: These results suggest that i) YAP overexpression is an early event in rat and human liver tumorigenesis; ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and, iii) VP-induced disruption of YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers

5-fluorouracil modulated by leucovorin, methotrexate and mitomycin: highly effective, low-cost chemotherapy for advanced colorectal cancer

We have reported that an alternating regimen of bolus and continuous infusion 5-fluorouracil (FU) was superior to bolus FU in terms of response rate and progression-free survival in advanced colorectal cancer. Biochemical modulation was an essential part of this regimen and it was selective for the schedule of FU administration: bolus FU was in fact modulated by methotrexate (MTX) while continuous infusion FU was potentiated by 6-s-leucovorin (LV). Considering the low cost and the favourable report on the activity of mitomycin C (mito) added to CI FU, we have incorporated this agent in the infusional part of our treatment programme. 105 patients with untreated, advanced, measurable colorectal cancer were accrued from 13 Italian centres and treated with the following regimen. 2 biweekly cycles of FU bolus (600 mg/m2), modulated by MTX (24 h earlier, 200 mg/m2) were alternated with a 3-week continuous infusion of FU (200 mg/m2daily), modulated by LV (20 mg/m2weekly bolus). Mito, 7 mg/m2, was given on the first day of the infusional period. After a 1 week rest, the whole cycle (8 weeks) was repeated, if indicated. 5 complete and 34 partial responses were obtained (response rate, 37% on the intention to treat basis; 95% confidence limits, 28–46%). After a median follow-up time of 26 months, 37 patients are still alive. The median progression-free survival is 7.7 months with an overall survival of 18.8 months and a 2-year survival rate of 30%. The regimen was very well tolerated with fewer than 13% of patients experiencing WHO grade III–IV toxicity. These results are consistent with those obtained by our group in 3 previous trials of schedule specific biochemical modulation of FU. They also indicate a highly active, little toxic, inexpensive regimen of old drugs to be used (a) as an alternative to the more expensive combinations including CPT-11 or oxaliplatin or (b) as the basis for combination programmes with these agents. © 2001 Cancer Research Campaign http://www.bjcancer.co

HER2 expression and efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients

No data are available on the role of HER2 overexpression in predicting the efficacy of dose-dense anthracycline-containing adjuvant chemotherapy in breast cancer patients. We retrospectively evaluated this role in patients enrolled in a phase III study comparing standard FEC21 (5-fluorouracil, epirubicin, and cyclophosphamide, administered every 3 weeks) vs dose-dense FEC14 (the same regimen repeated every 2 weeks). HER2 status was determined for 731 of 1214 patients. Statistical analyses were performed to test for interaction between treatment and HER2 status with respect to event-free survival (EFS) and overall survival (OS); EFS and OS were compared within each HER2 subgroup and within each treatment arm. Median follow-up was 6.7 years. Among FEC21-treated patients, both EFS (HR=2.07; 95% CI 1.27–3.38) and OS (HR=2.47; 95% CI 1.34–4.57) were significantly worse in HER2 + patients than in HER2 − patients. Among FEC14-treated patients, differences in either EFS (HR=1.21; 95% CI 0.65–2.24) or OS (HR=1.85; 95% CI 0.88–3.89) between HER2 + and HER2 − patients were not statistically significant. Interaction analysis suggested that the use of dose-dense FEC14 might remove the negative prognostic effect of HER2 overexpression on EFS and OS. Our data suggest a potential role of HER-2 overexpression in predicting the efficacy of dose-dense epirubicin-containing chemotherapy and the need to confirm this hypothesis in future prospective studies

Acinetobacter baumannii in intensive care unit: A novel system to study clonal relationship among the isolates

<p>Abstract</p> <p>Background</p> <p>The nosocomial infections surveillance system must be strongly effective especially in highly critic areas, such as Intensive Care Units (ICU). These areas are frequently an epidemiological epicentre for transmission of multi-resistant pathogens, like <it>Acinetobacter baumannii</it>. As an epidemic outbreak occurs it is very important to confirm or exclude the genetic relationship among the isolates in a short time. There are several molecular typing systems used with this aim. The Repetitive sequence-based PCR (REP-PCR) has been recognized as an effective method and it was recently adapted to an automated format known as the DiversiLab system.</p> <p>Methods</p> <p>In the present study we have evaluated the combination of a newly introduced software package for the control of hospital infection (VIGI@ct) with the DiversiLab system. In order to evaluate the reliability of the DiversiLab its results were also compared with those obtained using f-AFLP.</p> <p>Results</p> <p>The combination of VIGI@ct and DiversiLab enabled an earlier identification of an <it>A. baumannii </it>epidemic cluster, through the confirmation of the genetic relationship among the isolates. This cluster regards 56 multi-drug-resistant <it>A. baumannii </it>isolates from several specimens collected from 13 different patients admitted to the ICU in a ten month period. The <it>A. baumannii </it>isolates were clonally related being their similarity included between 97 and 100%. The results of the DiversiLab were confirmed by f-AFLP analysis.</p> <p>Conclusion</p> <p>The early identification of the outbreak has led to the prompt application of operative procedures and precautions to avoid the spread of pathogen. To date, 6 months after the last <it>A. baumannii </it>isolate, no other related case has been identified.</p

Effect of lactitol and lactulose administration on the fecal flora in cirrhotic patients.

We compared the effect of lactulose or lactitol on the fecal flora of 21 cirrhotic patients without hepatic encephalopathy. All were treated with an individualized disaccharide dose to achieve and maintain two semiliquid bowel movements per day. Stool pH and fecal flora were determined before and 10 days after stabilizing the cathartic effect. Increased counts of lactobacilli were obtained with both treatments. This increase, which was related to the decreased stool pH, was more constant with lactulose. In addition, lactitol decreased certain proteolytic bacteria such as enterococci and enterobacteria. Both total aerobic and anaerobic bacterial counts showed little quantitative variations with either treatment

Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

Background. To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. Methods: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. Results: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P =.008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P =.01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P<.001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P<.001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P<.001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P<.001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. Conclusion: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy