Comparative evaluation by semiquantitative reverse transcriptase polymerase chain reaction of MDR1, MRP and GSTp gene expression in breast carcinomas.

Identification and quantitative evaluation of drug resistance markers are essential to assess the impact of multidrug resistance (MDR) in clinical oncology. The MDR1 gene confers pleiotropic drug resistance in tumour cells, but other molecular mechanisms are also involved in drug resistance. In particular, the clinical pattern of expression of the other MDR-related genes is unclear and their interrelationships are still unknown. Here, we report standardization of the procedures used to determine a reliable method of semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) using a standard series of drug-sensitive and increasingly resistant cell lines to evaluate the expression of three MDR-related genes, i.e. MDR1 (multidrug resistance gene 1), MRP (multidrug resistance related protein) and GSTp (glutathione-S-transferase p), reported to be endogenous standard genes for normalization of mRNAs. A total of 74 breast cancer surgical biopsies, obtained before any treatment, were evaluated by this method. When compared with classical clinical and laboratory findings, GSTp mRNA level was higher in diploid tumours. However, the main finding of our study suggests a clear relationship between two of these MDR-related gene expressions, namely GSTp and MRP. This finding provides new insight into human breast tumours, which may possibly be linked to the glutathione conjugate carrier function of MRP. Well defined semiquantitative RT-PCR procedures can therefore constitute a powerful tool to investigate MDR phenotype at mRNA levels of different related genes in small and precious tumour biopsy specimens

A Taxonomy of Explainable Bayesian Networks

Artificial Intelligence (AI), and in particular, the explainability thereof, has gained phenomenal attention over the last few years. Whilst we usually do not question the decision-making process of these systems in situations where only the outcome is of interest, we do however pay close attention when these systems are applied in areas where the decisions directly influence the lives of humans. It is especially noisy and uncertain observations close to the decision boundary which results in predictions which cannot necessarily be explained that may foster mistrust among end-users. This drew attention to AI methods for which the outcomes can be explained. Bayesian networks are probabilistic graphical models that can be used as a tool to manage uncertainty. The probabilistic framework of a Bayesian network allows for explainability in the model, reasoning and evidence. The use of these methods is mostly ad hoc and not as well organised as explainability methods in the wider AI research field. As such, we introduce a taxonomy of explainability in Bayesian networks. We extend the existing categorisation of explainability in the model, reasoning or evidence to include explanation of decisions. The explanations obtained from the explainability methods are illustrated by means of a simple medical diagnostic scenario. The taxonomy introduced in this paper has the potential not only to encourage end-users to efficiently communicate outcomes obtained, but also support their understanding of how and, more importantly, why certain predictions were made

Salvage chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) in previously treated patients with advanced gastric cancer

PURPOSE: This phase II trial first describes the combination chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) for pretreated advanced gastric cancer (AGC) patients. METHODS: Patients who had previously been treated with greater than or equal to one regimen were enrolled. They received S-1 35 mg/m(2) twice daily on days 1-14 and irinotecan 150 mg/m(2) on days 1 and 15, every 4 weeks. The primary endpoint was overall survival (OS). RESULTS: Among the 38 patients enrolled, 18 patients were treated as second line, and the remaining 20 patients were enrolled as third- or fourth line. A total of 208 cycles were administered with the median being four cycles (range 1-16). The median OS was 8.7 months [95% confidence interval (CI) 7.5-10.3], and the median progression-free survival was 6.3 months (95% CI 5.3-7.3). Low serum albumin (<3.5 mg/dL) was an independent adverse prognosticator for survival. Overall response rate was 17% (95% CI 4-30%). The major grade 3/4 toxicities were neutropenia (26%) and diarrhea (18%). CONCLUSIONS: Biweekly IRIS showed the moderate activity as salvage treatment in AGC. Considering high neutropenia and gastrointestinal toxicity, patient selection should be warranted; serum albumin may be a predictive factor for treatment decisionope

The Inviscid Limit and Boundary Layers for Navier-Stokes Flows

The validity of the vanishing viscosity limit, that is, whether solutions of the Navier-Stokes equations modeling viscous incompressible flows converge to solutions of the Euler equations modeling inviscid incompressible flows as viscosity approaches zero, is one of the most fundamental issues in mathematical fluid mechanics. The problem is classified into two categories: the case when the physical boundary is absent, and the case when the physical boundary is present and the effect of the boundary layer becomes significant. The aim of this article is to review recent progress on the mathematical analysis of this problem in each category.Comment: To appear in "Handbook of Mathematical Analysis in Mechanics of Viscous Fluids", Y. Giga and A. Novotn\'y Ed., Springer. The final publication is available at http://www.springerlink.co

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer : A low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m−2 i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m−2 i.v. followed by 5-fluorouracil 400 mg m−2 i.v. bolus and 600 mg m−2 i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m−2 i.v. bolus on day 2, every 6 weeks. Grades 3–4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1–61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials

Detection of codon 12 K- ras mutations in non-neoplastic mucosa from bronchial carina in patients with lung adenocarcinomas

K- ras activation by point mutation in codon 12 has been reported in lung adenocarcinomas in various models of experimental lung tumours induced by chemical carcinogens. The hypothesis of the presence of cells containing K- ras mutation in non neoplastic bronchial carina, the main site of impaction of airborne contaminants, was investigated by evaluating concurrent lung tumour and non-neoplastic proximal bronchial carinae from 19 patients with lung adenocarcinomas. The restriction fragment length polymorphism enriched PCR method used can detect one mutant allele among 103normal alleles. A mutation was detected in 42% of lung adenocarcinoma samples. No mutation was detected in either tumour or bronchial carinae in nine patients (47%). K- ras mutation was detected in the lung tumour but not in bronchial carinae in four patients (21%), in both the lung tumour and bronchial carinae in four other patients (21%). In two patients (11%), K- ras mutation was detected in at least one bronchial carina, but not in the lung tumour. Mutations of codon 12, confirmed by sequencing analysis of ten samples, were G to T transversion, mostly TGT and GTT in bronchial carinae and lung tumours. Our data show that activated K- ras by point mutation can be present in non-neoplastic bronchial carina mucosa even when no mutation is detected in tumour samples. © 2000 Cancer Research Campaig

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Prognostic impact of multidrug resistance gene expression on the management of breast cancer in the context of adjuvant therapy based on a series of 171 patients

Study of the prognostic impact of multidrug resistance gene expression in the management of breast cancer in the context of adjuvant therapy. This study involved 171 patients treated by surgery, adjuvant chemotherapy±radiotherapy±hormonal therapy (mean follow-up: 55 months). We studied the expression of multidrug resistance gene 1 (MDR1), multidrug resistance-associated protein (MRP1), and glutathione-S-transferase P1 (GSTP1) using a standardised, semiquantitative rt–PCR method performed on frozen samples of breast cancer tissue. Patients were classified as presenting low or high levels of expression of these three genes. rt-PCR values were correlated with T stage, N stage, Scarff–Bloom–Richardson (SBR) grade, age and hormonal status. The impact of gene expression levels on 5-year disease-free survival (DFS) and overall survival (OS) was studied by univariate and multivariate Cox analysis. No statistically significant correlation was demonstrated between MDR1, MRP1 and GSTP1 expressions. On univariate analysis, DFS was significantly decreased in a context of low GSTP1 expression (P=0.0005) and high SBR grade (P=0.003), size ⩾5 cm (P=0.038), high T stage (P=0.013), presence of intravascular embolus (P=0.034), and >3 N+ (P=0.05). On multivariate analysis, GSTP1 expression and the presence of ER remained independent prognostic factors for DFS. GSTP1 expression did not affect OS. The levels of MDR1 and MRP1 expression had no significant influence on DFS or OS. GSTP1 expression can be considered to be an independent prognostic factor for DFS in patients receiving adjuvant chemotherapy for breast cancer

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group

Background: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. Patients and methods: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m2 alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. Results: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). Conclusions: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance statu