Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: A European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.

PURPOSE: To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma. PATIENTS AND METHODS: This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently. RESULTS: Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia. CONCLUSION: Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.

Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease.

BACKGROUND AND OBJECTIVES The elective treatment of patients with post-transplant lymphoproliferative disorders is controversial. The purpose of this trial was to evaluate the efficacy of treatment with extended doses of rituximab adapted to the response in patients with post-transplant lymphoproliferative disorders after solid organ transplantation. DESIGN AND METHODS This was a prospective, multicenter, phase II trial. Patients were treated with reduction of immunosuppression and four weekly infusions of rituximab. Those patients who did not achieve complete remission (CR) received a second course of four rituximab infusions. The primary end-point of the study was the CR rate. RESULTS Thirty-eight patients were assesable. One episode of grade 4 neutropenia was the only severe adverse event observed. After the first course of rituximab, 13 (34.2%) patients achieved CR, 8 patients did not respond, and 17 patients achieved partial remission. Among those 17 patients, 12 could be treated with a second course of rituximab, and 10 (83.3%) achieved CR, yielding an intention-to-treat CR rate of 60.5%. Eight patients excluded from the trial because of absence of CR were treated with rituximab combined with chemotherapy, and six (75%) achieved CR. Event-free survival was 42% and overall survival was 47% at 27.5 months. Fourteen patients died, ten of progression of their post-transplant lymphoproliferative disorder. INTERPRETATION AND CONCLUSIONS These results confirm that extended treatment with rituximab can obtain a high rate of CR in patients with post-transplant lymphoproliferative disorders after solid organ transplantation without increasing toxicity, and should be recommended as initial therapy for these patients.

The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.

Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.

Critical thinking and accuracy of nurses' diagnoses. Part II: application of cognitive skills and guidelines for self-development

Part I of this article, the author explained the difficulties of achieving accuracy of nurses' diagnoses, the relevance of critical thinking to the achievement of accuracy, and newer views of critical thinking. In Part II, the critical thinking dimensions identified as important for nursing practice are applied in the diagnostic process using a case study of a 16 year old girl with type 1 diabetes. Application of seven cognitive skills and ten habits of mind illustrate the importance of using critical thinking for accuracy of nurses' diagnoses. Ten strategies are proposed for self-development of critical thinking abilities.

Forensic intelligence framework. Part II: study of the main generic building blocks and challenges through the examples of illicit drugs and false identity documents monitoring

The development of forensic intelligence relies on the expression of suitable models that better represent the contribution of forensic intelligence in relation to the criminal justice system, policing and security. Such models assist in comparing and evaluating methods and new technologies, provide transparency and foster the development of new applications. Interestingly, strong similarities between two separate projects focusing on specific forensic science areas were recently observed. These observations have led to the induction of a general model (Part I) that could guide the use of any forensic science case data in an intelligence perspective. The present article builds upon this general approach by focusing on decisional and organisational issues. The article investigates the comparison process and evaluation system that lay at the heart of the forensic intelligence framework, advocating scientific decision criteria and a structured but flexible and dynamic architecture. These building blocks are crucial and clearly lay within the expertise of forensic scientists. However, it is only part of the problem. Forensic intelligence includes other blocks with their respective interactions, decision points and tensions (e.g. regarding how to guide detection and how to integrate forensic information with other information). Formalising these blocks identifies many questions and potential answers. Addressing these questions is essential for the progress of the discipline. Such a process requires clarifying the role and place of the forensic scientist within the whole process and their relationship to other stakeholders.

Appropriateness of colonoscopy in Europe (EPAGE II): presentation of methodology, general results, and analysis of complications.

BACKGROUND AND STUDY AIMS: Appropriate use of colonoscopy is a key component of quality management in gastrointestinal endoscopy. In an update of a 1998 publication, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE II) defined appropriateness criteria for various colonoscopy indications. This introductory paper therefore deals with methodology, general appropriateness, and a review of colonoscopy complications. METHODS:The RAND/UCLA Appropriateness Method was used to evaluate the appropriateness of various diagnostic colonoscopy indications, with 14 multidisciplinary experts using a scale from 1 (extremely inappropriate) to 9 (extremely appropriate). Evidence reported in a comprehensive updated literature review was used for these decisions. Consolidation of the ratings into three appropriateness categories (appropriate, uncertain, inappropriate) was based on the median and the heterogeneity of the votes. The experts then met to discuss areas of disagreement in the light of existing evidence, followed by a second rating round, with a subsequent third voting round on necessity criteria, using much more stringent criteria (i. e. colonoscopy is deemed mandatory). RESULTS: Overall, 463 indications were rated, with 55 %, 16 % and 29 % of them being judged appropriate, uncertain and inappropriate, respectively. Perforation and hemorrhage rates, as reported in 39 studies, were in general < 0.1 % and < 0.3 %, respectively CONCLUSIONS: The updated EPAGE II criteria constitute an aid to clinical decision-making but should in no way replace individual judgment. Detailed panel results are freely available on the internet (www.epage.ch) and will thus constitute a reference source of information for clinicians.

[Archives de la Parole]. , The daughter of the king of flowers : a fable in Kodaku from Surguja (C.P.) [i.e. Central Provinces] / [Sir George Grierson], éd. ; Linguistic survey of India ; [Jūthan Koḍākū], voix

[Traditions. Asie. Inde. Madhya Pradesh. Chhattisgarh]

Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study.

PURPOSE: To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas. PATIENTS: AND METHODS: This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment. RESULTS: A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor-A or -B were found. CONCLUSION: In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2- positive breast cancer-EORTC 10054 trial.

Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines.

Variability of apparently homogeneous soilscapes in São Paulo state, Brazil: II. quality of soil maps

The quality of semi-detailed (scale 1:100.000) soil maps and the utility of a taxonomically based legend were assessed by studying 33 apparently homogeneous fields with strongly weathered soils in two regions in São Paulo State: Araras and Assis. An independent data set of 395 auger sites was used to determine purity of soil mapping units and analysis of variance within and between mapping units and soil classification units. Twenty three soil profiles were studied in detail. The studied soil maps have a high purity for some legend criteria, such as B horizon type (> 90%) and soil texture class (> 80%). The purity for the "trophic character" (eutrophic, dystrophic, allic) was only 55% in Assis. It was 88% in Araras, where many soil units had been mapped as associations. In both regions, the base status of clay-textured soils was generally better than suggested by the maps. Analysis of variance showed that mapping was successful for "durable" soil characteristics such as clay content (> 80% of variance explained) and cation exchange capacity (≥ 50% of variance explained) of 0-20 and 60-80 cm layers. For soil characteristics that are easily modified by management, such as base saturation of the 0-20 cm layer, the maps had explained very little (< 15%) of the total variance in the study areas. Intermediate results were obtained for base saturation of the 60-80 cm layer (56% in Assis; 42% in Araras). Variance explained by taxonomic groupings that formed the basis for the legend of the soil maps was similar to, often even smaller than, variance explained by mapping units. The conclusion is that map boundaries have been very carefully located, but descriptions of mapping units could be improved. In future mappings, this could possibly be done at low cost by (a) bulk sampling to remove short range variation and enhance visualization of spatial patterns at distances > 100 m; (b) taking advantage of correlations between easily measured soil characteristics and chemical soil properties and, (c) unbending the link between legend criteria and a taxonomic system. The maps are well suited to obtain an impression of land suitability for high-input farming. Additional field work and data on former land use/management are necessary for the evaluation of chemical properties of surface horizons.

Three-dimensional aspects of fluid flows in channels. II. Effects of meniscus and thin film regimes on viscous fingers

We perform a three-dimensional study of steady state viscous fingers that develop in linear channels. By means of a three-dimensional lattice-Boltzmann scheme that mimics the full macroscopic equations of motion of the fluid momentum and order parameter, we study the effect of the thickness of the channel in two cases. First, for total displacement of the fluids in the channel thickness direction, we find that the steady state finger is effectively two-dimensional and that previous two-dimensional results can be recovered by taking into account the effect of a curved meniscus across the channel thickness as a contribution to surface stresses. Second, when a thin film develops in the channel thickness direction, the finger narrows with increasing channel aspect ratio in agreement with experimental results. The effect of the thin film renders the problem three-dimensional and results deviate from the two-dimensional prediction.