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.

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.

Optical crop sensor for variable-rate nitrogen fertilization in corn: II - indices of fertilizer efficiency and corn yield

Generally, in tropical and subtropical agroecosystems, the efficiency of nitrogen (N) fertilization is low, inducing a temporal variability of crop yield, economic losses, and environmental impacts. Variable-rate N fertilization (VRF), based on optical spectrometry crop sensors, could increase the N use efficiency (NUE). The objective of this study was to evaluate the corn grain yield and N fertilization efficiency under VRF determined by an optical sensor in comparison to the traditional single-application N fertilization (TSF). With this purpose, three experiments with no-tillage corn were carried out in the 2008/09 and 2010/11 growing seasons on a Hapludox in South Brazil, in a completely randomized design, at three different sites that were analyzed separately. The following crop properties were evaluated: aboveground dry matter production and quantity of N uptake at corn flowering, grain yield, and vegetation index determined by an N-Sensor® ALS optical sensor. Across the sites, the corn N fertilizer had a positive effect on corn N uptake, resulting in increased corn dry matter and grain yield. However, N fertilization induced lower increases of corn grain yield at site 2, where there was a severe drought during the growing period. The VRF defined by the optical crop sensor increased the apparent N recovery (NRE) and agronomic efficiency of N (NAE) compared to the traditional fertilizer strategy. In the average of sites 1 and 3, which were not affected by drought, VRF promoted an increase of 28.0 and 41.3 % in NAE and NRE, respectively. Despite these results, no increases in corn grain yield were observed by the use of VRF compared to TSF.

EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma.

The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents.

Multicenter phase II trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer (NSCLC): SAKK protocol 19/03.

BACKGROUND: Gefitinib is active in patients with pretreated non-small-cell lung cancer (NSCLC). We evaluated the activity and toxicity of gefitinib first-line treatment in advanced NSCLC followed by chemotherapy at disease progression. PATIENTS AND METHODS: In all, 63 patients with chemotherapy-naive stage IIIB/IV NSCLC received gefitinib 250 mg/day. At disease progression, gefitinib was replaced by cisplatin 80 mg/m(2) on day 1 and gemcitabine 1250 mg/m(2) on days 1, 8 for up to six 3-week cycles. Primary end point was the disease stabilization rate (DSR) after 12 weeks of gefitinib. RESULTS: After 12 weeks of gefitinib, the DSR was 24% and the response rate (RR) was 8%. Median time to progression (TtP) was 2.5 months and median overall survival (OS) 11.5 months. Never smokers (n = 9) had a DSR of 56% and a median OS of 20.2 months; patients with epidermal growth factor receptor (EGFR) mutation (n = 4) had a DSR of 75% and the median OS was not reached after the follow-up of 21.6 months. In all, 41 patients received chemotherapy with an overall RR of 34%, DSR of 71% and median TtP of 6.7 months. CONCLUSIONS: First-line gefitinib monotherapy led to a DSR of 24% at 12 weeks in an unselected patients population. Never smokers and patients with EGFR mutations tend to have a better outcome; hence, further trials in selected patients are warranted.

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.

Indicators of therapeutic effect in FIT-06, a Phase II trial of a DNA vaccine, GTU(®)-Multi-HIVB, in untreated HIV-1 infected subjects.

BACKGROUND: Combination highly active antiretroviral therapy (HAART) has significantly decreased HIV-1 related morbidity and mortality globally transforming HIV into a controllable condition. HAART has a number of limitations though, including limited access in resource constrained countries, which have driven the search for simpler, affordable HIV-1 treatment modalities. Therapeutic HIV-1 vaccines aim to provide immunological support to slow disease progression and decrease transmission. We evaluated the safety, immunogenicity and clinical effect of a novel recombinant plasmid DNA therapeutic HIV-1 vaccine, GTU(®)-multi-HIVB, containing 6 different genes derived from an HIV-1 subtype B isolate. METHODS: 63 untreated, healthy, HIV-1 infected, adults between 18 and 40 years were enrolled in a single-blinded, placebo-controlled Phase II trial in South Africa. Subjects were HIV-1 subtype C infected, had never received antiretrovirals, with CD4 ≥ 350 cells/mm(3) and pHIV-RNA ≥ 50 copies/mL at screening. Subjects were allocated to vaccine or placebo groups in a 2:1 ratio either administered intradermally (ID) (0.5mg/dose) or intramuscularly (IM) (1mg/dose) at 0, 4 and 12 weeks boosted at 76 and 80 weeks with 1mg/dose (ID) and 2mg/dose (IM), respectively. Safety was assessed by adverse event monitoring and immunogenicity by HIV-1-specific CD4+ and CD8+ T-cells using intracellular cytokine staining (ICS), pHIV-RNA and CD4 counts. RESULTS: Vaccine was safe and well tolerated with no vaccine related serious adverse events. Significant declines in log pHIV-RNA (p=0.012) and increases in CD4+ T cell counts (p=0.066) were observed in the vaccine group compared to placebo, more pronounced after IM administration and in some HLA haplotypes (B*5703) maintained for 17 months after the final immunisation. CONCLUSIONS: The GTU(®)-multi-HIVB plasmid recombinant DNA therapeutic HIV-1 vaccine is safe, well tolerated and favourably affects pHIV-RNA and CD4 counts in untreated HIV-1 infected individuals after IM administration in subjects with HLA B*57, B*8101 and B*5801 haplotypes.

Solid-phase synthesis and DNA binding studies of dichloroplatinum(II) conjugates of dicarba analogues of octreotide as a new anticancer drugs

The first dichloroplatinum(II) conjugates of dicarba analogues of octreotide , which is expected to act as a"tumour-targeting device", have been efficiently synthesized following a stepwise solid-phase approach; these compounds emulate the mechanism of cisplatin since they form a 1,2-intrastrand cross-link with two consecutive guanines of an oligonucleotide.

Phase II study of imatinib in advanced chordoma.

PURPOSE: To explore the antitumor activity of imatinib in patients with advanced platelet-derived growth factor β (PDGFB)/PDGF receptor β (PDGFRB)-positive chordomas.¦PATIENTS AND METHODS: In a collaborative Italian-Swiss, prospective, phase II clinical study conducted from November 2004 through April 2006, 56 patients with advanced PDGFB and/or PDGFRB chordoma received 800 mg/d of imatinib until progression. The primary end point was the overall tumor response rate (ORR), defined by RECIST. Secondary, exploratory end points included tissue response (ie, changes in tumor density or signal intensity/contrast enhancement, and/or [18F]-fluorodeoxyglucose positron emission tomography [PET] uptake), overall survival, progression-free survival (PFS), and pain score.¦RESULTS: Among 50 patients evaluable by RECIST, the best response was one partial response (PR) obtained at 6 months (ORR, 2%). There were 35 patients with stable disease (SD, 70%) and a 64% clinical benefit rate (ie, RECIST complete response + PR + SD ≥ 6 months). A minor dimensional response (< 20%) was detected in nine patients. A maximum standard uptake value decrease ≥ 25% was observed in 10 (39%) of 26 patients evaluable for PET response at 3 months. Changes in the Brief Pain Inventory score were consistent with the response assessment. Median PFS (intention-to-treat population, 56 patients) was 9 months. No unexpected toxicities were observed.¦CONCLUSION: This is the largest phase II study in chordoma to date. It confirms anecdotal evidence that imatinib has antitumor activity in this orphan disease, and therefore, it is worth further investigation.

An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients.

OBJECTIVES: Caspofungin was evaluated as first-line monotherapy of invasive aspergillosis (IA) in patients with haematological malignancies and undergoing autologous transplants. METHODS: Adults with proven or probable IA, defined strictly according to EORTC-MSG criteria, were eligible. Those with possible IA were enrolled, but were not evaluable for efficacy unless upgraded to proven/probable disease within 7 days of registration based on investigations performed within 48 h after enrolment. Caspofungin dosage was 70 mg (day 1) followed by 50 mg/day. The primary endpoint was the proportion of patients with complete or partial response at the end of caspofungin therapy in the modified intention to treat (MITT) group; secondary endpoints were response and survival at day 84 and safety. RESULTS: In the MITT group (n = 61), 75% of patients had cancer not in remission (relapsing or refractory), 85% were neutropenic at enrolment and 49% had a Karnofsky score of < or =50. At end of treatment, 1 and 19 patients had complete and partial response, respectively [success rate 33% (20/61)], 9 (15%) achieved stabilization and 31 (51%) had disease progression. One patient was not evaluable. The 6 and 12 week survival rates were 66% (40/61) and 53% (32/60), respectively. Baseline characteristics associated with survival at day 84 were an underlying disease in remission (not relapsing or refractory) and Karnofsky score. Recovery from neutropenia at the end of treatment was also significantly associated with survival. No serious drug-related adverse events or discontinuations due to drug-related adverse events were observed. CONCLUSIONS: Caspofungin provided an observed response rate compatible with the null hypothesis of a true response rate of < or =35%. Underlying disease-related factors had a major impact on results.