PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Diagnostic and prognostic role of PET/CT in patients with chronic lymphocytic leukemia and progressive disease.

In order to evaluate the predictive value of positron emission tomography-computed tomography (PET/CT) in discriminating the presence of a Richter's syndrome (RS) or a second malignancy (SM), as well as to evaluate its prognostic value in patients with chronic lymphocytic leukemia (CLL), we retrospectively analyzed the data of 90 patients who, in the suspicion of a RS or a SM, underwent PET/CT followed by the biopsy of the involved tissue. The median maximum Standardized Uptake Value (SUV max) in the presence of a CLL/small lymphocytic lymphoma, a diffuse large B-cell lymphoma (DLBCL), a Hodgkin lymphoma (HL), a SM were 3.5, 14.6, 7.0 and 6.3, respectively (P ⩽ 0.0001). A SUV max cutoff value ⩾ 5 showed a sensitivity, specificity, positive and negative predictive values of 88.2, 71.2, 51.3 and 94%, respectively, for the presence of a more aggressive disease (DLBCL, HL and SM). A SUV max ⩾ 5 identified also a subset of treatment naive patients with an inferior progression-free survival (P = 0.011) and overall survival (P = 0.067). These findings suggest that PET/CT may helpfully integrate the biologically-based prognostic stratification of CLL. Prospective clinical trials including larger cohorts of patients are needed to conclusively define the role and prognostic impact of PET/CT in the routine management of CLL patients.

Pharmacological perioperative brain neuroprotection: a qualitative review of randomized clinical trials.

Perioperative cerebral damage may be associated with surgery and anaesthesia. Pharmacological perioperative neuroprotection is associated with conflicting results. In this qualitative review of randomized controlled clinical trials on perioperative pharmacological brain neuroprotection, we report the effects of tested therapies on new postoperative neurological deficit, postoperative cognitive decline (POCD), and mortality rate. Studies were identified from Cochrane Central Register and MEDLINE and by hand-searching. Of 5904 retrieved studies, 25 randomized trials met our inclusion criteria. Tested therapies were: lidocaine, thiopental, S(+)-ketamine, propofol, nimodipine, GM1 ganglioside, lexipafant, glutamate/aspartate and xenon remacemide, atorvastatin, magnesium sulphate, erythropoietin, piracetam, rivastigmine, pegorgotein, and 17ß-estradiol. The use of atorvastatin and magnesium sulphate was associated with a lower incidence of new postoperative neurological deficit. The use of lidocaine, ketamine, and magnesium sulphate was associated with controversial results on POCD. The POCD did not differ between treated patients and control group for other tested drugs (thiopental, propofol, nimodipine, GM1 ganglioside, lexipafant, glutamate/aspartate, xenon, erythropoietin, remacemide, piracetam, rivastigmine, pegorgotein, and 17ß-estradiol). None of the tested drugs was associated with a reduction in mortality rate. Drugs with various mechanisms of action have been tested over time; current evidence suggests that pharmacological brain neuroprotection might reduce the incidence of new postoperative neurological deficits and POCD, while no benefits on perioperative mortality are described. Of importance from this review is the need for shared methodological approach when clinical studies on pharmacological neuroprotection are designed.

Different isoforms of the B-cell mutator activation-induced cytidine deaminase are aberrantly expressed in BCR-ABL1-positive acute lymphoblastic leukemia patients.

The main reason for the unfavorable clinical outcome of BCR-ABL1-positive acute lymphoblastic leukemia (ALL) is genetic instability. However, how normal B-cell precursors acquire the genetic changes that lead to transformation has not yet been completely defined. We investigated the expression of the activation-induced cytidine deaminase (AID) and its role in clinical outcome in 61 adult BCR-ABL1-positive ALL patients. AID expression was detected in 36 patients (59%); it correlated with the BCR-ABL1 transcript levels and disappeared after treatment with tyrosine kinase inhibitors. Different AID splice variants were identified: full-length isoform; AIDDeltaE4a, with a 30-bp deletion of exon 4; AIDDeltaE4, with the exon 4 deletion; AIDins3, with the retention of intron 3; AIDDeltaE3-E4 isoform without deaminase activity. AID-FL predominantly showed cytoplasmic localization, as did the AID-DeltaE4a and AID-DeltaE3E4 variants, whereas the C-terminal-truncated AID-DeltaE4 showed a slightly increased nuclear localization pattern. AID expression correlated with a higher number of copy number alterations identified in genome-wide analysis using a single-nucleotide polymorphism array. However, the expression of AID at diagnosis was not associated with a worse prognosis. In conclusion, BCR-ABL1-positive ALL cells aberrantly express different isoforms of AID that may act as mutators outside the immunoglobulin (Ig) gene loci in promoting genetic instability.

Risk index for peri-operative atrial fibrillation in patients undergoing open intracranial neurosurgical procedures.

The aim of this prospective study was to determine the prevalence of pre-operative atrial fibrillation and the incidence of postoperative atrial fibrillation in patients undergoing elective or emergency intracranial neurosurgical procedures and the relation to survival and neurological outcome at 6-months follow-up compared to patients with sinus rhythm. A total of 2020 patients were enrolled; 1540 patients underwent elective procedures and 480 underwent emergency procedures. Prevalence of pre-operative atrial fibrillation was 3.7% in elective and 7.2% in emergency procedures (p = 0.0012). In patients undergoing elective cerebral procedures with pre-operative atrial fibrillation, compared to patients with sinus rhythm, 6-month neurological outcome and survival rate are similar. In patients undergoing emergency neurosurgical cerebral procedures, the presence of pre-operative atrial fibrillation is related to an increased risk of poor neurological outcome but with similar survival rate.

Early postoperative cognitive recovery after remifentanil-propofol or sufentanil-propofol anaesthesia for supratentorial craniotomy: a randomized trial.

BACKGROUND AND OBJECTIVE: This study was designed to evaluate early postoperative cognitive recovery after total intravenous anaesthesia with remifentanil-propofol or sufentanil-propofol in patients undergoing craniotomy for supratentorial expanding lesions. METHODS: Sixty patients were consecutively enrolled, and randomly assigned to one of two study groups: remifentanil-propofol or sufentanil-propofol anaesthesia. To evaluate cognitive function the Short Orientation Memory Concentration Test (SOMCT) and Rancho Los Amigos Scale (RLAS) were administered to all patients in a double-blind procedure before surgery at 15, 45 min and 3 h after extubation. RESULTS: Mean extubation time was similar in the two groups (13 +/- 5 min vs. 19 +/- 6 min). A significantly larger number of patients in the remifentanil-propofol group than in the sufentanil-propofol group required antihypertensive medication postoperatively to maintain mean arterial pressure within 20% of baseline (18/30 vs. 4/29; P = 0.0004). Intergroup analysis showed no differences in baseline SOMCT scores (28 +/- 1 vs. 28 +/- 1) whereas mean SOMCT scores at 15, 45 min and 3 h after extubation were significantly higher in the remifentanil-propofol group (30 patients) than in the sufentanil-propofol group (29 patients) (22 +/- 3 vs. 16 +/- 3; P < 0.0001 and 27 +/- 1 vs. 22 +/- 3; P < 0.0001; 28 +/- 1 vs. 26 +/- 2; P = 0.0126). CONCLUSIONS: In conclusion, propofol-remifentanil and propofol-sufentanil are both suitable for fast-track neuroanaesthesia and provide similar intraoperative haemodynamics, awakening and extubation times. Despite a higher risk of treatable postoperative hypertension propofol-remifentanil allows earlier cognitive recovery.

Capecitabine and oxaliplatin in advanced colorectal cancer: a dose-finding study.

PURPOSE: Capecitabine and oxaliplatin are both active anticancer agents in the treatment of patients with advanced colorectal cancer (ACRC). The aim of this dose-finding trial was to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs) and the activity of the combination in patients with advanced colorectal cancer. PATIENTS AND METHODS: Twenty-five chemotherapy-pretreated patients received the combination of capecitabine and oxaliplatin. Capecitabine was administered orally twice a day continuously for 14 days in doses ranging from 1,650 to 2,500 mg/m2/d, and oxaliplatin was administered as a two-hour infusion on day 1 using dose, ranges from 100 to 130 mg/m2 repeated every three weeks. RESULTS: Twenty-five patients were assessable for toxicity, and DLTs were diarrhea (grade > or = 3: 27%) and stomatitis (grade > or = 3: 9%) at dose level VI. Dose level V (capecitabine 2500 mg/m2 and oxaliplatin 120 mg/m2) was found to be the MTD. Hematological toxicity was minimal, overall neurotoxicity (grade 1-4) was 27% with 1% grade 3-4. A global response rate was 17% (95% confidence interval (95% CI): 2%-32%) and the median overall survival was 12 months. CONCLUSION: The recommended dose for further phase II studies is capecitabine 2,500 mg/m2/d with intermittent schedule and oxaliplatin 120 mg/m2 every three weeks. The toxicities were mainly gastrointestinal: diarrhea, stomatitis and vomiting. This combination should be studied in phase II trials in advanced colorectal.

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable?

BACKGROUND: There are few clinical data on the sequential use of aromatase inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR + PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC) patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR). who had already received non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) or anastrozole (ANZ). PATIENTS AND METHODS: Twenty postmenopausal women with MBC were analysed in this retrospective two-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire population treated with FOR showed an overall CB of 55% (11 of 20) with a median duration of 15 months and median time to progression (TTP) of 6 months. CONCLUSIONS: Formestane 250 mg once bi-weekly seems to be an attractive alternative third-line hormonal therapy for the treatment of patients with MBC, previously treated with nSAI.

An error study on some linear reconstruction algorithms for electrical impedance tomography.

An error analysis on the Poisson-type linear reconstruction algorithms is performed. Three types of error are discussed and it is found that re-scaling error is dominant in most cases. It is also found that the commonly used small perturbation assumption in obtaining the Poisson's equation often fails but, due to the dominance of the re-scaling error, the reconstruction of the relative impedance distribution is still feasible by using the linear algorithms. The error analysis leads to a useful understanding of the mechanism of linear reconstruction approaches.

An integral equation approach to electrical conductance tomography.

A reconstruction procedure for electrical conductance tomography developed by solving a linear Fredholm integral equation of the first kind is discussed. The integral equation is obtained from a linearized Poisson's equations. Properties of the integral equation are discussed, and problems associated with numerical solution of the equation are treated. The reconstruction requires only one matrix multiplication and therefore can be computed in a short time. Test results of the algorithm using both simulated and measured data are presented.

Detection of lower hybrid waves within a plasma by microwave scattering.

The spatial distribution and intensity of electrostatic waves injected into a hot plasma may be inferred from the scattering of millimeter microwaves. We report measurements on the 30 degrees scattering of 8.6-mm microwaves by a 500-W, 2.45-GHz slow wave excited in a linear plasma by a phased array of two waveguides. From the magnitude of the scattered signal and auxiliary measurements with probes, we infer that a large fraction of the injected power penetrates to the center of the overdense test plasma.