Combined effects of PI3K and SRC kinase inhibitors with imatinib on intracellular calcium levels, autophagy, and apoptosis in CML-PBL cells

Imatinib induces a complete cytogenetic regression in a large percentage of patients affected by chronic myeloid leukemia (CML) until mutations in the kinase domain of BCR-ABL appear. Alternative strategies for CML patients include the inhibition of phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR ) pathway, which is constitutively activated in leukemia cells and seems important for the regulation of cell proliferation, viability, and autophagy. In this study, we verified the effect of imatinib mesylate (IM), alone or in association with LY294002 (LY) (a specific PI3K protein tyrosine kinase inhibitor) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]- pyrimidine (PP1) (a Src tyrosine kinase inhibitor), on viability, intracellular calcium mobilization, apoptosis, and autophagy, in order to verify possible mechanisms of interaction. Our data demonstrated that PP1 and LY interact synergistically with IM by inducing apoptosis and autophagy in Bcr/Abl+ leukemia cells and this mechanism is related to the stress of the endoplasmic reticulum (ER ). Our findings suggest a reasonable relationship between apoptotic and autophagic activity of tyrosine kinase inhibitors (TKIs) and the functionality of smooth ER Ca2+-AT Pase and inositol triphosphate receptors, independently of intracellular calcium levels. Therapeutic strategies combining imatinib with PI3K and/or Src kinase inhibitors warrant further investigations in Bcr/Abl+ malignancies, particularly in the cases of imatinib mesylate-resistant diseas

Simultaneous in-field boost for patients with 1 to 4 brain metastasis/es treated with volumetric modulated arc therapy: a prospective study on quality-of-life

<p>Abstract</p> <p>Purpose</p> <p>To assess treatment toxicity and patients' survival/quality of life (QoL) after volumetric modulated arc therapy (VMAT) with simultaneous in-field boost (SIB) for cancer patients with 1 - 4 brain metastases (BM) treated with or without surgery.</p> <p>Methods and Materials</p> <p>Between March and December 2010, 29 BM patients (total volume BM, < 40 cm³) aged < 80 years, KPS ≥ 70, RPA < III were included in this prospective trial. Whole brain VMAT (30 Gy) and a SIB to the BM (40 Gy) was delivered in 10 fraction. Mean age was 62.1 ± 8.5 years. Fifteen (51.7%) underwent surgery. KPS and MMSE were prospectively assessed. A self-assessed questionnaire was used to assess the QoL (EORTC QLQ-C30 with -BN20 module).</p> <p>Results</p> <p>As of April 2011 and after a mean FU of 5.4 ± 2.8 months, 14 (48.3%) patients died. The 6-month overall survival was 55.1%. Alopecia was only observed in 9 (31%) patients. In 3-month survivors, KPS was significantly (<it>p </it>= 0.01) decreased. MMSE score remained however stable (<it>p </it>= 0.33). Overall, QoL did decrease after VMAT. The mean QLQ-C30 global health status (<it>p </it>= 0.72) and emotional functional (<it>p </it>= 0.91) scores were decreased (low QoL). Physical (<it>p </it>= 0.05) and role functioning score (<it>p </it>= 0.01) were significantly worse and rapidly decreased during treatment. The majority of BN20 domains and single items worsened 3 months after VMAT except headaches (<it>p </it>= 0.046) and bladder control (<it>p </it>= 0.26) which improved.</p> <p>Conclusions</p> <p>The delivery of 40 Gy in 10 fractions to 1 - 4 BM using VMAT was achieved with no significant toxicity. QoL, performance status, but not MMSE, was however compromised 3 months after treatment in this selected cohort of BM patients.</p

Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe†‡

OBJECTIVES To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. RESULTS The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approache

Myocardial damage influences short- and mid-term survival after valve surgery: A prospective multicenter study.

Objective Myocardial damage occurs after valve surgery, but its prognostic implication has not been evaluated. The aim of the present study was to assess the influence of myocardial damage on mortality and morbidity in patients undergoing aortic surgery (AVS) and mitral valve surgery (MVS).Methods In a prospective multicenter study from the cardiac surgery registry of the Puglia region, cardiac troponin I (cTnI) was measured immediately after and the morning after the intervention in consecutive patients undergoing AVS or MVS. The percentile ranks of the cTnI peak values within each center were analyzed.Results Of 965 patients (age, 67 ± 12 years; 45.5% women), 579 had undergone AVS and 386 MVS. cTnI release was significantly greater in the MVS group than in the AVS group and in the nonsurvivors than in the survivors in both groups. The cTnI cutoff with the greatest sensitivity and specificity (60th percentile for AVS and 91st for MVS) in predicting hospital mortality (2.6%) was also associated with a greater rate of postoperative complications and mortality within 3 months postoperatively (multivariate hazard ratio, 3.38; P =.005). Compared with the reference model, which included the multivariate predictors of hospital mortality (active endocarditis, New York Heart Association class III-IV, left ventricular ejection fraction 30%, and cardiopulmonary bypass duration), the addition of cTnI greater than the cutoffs showed significant improvement in model performance (likelihood ratio test, P =.009; net reclassification improvement, 0.751; P &lt; integrated discrimination improvement, 0.048; P =.002; c-index 0.832 vs 0.838).Conclusions An elevated postoperative cTnI level was an independent risk factor for mortality and morbidity. Measurement of the cTnI level improved the risk reclassification of patients undergoing AVS or MVS

Results of Dose-adapted Salvage Radiotherapy After Radical Prostatectomy Based on an Endorectal MRI Target Definition Model

To assess the outcome of patients treated with a dose-adapted salvage radiotherapy (SRT) protocol based on an endorectal magnetic resonance imaging (erMRI) failure definition model after radical prostatectomy (RP)

Incremental value of anemia in cardiac surgical risk prediction with the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II model.

Background. Anemia is a risk factor for adverse events after cardiac operations. We evaluated the incremental value of preoperative anemia over the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II to predict hospital death after cardiac operations. Methods. Data for 4,594 consecutive adults (1,548 women [33.7%]), aged 67 ± 11 years, who underwent cardiac operations from January 2011 to July 2013 were extracted from the Regional Cardiac Surgery Registry of Puglia. The last preoperative hemoglobin value was used, according to World Health Organization criteria, to classify anemia as mild (hemoglobin 11.0 to 12.9 g/dL in men and 11.0 to 11.9 g/dL in women) in 1,021 patients (22.2%) and as moderate to severe (hemoglobin <11.0 g/dL) in 593 patients (12.9%). The EuroSCORE II was used to evaluate predicted hospital death after operations. Logistic regression analysis for in-hospital death was performed including EuroSCORE II risk factors and anemia, with model discrimination quantified by C statistic and risk classification by the use of net reclassification improvement (NRI). Results. Overall expected and observed mortality rates were 4.4% and 5.9%. Anemia was significantly associated with a mortality rate of 3.4% in patients without anemia, 7.7% in mild anemia, and 15.7% in moderate to severe anemia (p < 0.001) and also at multivariate analysis correcting for EuroSCORE II (p < 0.001). When anemia was analyzed with EuroSCORE II, the model improved in discrimination (C statistic = 0.852 vs 0.860; p = 0.007) and reclassification (category free-NRI, 0.592; p < 0.001), preserving the calibration with good concordance between predicted probabilities and outcome. Conclusions. Preoperative anemia has strong association with operative death in cardiac surgical patients. Anemia provides significant incremental value over the EuroSCORE II and should be considered for assessment of cardiac surgical ris

Sestamibi and FDG-PET scans to support diagnosis of jaw osteonecrosis

Abstract Osteonecrosis of the maxillary or mandibular bone is an infrequent but often severe event occurring in patients who undergo prolonged treatment with bisphosphonates. Histology is in some cases mandatory to differentiate it from neoplastic osteolysis, but a biopsy can further contribute to bone damage. Functional imaging obtained by a tracer that shows oncotropic properties, such as Tc99m-sestamibi, in comparison to a non-tumor-specific substance such as FDG-PET, can support the differential diagnosis, thus avoiding invasive procedures. Four patients affected by multiple myeloma and jaw osteonecrosis were prospectively evaluated by sestamibi and FDG-PET scans. Local diagnosis was performed by clinical, radiological and, in some cases, histological evaluations. Each patient was studied by Tc99m-sestamibi, performed by planar anterior and posterior whole-body scans and SPECT of the head and neck, and by PET/CT. Two nuclear medicine physicians, unaware of the final diagnosis, reviewed the images. No sestamibi uptake was evident in the four patients with jaw osteonecrosis, while FDG-PET/CT showed focal uptake in all of them. Our study suggests that the combined use of sestamibi scintigraphy and FDG-PET/CT could support the clinical diagnosis of oral osteonecrosis avoiding the risks of a surgical biopsy. Studies on higher number of patients are necessary to validate these preliminary observations