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

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

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.MTG6Molecular tumour pathology - and tumour genetic

Comparison between intensified neoadjuvant treatment and standard preoperative chemoradiation for rectal cancer

Objectives. The aim of the current study was to compare a neoadjuvant regimen containing oxaliplatin with standard preoperative treatment for rectal cancer. Methods. From December 2006 to December 2007, 20 patients with rectal cancer were treated at our Institution with the weekly addition of oxaliplatin (50 mg/mz) to radiotherapy (50.4-54.0 Gy in 28-30 daily fractions) and continuous infusion of 5-fluorouracil (200 mg/m(2)). The results of the regimen were compared with a historical control group including 21 consecutive patients previously treated with standard 5-fluorouracil treatment from December 2004 to October 2006. Results. Both the rate of sphincter preservation in low rectal cancer (91.7% vs 36.4%, P = 0.009) and the rate of downstaging (84.2% vs 47.6%, P = 0.023) were higher in the oxaliplatin group than in the control group. Pathological complete response was achieved in 8 patients (42.1%) in the oxaliplatin group and in 4 patients (19.0%) in the control group (P = 0.172). When ypT0-pT1 stages were analyzed together, the P value was 0.051, Acute toxicity was increased in the oxaliplatin group, with a higher incidence of G3 diarrhea and pelvic pain than in the control group (30.0% vs 14.3%, P = NS). Conclusions. Our data seem to correlate the addition of oxaliplatin to the standard treatment for rectal cancer with higher rates of sphincter preservation, down-staging and complete response. Toxicity is increased and requires careful monitoring. However, our results refer to a retrospective comparison of a small series of patients and need to be validated by the large, phase III randomized trial currently ongoing. Free full text available at www.tumorionline.i

Severe prosthesis-patient mismatch after aortic valve replacement for aortic stenosis: Analysis of risk factors for early and long-term mortality

Background Severe prosthesis-patient mismatch (PPM) is considered to further decrease survival compared to moderate PPM. This study aimed to assess the impact of severe PPM on survival after aortic valve replacement (AVR). Methods We retrospectively studied 2404 consecutive patients with PPM who underwent first-time AVR for pure stenosis between January 2003 and December 2014. Mismatch was moderate for indexed effective valve orifice >0.65 to 220 g/m2 and concomitant coronary artery revascularization. After propensity score matching, conditional logistic regression analysis demonstrated no relationship between severe mismatch and increased mortality at 5 postoperative years (HR, 0.9; 95% CI, 0.7–1.6; p = 0.06), whereas it was significant at 10 postoperative years (HR, 1.9; 95% CI, 1.2–2.5; p = 0.03). During the follow-up, severe mismatch was associated with more frequent hospital readmissions for cardiac events (0.12 vs. 0.08 events/patient/year, p = 0.007). Conclusions Patients with severe mismatch had lower long-term survival and higher incidence of hospital readmissions for cardiac events. However, the effect of severe mismatch on outcome appeared mainly related to the preoperative risk profile of each patient. © 2016 Japanese College of Cardiolog

Immunotherapy in elderly head and neck cancer patients: a systematic review and meta-analysis.

Over the past years, there has been a growing interest in the role of immunotherapy in locally advanced (LA) and recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). High-quality data from prospective trials are lacking for the elderly subpopulation. This systematic review and meta-analysis aims to review the efficacy and safety of immunotherapy in older patients. A systematic literature search was conducted. Randomized clinical trials providing outcome data on a subgroup of elderly (&gt;65 years old) were available for meta-analysis. Primary outcomes of interest were OS and PFS for efficacy analysis. Seven studies were included in the systematic review and four in the efficacy analysis. The pooled analysis of OS and PFS showed a consistent benefit (HR 0.78 and 0.91, respectively). Immunotherapy may be an effective and well-tolerated treatment option in the elderly population, but more prospective and randomized data are needed. PROSPERO (CRD42022333891)

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 disease. © 2013 Landes Bioscience

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

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

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