Induction Therapy and Stem Cell Mobilization in Patients with Newly Diagnosed Multiple Myeloma

Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients

Selective acetyl- and butyrylcholinesterase inhibitors reduce amyloid-β ex vivo activation of peripheral chemo-cytokines from Alzheimer's disease subjects: exploring the cholinergic anti-inflammatory pathway

Increasing evidence suggests that elevated production and/or reduced clearance of amyloid-β peptide (Aβ) drives the early pathogenesis of Alzheimer's disease (AD). Aβ soluble oligomers trigger a neurotoxic cascade that leads to neuronal dysfunction, neurodegeneration and, ultimately, clinical dementia. Inflammation, both within brain and systemically, together with a deficiency in the neurotransmitter acetylcholine (ACh) that underpinned the development of anticholinesterases for AD symptomatic treatment, are invariable hallmarks of the disease. The inter-relation between Aβ, inflammation and cholinergic signaling is complex, with each feeding back onto the others to drive disease progression. To elucidate these interactions plasma samples and peripheral blood mononuclear cells (PBMCs) were evaluated from healthy controls (HC) and AD patients. Plasma levels of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and Aβ were significantly elevated in AD vs. HC subjects, and ACh showed a trend towards reduced levels. Aβ challenge of PBMCs induced a greater release of inflammatory cytokines interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) from AD vs. HC subjects, with IL-10 being similarly affected. THP-1 monocytic cells, a cell culture counterpart of PBMCs and brain microglial cells, responded similarly to Aβ as well as to phytohaemagglutinin (PHA) challenge, to allow preliminary analysis of the cellular and molecular pathways underpinning Aβ-induced changes in cytokine expression. As amyloid-β precursor protein expression, and hence Aβ, has been reported regulated by particular cytokines and anticholinesterases, the latter were evaluated on Aβ- and PHA-induced chemocytokine expression. Co-incubation with selective AChE/BuChE inhibitors, (-)-phenserine (AChE) and (-)-cymserine analogues (BuChE), mitigated the rise in cytokine levels and suggest that augmentation of the cholinergic anti-inflammatory pathway may prove valuable in AD

Osimertinib-induced Cardiac Dysfunction in EGFR-Mutated Lung Cancer: A Case Series of Five Patients

Introduction: The gold standard treatment for Epidermal Growth Factor Receptor (EGFR) positive Non-Small Cell Lung Cancer (NSCLC)patients is represented byosimertinib, an irreversible third-generation EGFR inhibitor that has been providingimportant outcomes’ improvementscompared to chemotherapy and other target therapies; either upfront or as second line therapy, in case of  EGFR T790M detection after previous tyrosine kinase inhibitors (TKI).Osimertinib is generally well tolerated. Most common side effects are diarrhea, rash, paronychia, dry skin and alsochanges in QT interval.Presentation of case series: Here we report five cases of left ventricular dysfunction duringosimertinib treatment, observed between January 2017 and August 2018. The five patients, with a general low cardiovascular risk profile, required a dose modification/discontinuation of the TKI therapy and a specific cardio-protective treatment, normally with a recovery of the systolic function.Conclusion: Both American and European compound labels highlight warnings of cardiomyopathy and changes in cardiac contractility during osimertinib treatment, recommending cardiac monitoring and dose adjustment in patients with cardiac risk factors. In spite of this, a standardized echocardiographic follow-up in the entire population is still not available and recommendations about the use of tissue Doppler echocardiography with more sophisticated indices are missing. With the expanding use of osimertinib we need better strategies to prevent or mitigate cardiovascular damage from cancer therapy in a larger multidisciplinary approach in which every issue is carefully evaluated

Evidence of Non-Thermal Particles in Coronal Loops Heated Impulsively by Nanoflares

The physical processes causing energy exchange between the Sun's hot corona and its cool lower atmosphere remain poorly understood. The chromosphere and transition region (TR) form an interface region between the surface and the corona that is highly sensitive to the coronal heating mechanism. High resolution observations with the Interface Region Imaging Spectrograph (IRIS) reveal rapid variability (about 20 to 60 seconds) of intensity and velocity on small spatial scales at the footpoints of hot dynamic coronal loops. The observations are consistent with numerical simulations of heating by beams of non-thermal electrons, which are generated in small impulsive heating events called "coronal nanoflares". The accelerated electrons deposit a sizable fraction of their energy in the chromosphere and TR. Our analysis provides tight constraints on the properties of such electron beams and new diagnostics for their presence in the nonflaring corona.Comment: Published in Science on October 17: http://www.sciencemag.org/content/346/6207/1255724 . 26 pages, 10 figures. Movies are available at: http://www.lmsal.com/~ptesta/iris_science_mov

Shadow monochromatic backlighting: Large-field high resolution X-ray shadowgraphy with improved spectral tunability

The shadow monochromatic backlighting (SMB) scheme, a modification of the well-known soft X-ray monochromatic backlighting scheme, is proposed. It is based on a spherical crystal as the dispersive element and extends the traditional scheme by allowing one to work with a wide range of Bragg angles and thus in a wide spectral range. The advantages of the new scheme are demonstrated experimentally and supported numerically by ray-tracing simulations. In the experiments, the X-ray backlighter source is a laser-produced plasma, created by the interaction of an ultrashort pulse, Ti:Sapphire laser (120 fs, 3–5 mJ, 1016 W/cm2 on target) or a short wavelength XeCl laser (10 ns, 1–2 J, 1013 W/cm2 on target) with various solid targets (Dy, Ni + Cr, BaF2). In both experiments, the X-ray sources are well localized spatially (∼20 μm) and are spectrally tunable in a relatively wide wavelength range (λ = 8–15 Å). High quality monochromatic (δλ/λ ∼ 10−5–10−3) images with high spatial resolution (up to ∼4 μm) over a large field of view (a few square millimeters) were obtained. Utilization of spherically bent crystals to obtain high-resolution, large field, monochromatic images in a wide range of Bragg angles (35° < Θ < 90°) is demonstrated for the first time

ACCURATE WAVELENGTH MEASUREMENTS AND MODELING OF Fe XV TO Fe XIX SPECTRA RECORDED IN HIGH-DENSITY PLASMAS BETWEEN 13.5 AND 17 A

Iron spectra have been recorded from plasmas created at three different laser plasma facilities: the Tor Vergata University laser in Rome (Italy), the Hercules laser at ENEA in Frascati (Italy), and the Compact Multipulse Terawatt (COMET) laser at LLNL in California (USA). The measurements provide a means of identifying dielectronic satellite lines from Fe XVI and Fe XV in the vicinity of the strong 2p → 3d transitions of Fe XVII. About 80 Δn ≥ 1 lines of Fe XV (Mg-like) to Fe XIX (O-like) were recorded between 13.8 and 17.1 A with a high spectral resolution (λ/Δλ ≈ 4000); about 30 of these lines are from Fe XVI and Fe XV. The laser-produced plasmas had electron temperatures between 100 and 500 eV and electron densities between 1020 and 1022 cm-3. The Hebrew University Lawrence Livermore Atomic Code (HULLAC) was used to calculate the atomic structure and atomic rates for Fe XV-XIX. HULLAC was used to calculate synthetic line intensities at Te = 200 eV and ne = 1021 cm-3 for three different conditions to illustrate the role of opacity: optically thin plasmas with no excitation-autoionization/dielectronic recombination (EA/DR) contributions to the line intensities, optically thin plasmas that included EA/DR contributions to the line intensities, and optically thick plasmas (optical depth ≈200 μm) that included EA/DR contributions to the line intensities. The optically thick simulation best reproduced the recorded spectrum from the Hercules laser. However, some discrepancies between the modeling and the recorded spectra remain

18F-FDG Pet Parameters and Radiomics Features Analysis in Advanced Nsclc Treated with Immunotherapy as Predictors of Therapy Response and Survival

Objectives: (1.1) to evaluate the association between baseline 18F-FDG PET/CT semi-quantitative parameters of the primary lesion with progression free survival (PFS), overall survival (OS) and response to immunotherapy, in advanced non-small cell lung carcinoma (NSCLC) patients eligible for immunotherapy; (1.2) to evaluate the application of radiomics analysis of the primary lesion to identify features predictive of response to immunotherapy; (1.3) to evaluate if tumor burden assessed by 18F-FDG PET/CT (N and M factors) is associated with PFS and OS. Materials and Methods: we retrospectively analyzed clinical records of advanced NCSLC patients (stage IIIb/c or stage IV) candidate to immunotherapy who performed 18F-FDG PET/CT before treatment to stage the disease. Fifty-seven (57) patients were included in the analysis (F:M 17:40; median age = 69 years old). Notably, 38/57 of patients had adenocarcinoma (AC), 10/57 squamous cell carcinoma (SCC) and 9/57 were not otherwise specified (NOS). Overall, 47.4% patients were stage IVA, 42.1% IVB and 8.8% IIIB. Immunotherapy was performed as front-line therapy in 42/57 patients and as second line therapy after chemotherapy platinum-based in 15/57. The median follow up after starting immunotherapy was 10 months (range: 1.5&ndash;68.6). Therapy response was assessed by RECIST 1.1 criteria (CT evaluation every 4 cycles of therapy) in 48/57 patients or when not feasible by clinical and laboratory data (fast disease progression or worsening of patient clinical condition in nine patients). Radiomics analysis was performed by applying regions of interest (ROIs) of the primary tumor delineated manually by two operators and semi-automatically applying a threshold at 40% of SUVmax. Results: (1.1) metabolic tumor volume (MTV) (p = 0.028) and total lesion glycolysis (TLG) (p = 0.035) were significantly associated with progressive vs. non-progressive disease status. Patients with higher values of MTV and TLG had higher probability of disease progression, compared to those patients presenting with lower values. SUVmax did not show correlation with PD status, PFS and OS. MTV (p = 0.027) and TLG (p = 0.022) also resulted in being significantly different among PR, SD and PD groups, while SUVmax was confirmed to not be associated with response to therapy (p = 0.427). (1.2) We observed the association of several radiomics features with PD status. Namely, patients with high tumor volume, TLG and heterogeneity expressed by &ldquo;skewness&rdquo; and &ldquo;kurtosis&rdquo; had a higher probability of failing immunotherapy. (1.3) M status at 18F-FDG PET/CT was significantly associated with PFS (p = 0.002) and OS (p = 0.049). No significant associations were observed for N status. Conclusions: 18F-FDG PET/CT performed before the start of immunotherapy might be an important prognostic tool able to predict the disease progression and response to immunotherapy in patients with advanced NSCLC, since MTV, TLG and radiomics features (volume and heterogeneity) are associated with disease progression

Early Progression in Non-Small Cell Lung Cancer (NSCLC) with High PD-L1 Treated with Pembrolizumab in First-Line Setting: A Prognostic Scoring System Based on Clinical Features

Background: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored. Methods: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model. Results: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9–4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0–13, with three-risk group stratification: 0–2 (good prognosis), 3–6 (intermediate prognosis), and 7–13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70–0.81). Conclusions: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting