Introduction: Risk-adapted therapy in curable hematologic malignancies is commonly applied: low-risk patients (pts) may be cured with less intensive treatment, avoiding excessive toxicity, whereas ...high-riskpts require more intensive and toxic regimens. In multiple myeloma (MM), this model may not apply, since the disease is incurable. In recent years, there has been a marked improvement in patient outcome, due to the introduction of novel agents and optimized treatment strategies, including the use of transplant and maintenance. A better evaluation ofpts prognosis based on the new revised international staging system (R-ISS) has been also introduced in clinical practice. The objective of this analysis was to evaluate the impact of treatment intensification (specifically autologous stem cell transplantation ASCT and maintenance) inpts with different prognostic features.
Methods: Data from 3 phase III randomized trials in newly diagnosed MMpts (RV-MM-209; EMN441; GIMEMA-MM0305) were pooled together and analyzed. Baseline patient risk assessment was estimated using R-ISS. We evaluated: 1) the impact of treatment intensification with high-dose therapy followed by ASCTvs no-ASCT inpts with R-ISS Stage Ivs Stage II/III; 2) the impact of treatment intensification with maintenancevs no maintenance inpts with R-ISS Stage Ivs Stage II/III. RV-MM-209 and EMN441 studies randomizedpts to ASCTvs no-ASCT; allpts in the GIMEMA-MM0305 trial did not receive ASCT and were excluded from the first comparison; RV-MM-209 and GIMEMA-MM0305 studies randomizedpts to maintenance or no maintenance after induction/consolidation; allpts in the EMN441 trial received maintenance and were excluded from the second comparison. We evaluated progression free survival-1 (PFS1), PFS2 and overall survival (OS). Cox proportional hazards models were used to estimate hazard ratios (HRs). To account for potential confounders, the comparisons between ASCTvs no-ASCT and maintenancevs no maintenance were adjusted for the trial effect and the main prognostic features.
Results: Overall, 1302 pts were enrolled in the 3 trials. Median follow-up was 4 years.Comparison ASCTvs no-ASCT: 791pts were enrolled in the 2 trials, 529 were eligible for the ASCTvs no ASCT comparison. R-ISS Stage data were available for 419 pts. There was an overall advantage for ASCTvs no-ASCT in PFS1 (0.53; p<0.001), PFS2 (HR 0.53; p<0.001) and OS (HR 0.51; p<0.001). The 4-year PFS1 was 53% inpts with R-ISS Stage I randomized to ASCT, 35% inpts with R-ISS Stage II/III randomized to ASCT, 36% inpts with R-ISS Stage I randomized to no-ASCT and 19% in those with R-ISS Stage II/III randomized to no-ASCT (p<0.001); the 4-year PFS2 was 83%, 60%, 71% and 43% in the 4 subgroups, respectively (p<0.001) (Figure 1A, B); the4-year OS was 95%, 75%, 88% and 61%(p<0.001). Comparison maintenancevs no maintenance: 913pts were enrolled in the 2 trials, 550 could be eligible for maintenance. R-ISS data were available in 403 pts. Maintenance significantly improved PFS (HR 0.54, p<0.001), PFS2 (HR 0.52, p<0.001) and OS (HR 0.69, p=0.027) in comparison with no maintenance. The 4-year PFS was 48% forpts with R-ISS Stage-I assigned to maintenance, 37% forpts with R-ISS Stage II/III assigned to maintenance, 25% forpts with R-ISS Stage-I assigned to no maintenance and 18% forpts with R-ISS Stage II/III assigned to no maintenance (p<0.001); the 4-year PFS2 was 73%, 66%, 59% and 43% in the 4 subgroups, respectively (p<0.001) (Figure 1C, D); the 4-year OS was 80%, 73%, 77% and 63% (p<0.001).
Conclusions: Both ASCT and maintenance improved PFS1, PFS2 and OS in MM pts. The highest survival was reported in patients with R-ISS Stage I receiving ASCT and/or maintenance. Low-riskpts (R-ISS Stage I) not undergoing intensification with ASCT or maintenance lose their prognostic advantage over high-risk patients receiving the same intensification.
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Gay:Janssen-Cilag: Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria, Other: Advisory Board; Mundipharma: Other: Advisory Board. Hajek:Novartis: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Bringhen:Mundipharma: Other: Advisory Board; Karyopharm: Other: Advisory Board; BMS: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: Advisory Board; Celgene: Honoraria. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Caravita:Janssen-Cilag: Honoraria. Cavo:Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Foà:Pfizer: Speakers Bureau; Ariad: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen-Cilag: Consultancy, Speakers Bureau; Genetech: Consultancy; Roche: Consultancy, Speakers Bureau. Patriarca:Bristol-Myers Squibb: Other: Advisory board; Mundipharma: Other: Advisory board; Janssen-Cilag: Other: Advisory board; MSD: Consultancy; Celgene: Consultancy. Ria:Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbivie: Honoraria; Amgen: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; BMS: Honoraria, Research Funding.
Herein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure ...and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α‐helical conformation of the N‐terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post‐translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs.
Proteinsemisynthese wurde genutzt, um die Auswirkungen der Lysin‐Acetylierung und ‐Phosphorylierung sowie des Crosstalks zwischen diesen Modifizierungen auf die Struktur und Aggregation des mutierten Huntingtin‐Proteins Exon1 (Httex1) zu untersuchen. Während Phosphorylierung die Aggregation von Httext1 hemmt, hat Acetylierung keine Auswirkungen. Acetylierung an K6 hebt jedoch den inhibierenden Effekt der Phosphorylierung an T3 auf.
Background The conventional antiviral treatment of chronic hepatitis related to hepatitis C virus (HCV) often leads to anemia. In this case, it is necessary to reduce ribavirin dose or stop ...treatment, thus reducing the rate of sustained virological response. Aim We investigated whether epoetin alpha administration improves treatment adherence and leads to higher percentage of response at the end of therapy and sustained virological response. Methods Two hundred and fourteen individuals with genotype 1b HCV-related chronic hepatitis underwent treatment with pegylated (peg)-interferon alpha-2A 180 μg once weekly and ribavirin 1,000-1,200 mg/day; 174 were responders. Forty individuals completed treatment with no hemoglobin reduction; 134 developed anemia during therapy. Anemic responders were distributed randomly into two groups: group 1 continued therapy with epoetin alpha addiction; group 2 continued antiviral therapy with ribavirin reduction only. Results Patients in group 1 achieved better control of hemoglobin levels (13.8 ± 1.2 g/dl at the end of therapy) than tthose in group 2 (11.5 ± 0.8 g/dl). Sustained virological response was 59.7% in group 1 compared with 34.4% in group 2 (p < 0.01). Conclusions In patients with 1b HCV-related chronic hepatitis who develop anemia during antiviral treatment, administration of epoetin alpha increases hemoglobin levels and the end-of-treatment rate and sustains virological response by improving treatment adherence.
Background
We evaluated the efficacy of gemcitabine and carboplatin for patients affected by pretreated metastatic breast cancer. A subgroup analysis was performed to evaluate the predictive value of ...immunohistochemically defined breast cancer subtypes.
Methods
We included human epidermal growth factor 2 (HER-2) negative metastatic breast cancer resistant to previous anthracycline-based and taxane-based chemotherapy, and HER-2 positive metastatic breast cancer with at least two progressions of disease during protracted trastuzumab-based therapy. Treatment consisted of gemcitabine (1000 mg/m
2
intravenous (iv) on days 1 and 8) and carboplatin (area under the curve 5 iv on day 1) applied every 3 weeks.
Results
Forty-two patients were registered. Disease control was 58%, with a median time-to-progression (TTP) of 7 months (range 1–12) and a median overall survival of 10.5 months (range 1–34). Patients were grouped as triple negative (ER and PR negative, HER-2 negative), HER-2 (HER-2 positive, ER and PR negative), luminal B (ER and/or PR positive and either HER-2 positive and/or high Ki67), and luminal A (ER and/or PR positive and HER-2 negative and low Ki67). For luminal A patients, disease control was lower (luminal A 34 vs. others 67%;
P
= 0.02), TTP was shorter (luminal A 2.4 months vs. others 6.3 months,
P
= 0.015), and overall survival was shorter (luminal A 7.5 months vs. others 11.7 months,
P
= 0.034) than for other subtypes.
Conclusions
Gemcitabine and carboplatin are effective for pretreated patients with metastatic breast cancer. Luminal A subtype seems to fare poorly compared with other subtypes. Specific difference in gene expression might account for the different outcome.
Abstract Objectives This study investigated the effects of an electric field produced by a new device for the application of etch-and-rinse adhesives on demineralized dentin surfaces. Methods Three ...simplified etch-and-rinse adhesives (Single Bond, Prime&Bond NT and One-Step) were applied with the electric device and compared with controls prepared with disposable sponges. Specimens were processed for microtensile bond strength test and nanoleakage investigation using high resolution SEM. Results Microtensile testing revealed higher bond strengths ( p < 0.05) for all adhesives tested when electricity was used. Adhesive interfaces prepared with electric impulses exhibited very homogenous hybrid layers with minimal nanoleakage compared with the controls. Significance The use of electricity produced by a new electronic device during the application of dentin adhesives may increase adhesive adaptation to the dentin substrate and improve dentin hybridization due to the substrate modifications induced by an electric field on the demineralized dentin organic matrix.
Abstract Objectives The application of an electric field has been shown to positively influence the impregnation of the resin monomers currently used in dentin bonding systems during hybrid layer ...formation. This study presents an experimental characterization of the electrical properties of these monomers with the aim of both correlating them to their chemical structures and seeking an insight into the mechanisms of the monomer migration under an applied electric field. Methods Some common monomers examined were TEGDMA (triethyleneglycoldimethacrylate), HEMA (2-hydroxyethyl methacrylate), UDMA (urethane dimethacrylate), 2-MP (bis2-(methacryloyloxy)ethyl phosphate, TCDM di(hydroxyethyl methacrylate) ester of 5-(2,5-dioxotetrahydrofurfuryl)-3-methyl-3-cyclohexenyl-1,2-dicarboxylic anhydride) and Bis-GMA 2,2-bis(4-2-hydroxy-3-methacryloyloxypropoxyphenyl)propane. A customized cell produced for the measurement of the electrical properties of monomers was manufactured and electrical conductivity and permittivity of resin monomers were measured. Results The permittivity of the tested monomers is largely affected by electrical frequency. The large values of permittivity and dielectric losses observed as frequency decreased, indicate a dominant effect of ionic polarization, particularly evident in materials showing the highest conductivity. Permittivity and conductivity of the tested monomers showed a similar behavior, i.e. materials with the lowest permittivity also show small values of conductivity and vice versa. Significance The results of the present study revealed a good correlation between electrical properties and Hoy solubility parameters and, in particular, the higher the polar contribution (polar forces plus hydrogen bonding) the higher the permittivity and conductivity. The most relevant outcome of this study is that the electrophoretic mechanism prevails on the electroendoosmotic effect in determining the monomer migration under the application of electric fields.
Induction of multispecific, functional CD4+ and CD8+ T cells is the immunological hallmark of acute self-limiting hepatitis C virus (HCV) infection in humans. In the present study, we showed that ...gene electrotransfer (GET) of a novel candidate DNA vaccine encoding an optimized version of the nonstructural region of HCV (from NS3 to NS5B) induced substantially more potent, broad, and long-lasting CD4+ and CD8+ cellular immunity than naked DNA injection in mice and in rhesus macaques as measured by a combination of assays, including IFN-gamma ELISPOT, intracellular cytokine staining, and cytotoxic T cell assays. A protocol based on three injections of DNA with GET induced a substantially higher CD4+ T cell response than an adenovirus 6-based viral vector encoding the same Ag. To better evaluate the immunological potency and probability of success of this vaccine, we have immunized two chimpanzees and have compared vaccine-induced cell-mediated immunity to that measured in acute self-limiting infection in humans. GET of the candidate HCV vaccine led to vigorous, multispecific IFN-gamma+CD8+ and CD4+ T lymphocyte responses in chimpanzees, which were comparable to those measured in five individuals that cleared spontaneously HCV infection. These data support the hypothesis that T cell responses elicited by the present strategy could be beneficial in prophylactic vaccine approaches against HCV.
Huntington-Krankheit In der Zuschrift auf S.5286ff. nutzen H.A. Lashuel etal. die Proteinsemisynthese, um die Auswirkungen der Acetylierung und Phosphorylierung von Lysin auf die Aggregation eines ...mutierten Huntingtin-Proteins zu untersuchen. Während Phosphorylierung die Aggregation hemmt, hat Acetylierung keinen Effekt.
Huntington‐Krankheit In der Zuschrift auf S. 5286 ff. nutzen H. A. Lashuel et al. die Proteinsemisynthese, um die Auswirkungen der Acetylierung und Phosphorylierung von Lysin auf die Aggregation ...eines mutierten Huntingtin‐Proteins zu untersuchen. Während Phosphorylierung die Aggregation hemmt, hat Acetylierung keinen Effekt.
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