Histone deacetylase inhibitors in adult patients with diffuse large b-cell lymphoma relapsed/refractory: a phase II study with Panobinostat

Backgrounds:Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Panobinostat showed encouraging therapeutic activity in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies.Purpose:FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL) to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL patients and to evaluate a possible relationships between response and any biological features. Patients and Methods:Patients with R/R DLBCL were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR); secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient’s specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. ResultsThirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively. Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR

Thermoelectric performance of p-type TiCoSb half-Heusler compounds - Intrinsic phase separation and charge carrier concentration optimization as key to high efficiency

The world's rising demand of energy turns the development of sustainable and more efficient technologies for energy production and storage into an inevitable task. Thermoelectric generators, composed of pairs of n-type and p-type semiconducting materials, di¬rectly transform waste heat into useful electricity. The efficiency of a thermoelectric mate¬rial depends on its electronic and lattice properties, summarized in its figure of merit ZT. Desirable are high electrical conductivity and Seebeck coefficients, and low thermal con¬ductivity. Half-Heusler materials are very promising candidates for thermoelectric applications in the medium¬ temperature range such as in industrial and automotive waste heat recovery. The advantage of Heusler compounds are excellent electronic properties and high thermal and mechanical stability, as well as their low toxicity and elemental abundance. Thus, the main obstacle to further enhance their thermoelectric performance is their relatively high thermal conductivity.rn rnIn this work, the thermoelectric properties of the p-type material (Ti/Zr/Hf)CoSb1-xSnx were optimized in a multistep process. The concept of an intrinsic phase separation has recently become a focus of research in the compatible n-type (Ti/Zr/Hf)NiSn system to achieve low thermal conductivities and boost the TE performance. This concept is successfully transferred to the TiCoSb system. The phase separation approach can form a significant alternative to the previous nanostructuring approach via ball milling and hot pressing, saving pro¬cessing time, energy consumption and increasing the thermoelectric efficiency. A fundamental concept to tune the performance of thermoelectric materials is charge carrier concentration optimization. The optimum carrier concentration is reached with a substitution level for Sn of x = 0.15, enhancing the ZT about 40% compared to previous state-of-the-art samples with x = 0.2. The TE performance can be enhanced further by a fine-tuning of the Ti-to-Hf ratio. A correlation of the microstructure and the thermoelectric properties is observed and a record figure of merit ZT = 1.2 at 710°C was reached with the composition Ti0.25Hf0.75CoSb0.85Sn0.15.rnTowards application, the long term stability of the material under actual conditions of operation are an important issue. The impact of such a heat treatment on the structural and thermoelectric properties is investigated. Particularly, the best and most reliable performance is achieved in Ti0.5Hf0.5CoSb0.85Sn0.15, which reached a maximum ZT of 1.1 at 700°C. The intrinsic phase separation and resulting microstructure is stable even after 500 heating and cooling cycles.

Single-shot electron bunch length measurements using a spatial electro-optical autocorrelation interferometer

A spatial, electro-optical autocorrelation (EOA) interferometer using the vertically polarized lobes of coherent transition radiation (CTR) has been developed as a single-shot electron bunch length monitor at an optical beam port downstream the 100 MeV preinjector LINAC of the Swiss Light Source. This EOA monitor combines the advantages of step-scan interferometers (high temporal resolution) [D. Mihalcea et al., Phys. Rev. ST Accel. Beams 9, 082801 (2006) and T. Takahashi and K. Takami, Infrared Phys. Technol. 51, 363 (2008)] and terahertz-gating technologies [U. Schmidhammer et al., Appl. Phys. B: Lasers Opt. 94, 95 (2009) and B. Steffen et al., Phys. Rev. ST Accel. Beams 12, 032802 (2009)] (fast response), providing the possibility to tune the accelerator with an online bunch length diagnostics. While a proof of principle of the spatial interferometer was achieved by step-scan measurements with far-infrared detectors, the single-shot capability of the monitor has been demonstrated by electro-optical correlation of the spatial CTR interference pattern with fairly long (500 ps) neodymium-doped yttrium aluminum garnet (Nd:YAG) laser pulses in a ZnTe crystal. In single-shot operation, variations of the bunch length between 1.5 and 4 ps due to different phase settings of the LINAC bunching cavities have been measured with subpicosecond time resolution.

Coherent phase contrast imaging of THz phonon-polariton tunneling

We report on coherent spatiotemporal imaging of single-cycle THz waves in frustrated total internal reflection geometry. Our technique yields images of the spatiotemporal electric field distribution before and after tunneling through an air gap in between two LiNbO3 crystals. Measurements of the reflected and the transmitted THz waveforms for different tunnel distances allow for a direct comparison with results from a causal linear dispersion theory and excellent agreement is found.

CCSD(T), W1, and other model chemistry predictions for gas-phase deprotonation reactions

A series of CCSD(T) single-point calculations on MP4(SDQ) geometries and the W1 model chemistry method have been used to calculate ΔH° and ΔG° values for the deprotonation of 17 gas-phase reactions where the experimental values have reported accuracies within 1 kcal/mol. These values have been compared with previous calculations using the G3 and CBS model chemistries and two DFT methods. The most accurate CCSD(T) method uses the aug-cc-pVQZ basis set. Extrapolation of the aug-cc-pVTZ and aug-cc-pVQZ results yields the most accurate agreement with experiment, with a standard deviation of 0.58 kcal/mol for ΔG° and 0.70 kcal/mol for ΔH°. Standard deviations from experiment for ΔG° and ΔH° for the W1 method are 0.95 and 0.83 kcal/mol, respectively. The G3 and CBS-APNO results are competitive with W1 and are much less expensive. Any of the model chemistry methods or the CCSD(T)/aug-cc-pVQZ method can serve as a valuable check on the accuracy of experimental data reported in the National Institutes of Standards and Technology (NIST) database.

Competition between single and double electron transfer in collisions of doubly charged molecular pyrrole ions with neutral pyrrole molecules

Cross-sections have been determined for one- and two-electron transfer channels in the collisions of keV gas-phase doubly charged pyrrole ions with pyrrole molecules. Measured single and double electron transfer total cross-sections approximate 45 Å2 and 15 Å2, respectively. A combination of symmetric resonance charge exchange and multistate curve-crossing models has been invoked to describe these reactions.

Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase II trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03)

Patients with brain metastases (BM) rarely survive longer than 6months and are commonly excluded from clinical trials. We explored two combined modality regimens with novel agents with single agent activity and radiosensitizing properties.

Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines

CD8 T cells play a key role in mediating protective immunity against selected pathogens after vaccination. Understanding the mechanism of this protection is dependent upon definition of the heterogeneity and complexity of cellular immune responses generated by different vaccines. Here, we identify previously unrecognized subsets of CD8 T cells based upon analysis of gene-expression patterns within single cells and show that they are differentially induced by different vaccines. Three prime-boost vector combinations encoding HIV Env stimulated antigen-specific CD8 T-cell populations of similar magnitude, phenotype, and functionality. Remarkably, however, analysis of single-cell gene-expression profiles enabled discrimination of a majority of central memory (CM) and effector memory (EM) CD8 T cells elicited by the three vaccines. Subsets of T cells could be defined based on their expression of Eomes, Cxcr3, and Ccr7, or Klrk1, Klrg1, and Ccr5 in CM and EM cells, respectively. Of CM cells elicited by DNA prime-recombinant adenoviral (rAd) boost vectors, 67% were Eomes(-) Ccr7(+) Cxcr3(-), in contrast to only 7% and 2% stimulated by rAd5-rAd5 or rAd-LCMV, respectively. Of EM cells elicited by DNA-rAd, 74% were Klrk1(-) Klrg1(-)Ccr5(-) compared with only 26% and 20% for rAd5-rAd5 or rAd5-LCMV. Definition by single-cell gene profiling of specific CM and EM CD8 T-cell subsets that are differentially induced by different gene-based vaccines will facilitate the design and evaluation of vaccines, as well as enable our understanding of mechanisms of protective immunity.

Azacytidine for acute myeloid leukemia in elderly or frail patients: A phase II trial (SAKK 30/07)

Abstract This phase II trial treated elderly or frail AML patients with single agent subcutaneous azacytidine at 100 mg/m(2), on 5 of 28 days for up to 6 cycles. Treatment was stopped for lack of response, or continued to progression in responders. Primary endpoint was response within 6 months. A response rate >34% was considered a positive trial outcome. From 9/2008-4/2010, 45 patients from 10 centres (median age 74 (55-86) years) were accrued. Patients received 4 (1-21) cycles. Best response was CR/CRi in 8 (18%; 95% CI: 8%-32%.), 0 (0%) PR, 7 (16%) hematologic improvement, 17 (38%) stable disease. Three nonresponding patients stopped treatment after 6 cycles, 31 patients had stopped early and 11 patients continued treatment for 8-21 cycles. Adverse events (grade >III) were infections (13), febrile neutropenia (14), thrombocytopenia (7), dyspnea (6), bleeding (5) and anemia (4 patients). Median overall survival was 6 months. Peripheral blood blast counts, grouped at 30% had a borderline significant association with response (p = 0.07). This modified azacytidine schedule is feasible for elderly or frail AML patients in an outpatient setting with moderate, mainly hematologic, toxicity and response in a proportion of patients, although the primary objective was not reached.

Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer

The vascular disrupting agent (VDA) combretastatin A4 phosphate (CA4P) induces significant tumor necrosis as a single agent. Preclinical models have shown that the addition of an anti-VEGF antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity.

A new double-tracer gas single-breath washout to assess early cystic fibrosis lung disease

In cystic fibrosis (CF), tests for ventilation inhomogeneity are sensitive but not established for clinical routine. We assessed feasibility of a new double-tracer gas single-breath washout (SBW) in school-aged children with CF and control subjects, and compared SBW between groups and with multiple-breath nitrogen washout (MBNW). Three SBW and MBNW were performed in 118 children (66 with CF) using a side-stream ultrasonic flowmeter setup. The double-tracer gas containing 5% sulfur hexafluoride and 26.3% helium was applied during one tidal breath. Outcomes were SBW phase III slope (SIII(DTG)), MBNW-derived lung clearance index (LCI), and indices of acinar (S(acin)) and conductive (S(cond)) ventilation inhomogeneity. SBW took significantly less time to perform than MBNW. SBW and MBNW were feasible in 109 (92.4%) and 98 (83.0%) children, respectively. SIII(DTG) differed between children with CF and controls, mean±sd was -456.7±492.8 and -88.4±129.1 mg·mol·L(-1), respectively. Abnormal SIII(DTG) was present in 36 (59%) children with CF. SIII(DTG) was associated with LCI (r= -0.58) and S(acin) (r= -0.58), but not with S(cond). In CF, steeply sloping SIII(DTG) potentially reflects ventilation inhomogeneity near the acinus entrance. This tidal SBW is a promising test to assess ventilation inhomogeneity in an easy and fast way.

Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

This phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.

Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure

BACKGROUND: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation. METHODS AND RESULTS: By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal beta(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase"), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2) expression. Additional evidence for the cause-effect relationship between beta(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. CONCLUSIONS: Our study presents evidence of the pathobiochemical relevance of beta(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.

Immunohistochemical demonstration of interleukin-1 beta induced changes in acute-phase proteins and albumin in rat liver

Interleukin-1 beta is a potent mediator of the acute-phase response. However, the effects of interleukin-1 beta administration on the topic in vivo production of acute-phase proteins and albumin are so far not well understood. Overnight fasted rats were subcutaneously injected with 0.2 mL 0.9% NaCl (control group) or 6.25 micrograms recombinant human interleukin-1 beta, and rectal temperature was measured at intervals up to 48 h. Livers were perfused-fixed in vivo prior to injection (base-line), and at 9, 24, and 48 h following the interleukin-1 beta injection. Fibrinogen, orosomucoid (alpha 1-acid glycoprotein) and albumin were immunostained using a streptavidin-biotin-immunoperoxidase technique. Rectal temperature peaked 5 h after the single interleukin-1 beta injection, and fell gradually to base-line values by 24 h. Prior to injection only a few hepatocytes, randomly scattered throughout the liver lobule, stained positive for fibrinogen and orosomucoid. In contrast, all hepatocytes stained uniformly positive for fibrinogen and orosomucoid 9 h after interleukin-1 beta injection, whereas at 24 h a predominant centrilobular staining pattern occurred. Due to fasting, albumin positive hepatocytes were already reduced at base-line in both groups. Interleukin-1 beta induced a further significant loss of albumin positive cells in the periportal zone (35 +/- 21%) at 9 h when compared with controls (58 +/- 11%, p = 0.037). In conclusion, subcutaneous interleukin-1 beta (probably by stimulation of interleukin-6) strongly induces fibrinogen and orosomucoid expression in rat liver, and suppresses immunohistochemically stainable albumin in a heterogenous way, mainly in the periportal zone.

Effect of echo time pair selection on quantitative analysis for adrenal tumor characterization with in-phase and opposed-phase MR imaging: initial experience

PURPOSE: To determine the effect of two pairs of echo times (TEs) for in-phase (IP) and opposed-phase (OP) 3.0-T magnetic resonance (MR) imaging on (a) quantitative analysis prospectively in a phantom study and (b) diagnostic accuracy retrospectively in a clinical study of adrenal tumors, with use of various reference standards in the clinical study. MATERIALS AND METHODS: A fat-saline phantom was used to perform IP and OP 3.0-T MR imaging for various fat fractions. The institutional review board approved this HIPAA-compliant study, with waiver of informed consent. Single-breath-hold IP and OP 3.0-T MR images in 21 patients (14 women, seven men; mean age, 63 years) with 23 adrenal tumors (16 adenomas, six metastases, one adrenocortical carcinoma) were reviewed. The MR protocol involved two acquisition schemes: In scheme A, the first OP echo (approximately 1.5-msec TE) and the second IP echo (approximately 4.9-msec TE) were acquired. In scheme B, the first IP echo (approximately 2.4-msec TE) and the third OP echo (approximately 5.8-msec TE) were acquired. Quantitative analysis was performed, and analysis of variance was used to test for differences between adenomas and nonadenomas. RESULTS: In the phantom study, scheme B did not enable discrimination among voxels that had small amounts of fat. In the clinical study, no overlap in signal intensity (SI) index values between adenomas and nonadenomas was seen (P < .05) with scheme A. However, with scheme B, no overlap in the adrenal gland SI-to-liver SI ratio between adenomas and nonadenomas was seen (P < .05). With scheme B, no overlap in adrenal gland SI index-to-liver SI index ratio between adenomas and nonadenomas was seen (P < .05). CONCLUSION: This initial experience indicates SI index is the most reliable parameter for characterization of adrenal tumors with 3.0-T MR imaging when obtaining OP echo before IP echo. When acquiring IP echo before OP echo, however, nonadenomas can be mistaken as adenomas with use of the SI index value.