First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). CONCLUSION: Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation

Quantum Noise Limits for Nonlinear, Phase-Invariant Amplifiers

Any quantum device that amplifies coherent states of a field while preserving their phase generates noise. A nonlinear, phase-invariant amplifier may generate less noise, over a range of input field strengths, than any linear amplifier with the same amplification. We present explicit examples of such nonlinear amplifiers, and derive lower bounds on the noise generated by a nonlinear, phase-invariant quantum amplifier.Comment: RevTeX, 6 pages + 4 figures (included in file; hard copy sent on request

Coherent States for Particle Beams in the Thermal Wave Model

In this paper, by using an analogy among {\it quantum mechanics}, {\it electromagnetic beam optics in optical fibers}, and {\it charge particle beam dynamics}, we introduce the concept of {\it coherent states} for charged particle beams in the framework of the {\it Thermal Wave Model} (TWM). We give a physical meaning of the Gaussian-like coherent structures of charged particle distribution that are both naturally and artificially produced in an accelerating machine in terms of the concept of coherent states widely used in quantum mechanics and in quantum optics. According to TWM, this can be done by using a Schr\"{o}dinger-like equation for a complex function, the so-called {\it beam wave function} (BWF), whose squared modulus is proportional to the transverse beam density profile, where Planck's constant and the time are replaced by the transverse beam emittance and by the propagation coordinate, respectively. The evolution of the particle beam, whose initial BWF is assumed to be the simplest coherent state (ground-like state) associated with the beam, in an infinite 1-D quadrupole-like device with small sextupole and octupole aberrations, is analytically and numerically investigated.Comment: 21 pages, Late

Discovery of new molecular entities able to strongly interfere with Hsp90 C-terminal domain

Heat shock protein 90 (Hsp90) is an ATP dependent molecular chaperone deeply involved in the complex network of cellular signaling governing some key functions, such as cell proliferation and survival, invasion and angiogenesis. Over the past years the N-terminal protein domain has been fully investigated as attractive strategy against cancer, but despite the many efforts lavished in the field, none of the N-terminal binders (termed “classical inhibitors”), currently in clinical trials, have yet successfully reached the market, because of the detrimental heat shock response (HSR) that showed to induce; thus, recently, the selective inhibition of Hsp90 C-terminal domain has powerfully emerged as a more promising alternative strategy for anti-cancer therapy, not eliciting this cell rescue cascade. However, the structural complexity of the target protein and, mostly, the lack of a co-crystal structure of C-terminal domain-ligand, essential to drive the identification of new hits, represent the largest hurdles in the development of new selective C-terminal inhibitors. Continuing our investigations on the identification of new anticancer drug candidates, by using an orthogonal screening approach, here we describe two new potent C-terminal inhibitors able to induce cancer cell death and a considerable downregulation of Hsp90 client oncoproteins, without triggering the undesired heat shock response

The AOSpine North America Geriatric Odontoid Fracture Mortality Study: A Retrospective Review of Mortality Outcomes for Operative Versus Nonoperative Treatment of 322 Patients With Long-Term Follow-up.

STUDY DESIGN.: Retrospective, multicenter cohort study. OBJECTIVE.: Assess for differences in short- and long-term mortality between operative and nonoperative treatment for elderly patients with type II odontoid fractures. SUMMARY OF BACKGROUND DATA.: There is controversy regarding whether operative or nonoperative management is the best treatment for elderly patients with type II odontoid fractures. METHODS.: This is a retrospective study of consecutive patients aged 65 years or older with type II odontoid fracture from 3 level I trauma centers from 2003-2009. Demographics, comorbidities, and treatment were abstracted from medical records. Mortality outcomes were obtained from medical records and a public database. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. RESULTS.: A total of 322 patients were included (mean age, 81.8 yr; range, 65.0-101.5 yr). Compared with patients treated nonoperatively (n = 157), patients treated operatively (n = 165) were slightly younger (80.4 vs. 83.2 yr, P = 0.0014), had a longer hospital (15.0 vs. 7.4 d, P \u3c 0.001) and intensive care unit (1.5 vs. 1.1 d, P = 0.008) stay, and were more likely to receive a feeding tube (18% vs. 5%, P = 0.0003). Operative and nonoperative treatment groups had similar sex distribution (P = 0.94) and Charlson comorbidity index (P = 0.11). Within 30 days of presentation, 14% of patients died, and at maximal follow-up (average = 2.05 yr; range = 0 d-7.02 yr), 44% had died. On multivariate analysis, nonoperative treatment was associated with higher 30-day mortality (HR = 3.00, 95% CI = 1.51-5.94, P = 0.0017), after adjusting for age (HR = 1.10, 95% CI = 1.05-1.14; P \u3c 0.0001), male sex (P = 0.69), and Charlson comorbidity index (P = 0.16). At maximal follow-up, there was a trend toward higher mortality associated with nonoperative treatment (HR = 1.35, 95% CI = 0.97-1.89, P = 0.079), after adjusting for age (HR = 1.07, 95% CI = 1.05-1.10; P \u3c 0.0001), male sex (HR = 1.55, 95% CI = 1.10-2.16; P = 0.012), and Charlson comorbidity index (HR = 1.28, 95% CI = 1.16-1.40; P \u3c 0.0001). CONCLUSION.: Surgical treatment of type II odontoid fracture in this elderly population did not negatively impact survival, even after adjusting for age, sex, and comorbidities. The data suggest a significant 30-day survival advantage and a trend toward improved longer-term survival for operatively treated over nonoperatively treated patients.Level of Evidence: 4

Correction: Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors

Correction for 'Identification of the key structural elements of a dihydropyrimidinone core driving toward more potent Hsp90 C-terminal inhibitors' by S. Teracciano et al., Chem. Commun., 2016, 52, 12857–12860

Good for the heart, good for the Earth: proposal of a dietary pattern able to optimize cardiovascular disease prevention and mitigate climate change

Background and aims: Human and planetary health are inextricably interconnected through food systems. Food choices account for 50% of all deaths for cardiovascular diseases (CVD) - the leading cause of death in Europe - and food systems generate up to 37% of total greenhouse gas (GHG) emissions. Methods and results: Based on a systematic revision of meta-analyses of prospective studies exploring the association between individual foods/food groups and the incidence of CVD, we identified a dietary pattern able to optimize CVD prevention.. This dietary pattern was compared to the current diet of the European population. The nutritional adequacy of both diets was evaluated according to the European Food Safety Authority (EFSA) recommended nutrient intake for the adult population, and their environmental impact was evaluated in terms of carbon footprint (CF). As compared to the current diet, the desirable diet includes higher intakes of fruit, vegetables, wholegrains, low glycemic index (GI) cereals, nuts, legumes and fish, and lower amounts of beef, butter, high GI cereals or potatoes and sugar. The diet here identified provides appropriate intakes of all nutrients and matches better than the current Europeans' one the EFSA requirements. Furthermore, the CF of the proposed diet is 48.6% lower than that of the current Europeans' diet. Conclusion: The transition toward a dietary pattern designed to optimize CVD prevention would improve the nutritional profile of the habitual diet in Europe and, at the same time, contribute to mitigate climate change by reducing the GHG emissions linked to food consumption almost by half

Synthesis of highly luminescent wurtzite CdSe/CdS giant-shell nanocrystals using a fast continuous injection route

We synthesized CdSe/CdS giant-shell nanocrystals, with a CdSe core diameter between 2.8 nm and 5.5 nm, and a CdS shell thickness of up to 7–8 nm (equivalent to about 20 monolayers of CdS). Both the core and shell have a wurtzite crystal structure, yielding epitaxial growth of the shell and nearly defect-free crystals. As a result, the photoluminescence (PL) quantum efficiency (QE) is as high as 90%. Quantitative PL measurements at various excitation wavelengths allow us to separate the nonradiative decay into contributions from interface and surface trapping, giving us pathways for future optimization of the structure. In addition, the NCs do not blink, and the giant shell and concurring strong electron delocalization efficiently suppress Auger recombination, yielding a biexciton lifetime of about 15 ns. The corresponding biexciton PL QE equals 11% in 5.5/18.1 nm CdSe/CdS. Variable-temperature time-resolved PL and PL under magnetic fields further reveal that the emission at cryogenic temperature originates from a negative trion-state, in agreement with other CdSe/CdS giant-shell systems reported in the literature

Body mass index in HER2-negative metastatic breast cancer treated with first-line paclitaxel and bevacizumab

The evidence emerged from the TOURANDOT trial encourages evaluating the role of anthropometric determinants on treatment outcomes in HER2-negative metastatic breast cancer patients treated with bevacizumab-including regimens. We thus analyzed data from a subgroup of these patients from a larger cohort previously assessed for treatment outcomes. Patients were included in the present analysis if body mass index values had been recorded at baseline. Clinical benefit rates, progression free survival and overall survival were assessed for the overall study population and subgroups defined upon molecular subtype. One hundred ninety six patients were included (N:196). Body mass index showed no impact on clinical benefit rates in the overall study sample and in the luminal cancer subset (p = 0.12 and p = 0.79, respectively), but did so in the triple negative subgroup, with higher rates in patients with body mass index ≥25 (p = 0.03). In the overall study sample, body mass index did no impact progression free or overall survival (p = 0.33 and p = 0.67, respectively). Conversely, in triple negative patients, progression free survival was significantly longer with body mass index ≥25 (6 vs 14 months, p = 0.04). In this subset, overall survival was more favorable (25 vs 19 months, p = 0.02). The impact of the molecular subtype was confirmed in multivariate models including the length of progression free survival, and number of metastatic sites (p < 0.0001). Further studies are warranted to confirm our findings in more adequately sized, ad hoc, prospective studies

Hybrid photonic-bandgap accelerating cavities

In a recent investigation, we studied two-dimensional point-defected photonic bandgap cavities composed of dielectric rods arranged according to various representative periodic and aperiodic lattices, with special emphasis on possible applications to particle acceleration (along the longitudinal axis). In this paper, we present a new study aimed at highlighting the possible advantages of using hybrid structures based on the above dielectric configurations, but featuring metallic rods in the outermost regions, for the design of extremely-high quality factor, bandgap-based, accelerating resonators. In this framework, we consider diverse configurations, with different (periodic and aperiodic) lattice geometries, sizes, and dielectric/metal fractions. Moreover, we also explore possible improvements attainable via the use of superconducting plates to confine the electromagnetic field in the longitudinal direction. Results from our comparative studies, based on numerical full-wave simulations backed by experimental validations (at room and cryogenic temperatures) in the microwave region, identify the candidate parametric configurations capable of yielding the highest quality factor.Comment: 13 pages, 5 figures, 3 tables. One figure and one reference added; minor changes in the tex