Staging for distant metastases in operable breast cancer: a suggested expansion of the ESMO guideline recommendation for staging imaging of node-negative, hormonal receptor-negative disease

We evaluated the impact of staging procedures to detect asymptomatic distant metastases (DM) in the management of women with operable invasive breast cancer (BC, entire cohort: n = 866). Out of 472 patients with lymph node (LN)-negative disease (pN0), DM were found in four cases (detection rate: 0.8%). All four patients presented with established risk factors: hormone receptor (HR)-negative status, HER2-positive status, n = 3; ‘triple-negative' disease, n = 1. Considering the subgroup of LN-negative patients whose tumors showed the risk factor ‘negative HR status' (n = 66), the detection rate of DM was 6%. The detection rates of DM in higher pN categories were as follows: pN1:1.7%; pN2:9.5%; pN3:13.5%. We generally support the international guidelines, including those published by the European Society for Medical Oncology (ESMO) which emphasize that patients with early-stage BC do not profit from radiological staging for the detection of DM and recommend refraining from this. However, we would expand these guidelines and propose that screening should be carried out in node-negative patients whose tumors show established tumor-related risk factors (e.g. HR-negative and HER2-positive status), since in this particular subcohort, the detection rate of DM is with 6% similarly high as that of patients with four to nine positive LN

Fostering Intrapreneurship through the Implementation of Internal Corporate Accelerators

Today’s markets are characterized by fast and radical changes, posing an essential challenge to established companies. Startups, yet, seem to be more capable in developing radical innovations to succeed in those volatile markets. Thus, established companies started to experiment with various approaches to implement startup-like structures in their organization. Internal corporate accelerators (ICAs) are a novel form of corporate venturing, aiming to foster bottom-up innovations through intrapreneurship. However, ICAs still lack empirical investigations. This work contributes to a deeper understanding of the interface between the ICA and the core organization and the respective support activities (resource access and support services) that create an innovation-supportive work environment for the intrapreneurial team. The results of this qualitative study, comprising 12 interviews with ICA teams out of two German high-tech companies, show that the resources provided by ICAs differ from the support activities of external accelerators. Further, the study shows that some resources show both supportive as well as obstructive potential for the intrapreneurial teams within the ICA

An unidentified TeV source in the vicinity of Cygnus OB2

Deep observation (∼113 hrs) of the Cygnus region at TeV energies using the HEGRA stereoscopic system of air Čerenkov telescopes has serendipitously revealed a signal positionally inside the core of the OB association Cygnus OB2, at the edge of the 95% error circle of the EGRET source 3EG J2033+4118, and ∼0.5° north of Cyg X-3. The source centre of gravity is RA αJ2000: 20hr32m07s± 9.2stats±2.2syss, Dec δJ2000: +41°30′30″2.0stat±0.4′sys. The source is steady, has a post-trial significance of +4.6σ, indication for extension with radius 5.6′ at the ∼3σ level, and has a differential power-law flux with hard photon index of - 1.9 ± 0.3stat ± 0.3sys. The integral flux above 1 TeV amounts ∼3% that of the Crab. No counterpart for the TeV source at other wavelengths is presently identified, and its extension would disfavour an exclusive pulsar or AGN origin. If associated with Cygnus OB2, this dense concentration of young, massive stars provides an environment conducive to multi-TeV particle acceleration and likely subsequent interaction with a nearby gas cloud. Alternatively, one could envisage γ-ray production via a jet-driven termination shock.F. A. Aharonian, ... G. P. Rowell, ... [et al

The systematic tunability of nanoparticle dimensions through the controlled loading of surface-deposited diblock copolymer micelles

The continuous tunability of iron oxide nanoparticle dimensions is demonstrated using the pH controlled loading of ferric nitrate from aqueous solution into polystyrene–block–polyacrylic acid reverse micelles deposited on a silicon substrate. Quasi-hexagonally ordered two-dimensional arrays of iron oxide nanoparticles with a systematic tunability of particle heights in the sub-10 nm regime and a constant periodicity are obtained and characterized with atomic force microscopy and x-ray photoelectron spectroscopy

Nanodispenser for attoliter volume deposition using atomic force microscopy probes modified by focused-ion-beam milling

In this letter, we describe the on-demand dispensing of single liquid droplets with volumes down to a few attoliters and submicrometric spacing. This dispensing is achieved using a standard atomic force microscope probe, with a 200 nm aperture at the tip apex, opened by focused ion beam milling. The inside of the tip is used as reservoir for the liquid. This maskless dispensing, realized in ambient environment, permits the direct creation of droplet arrays. Nanoparticles, suspended in the liquid, were organized on a surface

5PMICROTUBULE-DEPOLYMERIZING AGENTS USED IN ANTIBODY-DRUG-CONJUGATES INDUCE ANTITUMOR ACTIVITY BY STIMULATION OF DENDRITIC CELLS

Antibody drug conjugates (ADCs) are emerging as powerful treatment strategies with outstanding target specificity and high therapeutic activity in cancer patients. While >30 ADCs are currently being investigated in clinical trials, brentuximabvedotin and T-DM1 represent clinically approved ADCs in cancer patients. We hypothesized that their sustained clinical responses could be related to the stimulation of an antitumor immune response. Indeed, the two microtubule-destabilizing agents Dolastatin 10 and Ansamitocin P3, from which the cytotoxic components of brentuximabvedotin and T-DM1 are derived, may serve as prototypes for a class of agents that induce tumor cell death and convert tumor resident, tolerogenic dendritic cells (DCs) into efficient antigen presenting cells (APCs). The two drugs induced phenotypic and functional maturation of murine splenic as well as human monocyte-derived DCs. In contrast, microtubule-stabilizing agents such as taxanes did not display this feature. In tumor models, both Dolastatin 10 and Ansamitocin P3 efficiently promoted antigen uptake and migration of tumor-resident DCs to tumor-draining lymph nodes, thereby potentiating tumor-specific T cell responses. Underlining the requirement of an intact host immune system for the full therapeutic benefit of these two compounds, their antitumor effect was far less pronounced in mice lacking adaptive immunity or dendritic cells. Combinations with immune checkpoint inhibition (anti-CTLA-4/-PD-1) did further augment antitumor immunity and tumor rejection, which was reflected by reduced Treg numbers and elevated effector function of tumor resident T cells. Ultimately, we were able to demonstrate peripheral immune cell activation and brisk T cell infiltration into tumors in patients previously treated with BrentuximabVedotin. Experiments are currently ongoing to investigate the immunological mode of action of T-DM1 using orthotopic breast cancer models and patients undergoing treatment. Our data reveal a novel mode of action for microtubule-depolymerizing agents and provide a strong rationale for clinical treatment regimens combining these with immune-based therapies. Disclosure: All authors have declared no conflicts of interes

Immobilization of trypsin in organic and aqueous media for enzymatic peptide synthesis and hydrolysis reactions

Background: Immobilization of enzymes onto different carriers increases enzyme\u27s stability and reusability within biotechnological and pharmaceutical applications. However, some immobilization techniques are associated with loss of enzymatic specificity and/or activity. Possible reasons for this loss are mass transport limitations or structural changes. For this reason an immobilization method must be selected depending on immobilisate\u27s demands. In this work different immobilization media were compared towards the synthetic and hydrolytic activities of immobilized trypsin as model enzyme on magnetic micro-particles. Results: Porcine trypsin immobilization was carried out in organic and aqueous media with magnetic microparticles. The immobilization conditions in organic solvent were optimized for a peptide synthesis reaction. The highest carrier activity was achieved at 1 % of water (v/v) in dioxane. The resulting immobilizate could be used over ten cycles with activity retention of 90 % in peptide synthesis reaction in 80 % (v/v) ethanol and in hydrolysis reaction with activity retention of 87 % in buffered aqueous solution. Further, the optimized method was applied in peptide synthesis and hydrolysis reactions in comparison to an aqueous immobilization method varying the protein input. The dioxane immobilization method showed a higher activity coupling yield by factor 2 in peptide synthesis with a maximum activity coupling yield of 19.2 % compared to aqueous immobilization. The hydrolysis activity coupling yield displayed a maximum value of 20.4 % in dioxane immobilization method while the aqueous method achieved a maximum value of 38.5 %. Comparing the specific activity yields of the tested immobilization methods revealed maximum values of 5.2 % and 100 % in peptide synthesis and 33.3 % and 87.5 % in hydrolysis reaction for the dioxane and aqueous method, respectively. Conclusions: By immobilizing trypsin in dioxane, a beneficial effect on the synthetic trypsin activity resilience compared to aqueous immobilization medium was shown. The results indicate a substantial potential of the micro-aqueous organic protease immobilization method for preservation of enzymatic activity during enzyme coupling step. These results may be of substantial interest for enzymatic peptide synthesis reactions at mild conditions with high selectivity in industrial drug production. © 2015 Stolarow et al