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

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I-III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimen

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

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

The unidentified TeV source (TeVJ2032+4130) and surrounding field: Final HEGRA IACT-System results

The unidentified TeV source in Cygnus is now confirmed by follow-up observations from 2002 with the HEGRA stereoscopic system of Cherenkov Telescopes. Using all data (1999 to 2002) we confirm this new source as steady in flux over the four years of data taking, extended with radius 6.2 arcmin (+-1.2 arcmin (stat) +-0.9 arcmin (sys)) and exhibiting a hard spectrum with photon index -1.9. It is located in the direction of the dense OB stellar association, Cygnus OB2. Its integral flux above energies E>1 TeV amounts to \~5% of the Crab assuming a Gaussian profile for the intrinsic source morphology. There is no obvious counterpart at radio, optical nor X-ray energies, leaving TeVJ2032+4130 presently unidentified. Observational parameters of this source are updated here and some astrophysical discussion is provided. Also included are upper limits for a number of other interesting sources in the FoV, including the famous microquasar Cygnus X-3.Comment: 7 pages, 3 figures. Accepted for publication in Astronomy & Astrophysic

Simultaneous X-Ray and TeV Gamma-Ray Observations of the TeV Blazar Markarian 421 during February and May 2000

In this paper we present the results of simultaneous observations of the TeV blazar Markarian 421 (Mrk 421) at X-ray and TeV Gamma-ray energies with the Rossi X-Ray Timing Explorer (RXTE) and the stereoscopic Cherenkov Telescope system of the HEGRA (High Energy Gamma Ray Astronomy) experiment, respectively. The source was monitored from February 2nd to February 16th and from May 3rd to May 8th, 2000. We discuss in detail the temporal and spectral properties of the source. Remarkably, the TeV observations of February 7th/8th showed statistically significant evidence for substantial TeV flux variability on 30 min time scale. We show the results of modeling the data with a time dependent homogeneous Synchrotron Self-Compton (SSC) model. The X-ray and TeV gamma-ray emission strengths and energy spectra together with the rapid flux variability strongly suggest that the emission volume is approaching the observer with a Doppler factor of 50 or higher. The different flux variability time scales observed at X-rays and TeV Gamma-rays indicate that a more detailed analysis will require inhomogeneous models with several emission zones.Comment: Accepted for Publication in ApJ, 21 Pages, 5 Figure

Is the giant radio galaxy M 87 a TeV gamma-ray emitter?

For the first time an excess of photons above an energy threshold of 730 GeV from the giant radio galaxy M 87 has been measured at a significance level above 4 σ. The data have been taken during the years 1998 and 1999 with the HEGRA stereoscopic system of 5 imaging atmospheric Cherenkov telescopes. The excess of 107.4 ± 26.8 events above 730 GeV corresponds to an integral flux of 3.3% of the Crab flux or Nγ (E > 730 GeV) = (0.96 ± 0.23) × 10-12 phot cm-2 s-1. M 87 is located at the center of the Virgo cluster of galaxies at a relatively small redshift of z = 0.00436 and is a promising candidate among the class of giant radio galaxies for the emission of TeV γ-radiation. The detection of TeV γ-rays from M 87 - if confirmed - would establish a new class of extragalactic source in this energy regime since all other AGN detected to date at TeV energies are BL Lac type objects.F. A. Aharonian ...G. P. Rowell...et al

Fabrication and use of the dual-flow-rootChip for the imaging of arabidopsis roots in asymmetric microenvironments

Fabrication and Use of the Dual-Flow-RootChip for the Imaging of Arabidopsis Roots in Asymmetric Microenvironment