Tumor slice culture system to assess drug response of primary breast cancer

Background The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary treatment that would mainly result in the unwanted side effects of the therapy. This selection can be facilitated by characterization of individual tumors using robust and specific functional assays, which requires development of powerful ex vivo culture systems and procedures to analyze the response to treatment. Methods We optimized culture methods for primary breast tumor samples that allowed propagation of tissue ex vivo. We combined several tissue culture strategies, including defined tissue slicing technology, growth medium optimization and use of a rotating platform to increase nutrient exchange. Results We could maintain tissue cultures for at least 7 days without losing tissue morphology, viability or cell proliferation. We also developed methods to determine the cytotoxic response of individual tumors to the chemotherapeutic treatment FAC (5-FU, Adriamycin [Doxorubicin] and Cyclophosphamide). Using this tool we designated tumors as sensitive or resistant and distinguished a clinically proven resistant tumor from other tumors. Conclusion This method defines conditions that allow ex vivo testing of individual tumor responses to anti-cancer drugs and therefore might improve personalization of breast cancer treatment

Performance of BRCA1/2 mutation prediction models in male breast cancer patients

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources

Tumor slice culture system to assess drug response of primary breast cancer

Background: The high incidence of breast cancer has sparked the development of novel targeted and personalized therapies. Personalization of cancer treatment requires reliable prediction of chemotherapy responses in individual patients. Effective selection can prevent unnecessary treatment that would mainly result in the unwanted side effects of the therapy. This selection can be facilitated by characterization of individual tumors using robust and specific functional assays, which requires development of powerful ex vivo culture systems and procedures to analyze the response to treatment. Methods: We optimized culture methods for primary breast tumor samples that allowed propagation of tissue ex vivo. We combined several tissue culture strategies, including defined tissue slicing technology, growth medium optimization and use of a rotating platform to increase nutrient exchange. Results: We could maintain tissue cultures for at least 7days without losing tissue morphology, viability or cell proliferation. We also developed methods to determine the cytotoxic response of individual tumors to the chemotherapeutic treatment FAC (5-FU, Adriamycin [Doxorubicin] and Cyclophosphamide). Using this tool we designated tumors as sensitive or resistant and distinguished a clinically proven resistant tumor from other tumors. Conclusion: This method defines conditions that allow ex vivo testing of individual tumor responses to anti-cancer drugs and therefore might improve personalization of breast cancer treatment

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

Measurement of the p-pbar -> Wgamma + X cross section at sqrt(s) = 1.96 TeV and WWgamma anomalous coupling limits

The WWgamma triple gauge boson coupling parameters are studied using p-pbar -> l nu gamma + X (l = e,mu) events at sqrt(s) = 1.96 TeV. The data were collected with the DO detector from an integrated luminosity of 162 pb^{-1} delivered by the Fermilab Tevatron Collider. The cross section times branching fraction for p-pbar -> W(gamma) + X -> l nu gamma + X with E_T^{gamma} > 8 GeV and Delta R_{l gamma} > 0.7 is 14.8 +/- 1.6 (stat) +/- 1.0 (syst) +/- 1.0 (lum) pb. The one-dimensional 95% confidence level limits on anomalous couplings are -0.88 < Delta kappa_{gamma} < 0.96 and -0.20 < lambda_{gamma} < 0.20.Comment: Submitted to Phys. Rev. D Rapid Communication

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt{s} = 1.96 TeV using Kinematic Characteristics of Lepton + Jets Events

We present a measurement of the top quark pair ttbar production cross section in ppbar collisions at a center-of-mass energy of 1.96 TeV using 230 pb**{-1} of data collected by the DO detector at the Fermilab Tevatron Collider. We select events with one charged lepton (electron or muon), large missing transverse energy, and at least four jets, and extract the ttbar content of the sample based on the kinematic characteristics of the events. For a top quark mass of 175 GeV, we measure sigma(ttbar) = 6.7 {+1.4-1.3} (stat) {+1.6- 1.1} (syst) +/-0.4 (lumi) pb, in good agreement with the standard model prediction.Comment: submitted to Phys.Rev.Let

Measurement of the ttbar Production Cross Section in ppbar Collisions at sqrt(s)=1.96 TeV using Lepton + Jets Events with Lifetime b-tagging

We present a measurement of the top quark pair ($t\bar{t}$) production cross section ($\sigma_{t\bar{t}}$) in $p\bar{p}$ collisions at $\sqrt{s}=1.96$ TeV using 230 pb$^{-1}$ of data collected by the D0 experiment at the Fermilab Tevatron Collider. We select events with one charged lepton (electron or muon), missing transverse energy, and jets in the final state. We employ lifetime-based b-jet identification techniques to further enhance the $t\bar{t}$ purity of the selected sample. For a top quark mass of 175 GeV, we measure $\sigma_{t\bar{t}}=8.6^{+1.6}_{-1.5}(stat.+syst.)\pm 0.6(lumi.)$ pb, in agreement with the standard model expectation.Comment: 7 pages, 2 figures, 3 tables Submitted to Phys.Rev.Let

Measurement of the ratios of the Z/G* + >= n jet production cross sections to the total inclusive Z/G* cross section in ppbar collisions at sqrt(s) = 1.96 TeV

We present a study of events with Z bosons and jets produced at the Fermilab Tevatron Collider in ppbar collisions at a center of mass energy of 1.96 TeV. The data sample consists of nearly 14,000 Z/G* -> e+e- candidates corresponding to the integrated luminosity of 0.4 fb-1 collected using the D0 detector. Ratios of the Z/G* + >= n jet cross sections to the total inclusive Z/G* cross section have been measured for n = 1 to 4 jet events. Our measurements are found to be in good agreement with a next-to-leading order QCD calculation and with a tree-level QCD prediction with parton shower simulation and hadronization.Comment: 7 pages, 2 figures, slightly modified, submitted to Phys. Lett.

The RECAP Test Rapidly and Reliably Identifies Homologous Recombination-Deficient Ovarian Carcinomas

Recent studies have shown that the efficacy of PARP inhibitors in epithelial ovarian carcinoma (EOC) is related to tumor-specific defects in homologous recombination (HR) and extends beyond BRCA1/2 deficient EOC. A robust method with which to identify HR-deficient (HRD) carcinomas is therefore of utmost clinical importance. In this study, we investigated the proficiency of a functional HR assay based on the detection of RAD51 foci, the REcombination CAPacity (RECAP) test, in identifying HRD tumors in a cohort of prospectively collected epithelial ovarian carcinomas (EOCs). Of the 39 high-grade serous ovarian carcinomas (HGSOC), the RECAP test detected 26% (10/39) to be HRD, whereas ovarian carcinomas of other histologic subtypes (n = 10) were all HR-proficient (HRP). Of the HRD tumors that could be sequenced, 8/9 showed pathogenic BRCA1/2 variants or BRCA1 promoter hypermethylation, indicating that the RECAP test reliably identifies HRD, including but not limited to tumors related to BRCA1/2 deficiency. Furthermore, we found a trend towards better overall survival (OS) of HGSOC patients with RECAP-identified HRD tumors compared to patients with HRP tumors. This study shows that the RECAP test is an attractive alternative to DNA-based HRD tests, and further development of a clinical grade RECAP test is clearly warranted

Measurement of the Isolated Photon Cross Section in p-pbar Collisions at sqrt{s}=1.96 TeV

The cross section for the inclusive production of isolated photons has been measured in p anti-p collisions at sqrt{s}=1.96 TeV with the D0 detector at the Fermilab Tevatron Collider. The photons span transverse momenta 23 to 300 GeV and have pseudorapidity |eta|<0.9. The cross section is compared with the results from two next-to-leading order perturbative QCD calculations. The theoretical predictions agree with the measurement within uncertainties.Comment: 7 pages, 5 figures, submitted to Phys.Lett.