Human epidermal growth factor receptor 2 expression in early breast cancer patients: a Swiss cost-effectiveness analysis of different predictive assay strategies

Trastuzumab has conferred significant clinical benefits in HER-2-positive breast carcinomas. HER-2 status is determined by immunohistochemistry (IHC) and/or fluorescence in situ hybridisation (FISH), but appropriate assessment of HER2 status remains subject to considerable debate. Data on the health economic impact of HER-2 test strategies are limited. A life-long Markov state transition model was used to assess costs and effectiveness of HER-2 assay strategies (based on IHC, FISH, both combined or FISH confirmation of IHC2+) for a hypothetical cohort of early breast cancer patients from the perspective of the Swiss health system. We compared clinically relevant strategies of predictive testing and subsequent trastuzumab treatment of HER-2-positive patients only. FISH testing was the most cost-effective strategy with an incremental cost-effectiveness ratio of €12,245 per additional quality-adjusted life-year (QALY) gained, compared to no trastuzumab treatment. The next best strategy was parallel IHC and FISH, with costs of €400,154/QALY gained compared to FISH alone. FISH as primary HER-2 testing modality remained the preferred option in deterministic and probabilistic sensitivity analysis. Predictive testing to identify adjuvant breast cancer patients who benefit from trastuzumab treatment is a clinical and economic necessity. Our model identifies FISH as the most cost-effective approac

The expression of PD-L1 in salivary gland carcinomas

Objective was to analyze the role of PD-L1 and its relation to demographic, patho-clinical and outcome parameters in salivary gland carcinoma (SGC) patients. Patients treated for salivary gland carcinomas between 1994 and 2010 were included. A retrospective chart review for baseline characteristics, pathohistological, clinical and outcome data was performed. Immunohistochemistry for PD-L1 was performed using tissue microarrays. PD-L1 expression was assessed in tumor cells and tumor-infiltrating immune cells (TIIC) and statistical analysis with regard to baseline and outcome data was performed. Expression of PD-L1 (by means ≥1% of the cells with PD-L1 positivity) was present in the salivary gland carcinoma cells of 17%, in the TIIC of 20% and in both tumor cells and TIIC of 10% the patients. PD-L1 expression in tumor cells and both tumor cells and TIIC was related to tumor grading (p = 0.035 and p = 0.031, respectively). A trend towards higher grading was also seen for PD-L1 expression in TIICs (p = 0.058). Patients with salivary duct carcinomas and PD-L1 expressing TIICs showed a significantly worse DFS and OS (p = 0.022 and p = 0.003, respectively), those with both tumor cells and TIIC expressing PD-L1 a significantly worse DFS (p = 0.030). PD-L1 expression is present in 17% and 20% of salivary gland carcinoma cells and TIIC. Ten percent of the patient showed a PD-L1 positivity in both tumor cells and TIIC. This is related to high tumor grading and therefore might be a negative prognostic factor

Higgs Decay to Gluons at NNLO

We present an analytical calculation of the next-to-next-to-leading order corrections to the partial decay width $H\to gg$ for a Higgs boson in the intermediate mass range. We apply an asymptotic expansion for $M_H\ll 2M_t$ and compute three terms in the expansion. The leading term confirms the results present in the literature. It is argued that our result is equivalent to an exact calculation up to $M_H\approx M_t$. For a Higgs boson mass of 120 GeV the power-suppressed terms lead to corrections of about 9% in the next-to-next-to-leading order coefficient.Comment: 13 pages, minor corrections, references corrected and added, to be published in Phys. Lett.

Analysis of the PARP1, ADP-Ribosylation, and TRIP12 Triad With Markers of Patient Outcome in Human Breast Cancer

PARP inhibitors (PARPi) are increasingly used in breast cancer therapy, including high-grade triple-negative breast cancer (TNBC) treatment. Varying treatment responses and PARPi resistance with relapse currently limit the efficacy of PARPi therapy. The pathobiological reasons why individual patients respond differently to PARPi are poorly understood. In this study, we analyzed the expression of PARP1, the main target of PARPi, in normal breast tissue, breast cancer, and its precursor lesions using human breast cancer tissue microarrays covering a total of 824 patients, including more than 100 TNBC cases. In parallel, we analyzed nuclear adenosine diphosphate (ADP)-ribosylation as a marker of PARP1 activity and TRIP12, an antagonist of PARPi-induced PARP1 trapping. Although we found PARP1 expression generally increased in invasive breast cancer, PARP1 protein levels and nuclear ADP-ribosylation were lower in higher tumor grade and TNBC samples than non-TNBCs. Cancers with low levels of PARP1 and low levels of nuclear ADP-ribosylation were associated with significantly reduced overall survival. This effect was even more pronounced in cases with high levels of TRIP12. These results indicate that PARP1-dependent DNA repair capacity may be compromised in aggressive breast cancers, potentially fueling enhanced accumulation of mutations. Moreover, the results revealed a subset of breast cancers with low PARP1, low nuclear ADP-ribosylation, and high TRIP12 levels, which may compromise their response to PARPi, suggesting a combination of markers for PARP1 abundance, enzymatic activity, and trapping capabilities might aid patient stratification for PARPi therapy

Three-loop off-forward evolution kernel for axial-vector operators in Larin’s scheme

Evolution equations for leading-twist operators in high orders of perturbation theory can be restored from the spectrum of anomalous dimensions and the calculation of the special conformal anomaly at one order less using conformal symmetry of QCD at the Wilson-Fisher critical point at noninteger d=4−2ϵ space-time dimensions. In this work, we generalize this technique to axial-vector operators. We calculate the corresponding three-loop evolution kernels in Larin’s scheme and derive explicit expressions for the finite renormalization kernel that describes the difference to the vector case to restore the conventional modified minimal subtraction scheme. The results are directly applicable to deeply virtual Compton scattering and the transition form factor γ∗γ→π

Infrared Singularities and Soft Gluon Resummation with Massive Partons

Infrared divergences of QCD scattering amplitudes can be derived from an anomalous dimension matrix, which is also an essential ingredient for the resummation of large logarithms due to soft gluon emissions. We report a recent analytical calculation of the anomalous dimension matrix with both massless and massive partons at two-loop level, which describes the two-loop infrared singularities of any scattering amplitudes with an arbitrary number of massless and massive partons, and also enables soft gluon resummation at next-to-next-to-leading-logarithmic order. As an application, we calculate the infrared poles in the q qbar -> t tbar and gg -> t tbar scattering amplitudes at two-loop order.Comment: Talk presented at Loops and Legs in Quantum Field Theory 2010, Woerlitz, Germany, April 25-30, 201

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours

On the Structure of Infrared Singularities of Gauge-Theory Amplitudes

A closed formula is obtained for the infrared singularities of dimensionally regularized, massless gauge-theory scattering amplitudes with an arbitrary number of legs and loops. It follows from an all-order conjecture for the anomalous-dimension matrix of n-jet operators in soft-collinear effective theory. We show that the form of this anomalous dimension is severely constrained by soft-collinear factorization, non-abelian exponentiation, and the behavior of amplitudes in collinear limits. Using a diagrammatic analysis, we demonstrate that these constraints imply that to three-loop order the anomalous dimension involves only two-parton correlations, with the possible exception of a single color structure multiplying a function of conformal cross ratios depending on the momenta of four external partons, which would have to vanish in all two-particle collinear limits. We argue that such a function does not appear at three-loop order, and that the same is true in higher orders. Our formula predicts Casimir scaling of the cusp anomalous dimension to all orders in perturbation theory, and we explicitly check that the constraints exclude the appearance of higher Casimir invariants at four loops. Using known results for the quark and gluon form factors, we derive the three-loop coefficients of the 1/epsilon^n pole terms (with n=1,...,6) for an arbitrary n-parton scattering amplitude in massless QCD. This generalizes Catani's two-loop formula proposed in 1998.Comment: 46 pages, 9 figures; v2: improved treatment of collinear limits, references added; v3: improved discussion of non-abelian exponentiation, references updated; v4: typo in eq. (17) fixed, references updated; v5: additional term in (17

Ultra-deep sequencing confirms immunohistochemistry as a highly sensitive and specific method for detecting BRAF V600E mutations in colorectal carcinoma

The activating BRAF V600 mutation is a well-established negative prognostic biomarker in metastatic colorectal carcinoma (CRC). A recently developed monoclonal mouse antibody (clone VE1) has been shown to detect reliably BRAF V600E mutated protein by immunohistochemistry (IHC). In this study, we aimed to compare the detection of BRAF V600E mutations by IHC, Sanger sequencing (SaS), and ultra-deep sequencing (UDS) in CRC. VE1-IHC was established in a cohort of 68 KRAS wild-type CRCs. The VE1-IHC was only positive in the three patients with a known BRAF V600E mutation as assessed by SaS and UDS. The test cohort consisted of 265 non-selected, consecutive CRC samples. Thirty-nine out of 265 cases (14.7%) were positive by VE1-IHC. SaS of 20 randomly selected IHC negative tumors showed BRAF wild-type (20/20). Twenty-four IHC-positive cases were confirmed by SaS (24/39; 61.5%) and 15 IHC-positive cases (15/39; 38.5%) showed a BRAF wild-type by SaS. UDS detected a BRAF V600E mutation in 13 of these 15 discordant cases. In one tumor, the mutation frequency was below our threshold for UDS positivity, while in another case, UDS could not be performed due to low DNA amount. Statistical analysis showed sensitivities of 100% and 63% and specificities of 95 and 100% for VE1-IHC and SaS, respectively, compared to combined results of SaS and UDS. Our data suggests that there is high concordance between UDS and IHC using the anti-BRAFV600E (VE1) antibody. Thus, VE1 immunohistochemistry is a highly sensitive and specific method in detecting BRAF V600E mutations in colorectal carcinom

Board examination for anatomical pathology in Switzerland: two intense days to verify professional competence

About 15years ago, the Swiss Society of Pathology has developed and implemented a board examination in anatomical pathology. We describe herein the contents covered by this 2-day exam (autopsy pathology, cytology, histopathology, molecular pathology, and basic knowledge about mechanisms of disease) and its exact modalities, sketch a brief history of the exam, and finish with a concise discussion about the possible objectives and putative benefits weighed against the hardship that it imposes on the candidate