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Meta-analysis of the overall survival effect of CDK4/6 inhibitors + endocrine therapy combinations in prespecified clinically relevant subgroups of HR+ HER2- metastatic breast cancer

Background: Despite international guidelines support the administration of hormone therapies (HT) ± targeted agents (TA) in postmenopausal hormone receptor positive (HR+ve), human epidermal growth factor receptor 2 negative (HER2-ve) metastatic breast cancer (mBC) [1-3], upfront use of chemotherapy (CT) is still common, even in the absence of life-threatening visceral disease [4-7]. This might be partly due to the lack of direct comparisons among HT and CT regimens. Therefore, in order to compare efficacy and activity of 1st/2nd line CT and HT-based strategies, we planned to perform a network meta-analysis (NMA) using the only methodology capable to compare different treatments that were not investigated head-to-head in randomized controlled trials (RCTs) [8,9]. Methods: We plan a systematic literature search to select all available phase II-III RCT published between January 2000 and December 2017, which evaluate CT or HT ± TA, as 1st and/or 2nd line treatments for postmenopausal women with HR+/HER2-mBC. Primary endpoint: progression-free survival (PFS)/time to tumor progression (TTP). Secondary endpoint: overall response rate (ORR). A Bayesian NMA will be generated to compare posterior median hazard ratios (HR) for PFS and odds ratios (OR) for ORR [8-16]. An endocrine standard first line treatment will be chosen as the HT common comparator for the overall analyses, among the most frequent treatments in the dataset. The combination of palbociclib (palbo) + letrozole (let) will be chosen as the HT + TA common comparator being, among the new 1st line standard of care, the first to be approved worldwide. References Cardoso F, Costa A, Senkus E et al., Ann Oncol 2017; 28 (1):16–33. NCCN clinical practice guidelines in Oncology – Breast Cancer 2018. Available on https://www.nccn.org/professionals Rugo HS, Rumble RB, Macrae E et al., J Clin Oncol 2016; 34(25):3069-3103. Andrè F, Neven P, Marinsek N, et al., Curr Med Res Opin 2014; 30:1007-1016. Bonotto M, Gerratana L, Di Maio M et al, The Breast 2017; 31:114-120. Cazzaniga M, Mustacchi G, Giordano M, et al. Ann Oncol 2017; 28(suppl_5): mdx365.022. Lobbezoo DJA, van Kampen RJW, Voogd AC et al., Ann Oncol 2016; 27: 256–262. Hoaglin DC, Hawkins N, Jansen JP et al., Value Health 2011; 14:429–437. Jansen JP, Fleurence R, Devine B et al., Value Health 2011; 14:417–428. Dias S, Welton NJ, Sutton AJ et al., Technical support document, NICE DSU, 2011. Available from http://www.nicedsu.org.uk. Gelman A, Carlin JB, Stern HS et al. Bayesian Data Analysis. 3rd edition: CRC Press, Boca Raton, Florida, USA, 2014. Jansen JP, BMC Medical Research Methodology 2011; 11: 1–14. Guyot P, Ades AE, Ouwens MJNM et al., BMC Medical Research Methodology 2012; 12:9. Ouwens MJNM, Philips Z, Jansen JP, Research Synthesis Methods 2010; 1:258–271. Parmar MKB, Torri V, Stewart L, Statistics in Medicine 1998; 17:2815–2834. Lunn DJ, Thomas A, Best N et al., Statistics and Computing 2000; 10:325–337.

The following paper is a variation on a theme of Gianfranco Cimmino on some integral representation formulas for the solution of a linear equations system. Cimmino was probably motivated for giving a representation formula suitable not only for theoretical investigations but also for applied computation. In this paper we will prove that the Cimmino integrals are strictly related to the residues of some zeta-like functions associated to the linear system., Comment: 17 pages, to appear in Mathematicians in Bologna 1861-1960, Salvatore Coen (Editor), Universit\`a di bologna, Italy, Birkh\"auser. ISBN 978-3-0348-0226-0

Let V be a real hypersurface of class C^k, k>=3, in a complex manifold M of complex dimension n+1, HT(V) the holomorphic tangent bundle to V giving the induced CR structure on V. Let \theta be a contact form for (V,HT(V)), \xi_0 the Reeb vector field determined by \theta and assume that \xi_0 is of class C^k. In this paper we prove the following theorem (cf. Theorem 4.1): if the integral curves of \xi_0 are real analytic then there exist an open neighbourhood N\subset M of V and a solution u\in C^k(N) of the complex Monge-Amp\`ere equation (dd^c u)^(n+1)=0 on N which is a defining equation for V. Moreover, the Monge-Amp\`ere foliation associated to u induces on V that one associated to the Reeb vector field. The converse is also true. The result is obtained solving a Cauchy problem for infinitesimal symmetries of CR distributions of codimension one which is of independent interest (cf. Theorem 3.1)., Comment: 15 pages

An important question in health services research is the estimation of the proportion of medical expenditures that exceed a given threshold. Typically, medical expenditures present highly skewed, heavy tailed distributions, for which (a) simple variable transformations are insufficient to achieve a tractable low-dimensional parametric form and (b) nonparametric methods are not efficient in estimating exceedance probabilities for large thresholds. Motivated by this context, in this paper we propose a general Bayesian approach for the estimation of tail probabilities of heavy-tailed distributions, based on a mixture of gamma distributions in which the mixing occurs over the shape parameter. This family provides a flexible and novel approach for modeling heavy-tailed distributions, it is computationally efficient, and it only requires to specify a prior distribution for a single parameter. By carrying out simulation studies, we compare our approach with commonly used methods, such as the log-normal model and nonparametric alternatives. We found that the mixture-gamma model significantly improves predictive performance in estimating tail probabilities, compared to these alternatives. We also applied our method to the Medical Current Beneficiary Survey (MCBS), for which we estimate the probability of exceeding a given hospitalization cost for smoking attributable diseases. We have implemented the method in the open source GSM package, available from the Comprehensive R Archive Network., Published in at http://dx.doi.org/10.1214/07-AOAS156 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)

Let $Q(x)$ be a quadratic form over $\mathbb{R}^n$. The Epstein zeta function associated to $Q(x)$ is a well known function in number theory. We generalize the construction of the Epstein zeta function to a class of function $\phi(x)$ defined in $\mathbb{R}^n$ that we call $A-$homogeneous, where $A$ is a real aquare matrix of order $n$ having each eigenvalue in the left hal space $\Re\lambda>0$. Such a class includes all the homogeneous polynomials (positive outside the origin) and all the norms on $\mathbb{R}^n$ which are smooth outside the origin. As in the classical (i.e. quadratic) case we prove that such zeta functions are obtained from the Mellin transforms of theta function of Jacobi type associated to the $A-$homogeneous function $\phi(x)$. We prove that the zeta function associated to a $A-$homogeneous function $\phi(x)$ which is positive and smooth outside the origin is an entire meromorphic function having a unique simple pole at $s=\alpha$ the trace of the matrix $A$ with residue given by the product of the trace $\alpha$ and the Lebesgue volume of the unit ball associated to $\phi(x)$, that is the volume of the set $x\in\R^n$ satisfying $\phi(x), Comment: 24 pages

The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naïve bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA.

// Manuela Milani 1, * , Sergio Venturini 2, * , Simone Bonardi 1 , Giovanni Allevi 1 , Carla Strina 1 , Maria Rosa Cappelletti 1 , Silvia Paola Corona 3 , Sergio Aguggini 1 , Alberto Bottini 1 , Alfredo Berruti 4 , Adrian Jubb 5 , Leticia Campo 5 , Adrian L. Harris 5 , Kevin Gatter 5 , Stephen B. Fox 6 , Daniele Generali 1, 7 and Giandomenico Roviello 7, 8 1 U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, ASST Cremona, Viale Concordia 1, Cremona, Italy 2 CE.R.G.A.S., Universita Bocconi, Milano, Italy 3 Peter MacCallum Cancer Centre, Bentleigh East VIC, Australia 4 U.O. Oncologia Medica, Spedali Civili si Brescia, University of Brescia, Brescia, Italy 5 Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK 6 Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia 7 Department of Medical, Surgery and Health Sciences, University of Trieste, Piazza Ospitale 1, Trieste, Italy 8 Department of Oncology, Medical Oncology Unit, San Donato Hospital, Italy * Manuela Milani and Sergio Venturini contributed equally to the study Correspondence to: Daniele Generali, email: daniele.generali@gmail.com Keywords: epirubicin resistance, haemoglobin, hypoxia-inducible factor, neoadjuvant, breast cancer Received: September 21, 2015 Accepted: July 18, 2017 Published: August 14, 2017 ABSTRACT Purpose: To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer. Patients and Methods: One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization. Results: VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival. Conclusion: Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome.

we report a prospective study to define the epidemiological, clinical, microbiological, echocardiographic characteristics and the out-come of IE in different age groups in order to evaluate age-related differences.