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BACKGROUND: In a pre-vaccination era serologic tests may be used to evaluate the seroprevalence and efficacy of containment strategies applied to the community. Subsequently, SARS-CoV-2 vaccination has successfully reduced hospitalization and admission to intensive care. The role of antiviral treatment for COVID-19 remains debated. OBJECTIVE: We investigated the effect of SARS-CoV-2 IgG Spike (S) antibody responses in hospitalized patients on 30-day mortality. Finally, we assessed whether other predictive factors affected mortality after 30 days. METHODS: Observational study on COVID-19 patients admitted from October 1, 2021, to January 30, 2022. RESULTS: 520 patients were studied; 108 died at the 30-day follow-up (21%). A borderline significance for mortality was observed in favour of the high antibody titer group (24% vs 17%, p=0.05). From the univariate Cox regression analysis, a high IgG-S titer was significantly correlated to lower 30-day mortality (p=0.04, HR: 0.7; 95%CI: 0.44–0.98). The administration of remdesivir (p=0.01) and the age

BACKGROUND: Catheter-related bloodstream infections (CRBSI) represent a frequent complication of vascular catheterization, with high morbidity, mortality, and associated costs. Most infections are caused by Gram-positive bacteria; thus dalbavancin, a new long-acting lipoglicopeptide, may have a role in early patient discharge strategies optimizing treatment and reducing overall costs. METHODS: In this small pilot feasibility study, we assessed the efficacy and safety of a “single step” treatment strategy combining dalbavancin administration (1500 mg IV single dose), catheter removal, and early discharge in adult patients admitted to medical wards in a three-year period. RESULTS: We enrolled sixteen patients with confirmed Gram-positive CRBSI, with a mean age of 68 years and relevant comorbidities (median Charlson Comorbidity index=7). The most frequent causative agents were staphylococci, with 25% of methicillin-resistant strains, and the majority of infected devices were short term central venous catheter (CVC) and peripherally inserted central catheter (PICC). Ten out of sixteen patients had been treated empirically before dalbavancin administration. The mean time from dalbavancin administration to discharge was 2 days; none of the patients had adverse drug-related reactions; at 30- and 90-day follow-up, no patients have been readmitted to the hospital due to bacteraemia recurrence. CONCLUSIONS: Our results indicate that single-dose dalbavancin is highly effective, well-tolerated, and cost-saving for Gram-positive CRBSI.

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.

We introduce the stepp packages for R and Stata that implement the subpopulation treatment effect pattern plot (STEPP) method. STEPP is a nonparametric graphical tool aimed at examining possible heterogeneous treatment effects in subpopulations defined on a continuous covariate or composite score. More pecifically, STEPP considers overlapping subpopulations defined with respect to a continuous covariate (or risk index) and it estimates a treatment effect for each subpopulation. It also produces confidence regions and tests for treatment effect heterogeneity among the subpopulations. The original method has been extended in different directions such as different survival contexts, outcome types, or more efficient procedures for identifying the overlapping subpopulations. In this paper, we also introduce a novel method to determine the number of subjects within the subpopulations by minimizing the variability of the sizes of the subpopulations generated by a specific parameter combination. We illustrate the packages using both synthetic data and publicly available data sets. The most intensive computations in R are implemented in Fortran, while the Stata version exploits the powerful Mata language.

Let $L(s)=\sum_{n=1}^{+\infty}\dfrac{a(n)}{n^s}$ be a Dirichlet series were $a(n)$ is a bounded completely multiplicative function. We prove that if $L(s)$ extends to a holomorphic function on the open half space $\Re s >1-\delta$, $\delta>0$ and $L(1)=0$ then such a half space is a zero free region of the Riemann zeta function $\zeta(s)$. Similar results is proven for completely multiplicative functions defined on the space of the ideals of the ring of the algebraic integers of a number field of finite degree., Comment: 24 pages. Published in Riv. Mat. Univ. Parma with the title "Non vanishing of Dirichlet series of completely multiplicative functions"

Let $\MSpace$ be a locally compact metric space and let $\pMap:\MSpace\to\MSpace$ be a not expansive map. We prove that for each $\ppa_0\in\MSpace$ the sequence $\ppa_0,\pMap(\ppa_0),\pMap^2(\ppa_0),\ldots$ is either relatively compact in $\MSpace$ or compactly divergent in $\MSpace$. As applications we study the structure of the functions which are limits of the iterates of the map $\pMap$ and we prove the analyticity of the set of $\pMap$-recurrent points when $\pMap:\MSpace\to\MSpace$ is a holomorphic and $\MSpace$ is a complex hyperbolic spaces in the sense of Kobayashi., 22 pages

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 $M$ be a complex manifold of complex dimension $n+k$. We say that the functions $u_1,...s,u_k$ and the vector fields $\xi_1,...,\xi_k$ on $M$ form a \emph{complex gradient system} if $\xi_1,...,\xi_k,J\xi_1,...,J\xi_k$ are linearly independent at each point $p\in M$ and generate an integrable distribution of $TM$ of dimension $2k$ and $du_\alpha(\xi_\beta)=0$, $\d^c\u_\alpha(\xi_\beta)=\delta_{\alpha\beta}$ for $\alpha,\beta=1,...,k$. We prove a Cauchy theorem for such complex gradient systems with initial data along a $\CR-$submanifold of type $(\CRdim,\CRcodim)$. We also give a complete local characterization for the complex gradient systems which are \emph{holomorphic} and \emph{abelian}, which means that the vector fields $\xi_\alpha^c=\xi_\alpha-J\xi_\beta$, $\alpha=1,...,k$ are holomorphic and satisfy $[\xi_alpha^c,\bar{\xi_\beta^c}]=0$ for each $\alpha,\beta=1,...,k$., Comment: 17 pages

We consider real analytic foliations X with complex leaves of transversaò dimension one and we give the notion of transversal pseudoconvexity. This amounts to require that the transverse bundle N_F to the leaves carries a metric on the fibresa having tangential pseudo-Levi form positive. This condition is of a special intererest if the foliation X is 1 complete i.e. admits a smooth exaustion function phi which is plurisubharmonic along the leaves. In this situation we prove that there exist an open neighbourhood U of X in the complexification X^ of X and a non negative smooth function u:UtoR which is plurisubharmonic in U, strongly plurisubharmonic on UX and such that X is the zero set of u. This result has many implications; every compact sublevel of u is a Stein compact and if S(X) is the algebra of smooth CR functions on $X$, the restriction map S(X)->S(X_c) has a dense image (Theorem 4.1); a transversally pseudoconvex , 1-complete, real analytic foliation X with complex leaves of dimension n properly embeds in C^{2n+3} by a CR map and the sheaf S=S_X of germ of smooth CR functions on X is cohomologically trivial

We analyze the general (multiallelic) Hardy-Weinberg equilibrium problem from an objective Bayesian testing standpoint. We argue that for small or moderate sample sizes the answer is rather sensitive to the prior chosen, and this suggests to carry out a sensitivity analysis with respect to the prior. This goal is achieved through the identification of a class of priors specifically designed for this testing problem. In this paper we consider the class of intrinsic priors under the full model, indexed by a tuning quantity, the training sample size. These priors are objective, satisfy Savage’s continuity condition and have proved to behave extremely well for many statistical testing problems. We compute the posterior probability of the Hardy-Weinberg equilibrium model for the class of intrinsic priors, assess robustness over the range of plausible answers, as well as stability of the decision in favor of either hypothesis.

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

Immunotherapy; PARP inhibitors; Pembrolizumab Immunoteràpia; Inhibidors de PARP; Pembrolizumab Inmunoterapia; Inhibidores de PARP; Pembrolizumab Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non‐pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450–480 mg/m2. Following three pivotal first‐line phase III trials in HER2‐negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2‐negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms., SCOPUS: re.j, info:eu-repo/semantics/published

Infliximab is an IgG1 antitumor necrosis factor monoclonal antibody that is commonly used to treat inflammatory bowel disease (IBD) and other autoimmune disorders. However, it is known to increase the risk of reactivation of latent tuberculosis (LTBI) due to its capability to disrupt TB granulomas. We describe a case of extrapulmonary TB in a patient with ulcerative colitis who was treated with Infliximab after a negative Quantiferon Test. In addition, we report briefly on the current controversy about the appropriateness, interval, and methods for the repeated screening of latent TB in IBD patients that are treated with antitumor necrosis factor alpha (TNF-α) antibodies.

Simple Summary Hormone receptor-positive (HR+)/HER2-negative is the most frequent subgroup of metastatic breast cancer (MBC). Important therapeutic advances in the treatment of this tumor type have been observed in the last 20 years, with the approval of numerous endocrine therapies (ET) with or without target therapies (TT). To improve our current knowledge and support clinical decision-making, we conducted a systematic literature and meta-analysis focused on the most relevant/promising first-/second-line ET ± TT of the last 20 years. We observed that CDK4/6-inhibitors(i) + ET were the most effective regimens. At the same time, mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant patients. Single agent ET might still be a valuable upfront treatment in endocrine sensitive and non-visceral disease. Abstract A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.

Summary Background Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches. Methods We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR. Findings We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25–0·70), ribociclib plus letrozole (0·43; 0·24–0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23–0·76), palbociclib plus fulvestrant (0·37; 0·23–0·59), ribociclib plus fulvestrant (0·48; 0·31–0·74), abemaciclib plus fulvestrant (0·44; 0·28–0·70), everolimus plus exemestane (0·42; 0·28–0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22–0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8·95; 95% CrI 1·03–76·92). Interpretation In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer. Funding None.

Introduction To assess the role of the tumour response rate (RR) after immune checkpoint inhibitors–based therapy as a potential surrogate end-point of progression-free survival (PFS) and overall survival (OS) in patients with solid tumours, we performed a trial-based meta-regression of randomised studies comparing different immune checkpoint inhibitors–based treatments. Methods The systematic literature search included the electronic databases and the proceedings of oncologic meetings. Treatment effects on PFS and OS were expressed as hazard ratios (HRs); treatment effects on RR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome. Results Twenty-four trials, for a total of 11,894 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for PFS or the log(HR) for OS on the log(OR) for RR demonstrated weak associations (R2 = 0.47; 95% confidence interval [CI], 0.03–0.77; P = 0.001; and R2 = 0.32; 95% CI, 0.02–0.76; P = 0.01, respectively). The pre-planned analyses stratifying trials according to different type of disease and different mechanism of action of immune checkpoint inhibitors showed a very weak association of the RR with the OS for non–small cell lung cancer indicated and a modest association of the RR with the PFS for cytotoxic T lymphocyte–associated antigen 4 checkpoint inhibitors. Conclusion The results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.

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.

Background: Several randomized phase III trials in neuroendocrine tumors (NETs) showed the clinical role of new targeted agents and their impact on tumor response and outcome of whose patients affected by advanced NET. In this study, we summarize the available clinical data related to clinical efficacy of targeted therapies in the treatment of advanced NETs. Methods: A meta-analysis of randomized studies in accordance with the PRISMA guidelines was performed after searching the databases of PubMed, the Cochrane Library, and the ASCO University Meeting for relevant publications. Results: One thousand 9 hundred and 8 cases were included in the meta-analysis; among these, 1012 were in the experimental arm and 896 were in the control arm. The pooled analysis of the use of target agents in NETs revealed significantly increased of progression free survival compared to control group (hazard ratio = 0.59, 95% CI:0.42-0.84; P = 0.003). Subgroup analysis of patients according to tumor site showed a difference in favor of pancreatic neuroendocrine tumors. Moreover, targeted therapies improved the overall survival (hazard ratio = 0.79, 95%CI: 0.63-0.98; P = 0.03), and response rate (hazard ratio = 3.33, 95% CI 2.02-5.49; P < 0.00001) in all types of NETs. Conclusion: Our analysis supports the routine use of targeted agents for treatment of neuroendocrine tumors with particular regards to the pancreatic neuroendocrine tumors.

// 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.

Personalized medicine is an emerging field that promises to bring radical changes in health care. It can be defined as “a medical model that uses molecular profiling technologies for tailoring the right therapeutic option for the right person at the right time and being potentially able to determine the predisposition to disease at the population level and to deliver timely and stratified prevention” (1–3). The sequencing of the human genome together with the development and implementation of new high-throughput technologies (so-called omics) have greatly enhanced not only our knowledge on human cancer biology but have also opened up the ways to breakthroughs bringing much closer the possibility to a personalized patient treatment. Although all these omics have been widely used at experimental level to identify new targets, to define the impact of alteration on activity of classical anticancer agents or target-oriented drugs, and to characterize the toxicological profile of new drugs leading to a dramatic improvement in our knowledge on the molecular basis of cancer, we are still far from having clarified the entire picture. There is therefore the need to support studies aimed at defining the mechanisms of cancer biology as this will lead to the rational discovery of omics-based markers and the development of more reliable preclinical disease models. Several omics platforms, particularly those for the analysis of nucleic acids, are ready for clinical application but others, such as proteomics, epigenomics, cell functional analysis, etc, require further development before they can contribute to large-scale clinical translational studies that aim at identifying and validating biomarkers and biosignatures. Breast cancer represents the oncologic field in which application of these omics has been most widely applied. Several translational clinical trials have introduced genomic and transcriptomic studies with the aim of selecting patients more likely to respond to a given therapy (4–7). For example, it has been suggested that gene expression signatures of breast carcinomas may not only lead to new classifications of tumor subgroups but also carry prognostic and predictive information. Gene profiling studies have consistently showed that estrogen receptor (ER)–negative and ER-positive breast cancers are different biological diseases and that each of them can be further divided in subgroups with distinct disease-free and overall survivals and thus different oncological approaches are needed. This new molecular classification of breast cancer has been reproduced across different laboratories, patient populations, and array platforms (8). We will first summarize the different omics technologies that have been developed and then discuss how these have been applied in the context of the primary setting of breast cancer.