Cancer stem cells (CSCs) are considered the cell subpopulation responsible for breast cancer (BC) initiation, growth, and relapse. CSCs are identified as self-renewing and tumor-initiating cells, conferring resistance to chemo- and radio-therapy to several neoplasias. Nowadays, th (about 10mM)e pharmacological targeting of CSCs is considered an ineludible therapeutic goal. The antidiabetic drug metformin was reported to suppress in vitro and in vivo CSC survival in different tumors and, in particular, in BC preclinical models. However, few studies are available on primary CSC cultures derived from human postsurgical BC samples, likely because of the limited amount of tissue available after surgery. In this context, comparative oncology is acquiring a relevant role in cancer research, allowing the analysis of larger samples from spontaneous pet tumors that represent optimal models for human cancer. Isolation of primary canine mammary carcinoma (CMC) cells and enrichment in stem-like cell was carried out from fresh tumor specimens by culturing cells in stem-permissive conditions. Phenotypic and functional characterization of CMC-derived stem cells was performed in vitro, by assessment of self-renewal, long-lasting proliferation, marker expression, and drug sensitivity, and in vivo, by tumorigenicity experiments. Corresponding cultures of differentiated CMC cells were used as internal reference. Metformin efficacy on CMC stem cell viability was analyzed both in vitro and in vivo. We identified a subpopulation of CMC cells showing human breast CSC features, including expression of specific markers (i.e. CD44, CXCR4), growth as mammospheres, and tumor-initiation in mice. These cells show resistance to doxorubicin but were highly sensitive to metformin in vitro. Finally, in vivo metformin administration significantly impaired CMC growth in NOD-SCID mice, associated with a significant depletion of CSCs. Similarly to the human counterpart, CMCs contain stem-like subpopulations representing, in a comparative oncology context, a valuable translational model for human BC, and, in particular, to predict the efficacy of antitumor drugs. Moreover, metformin represents a potential CSC-selective drug for BC, as effective (neo-)adjuvant therapy to eradicate CSC in mammary carcinomas of humans and animals.

Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2–17 years, who underwent an allogeneic hematopoietic stem cell transplantation. Methods: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. Results: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (C_trough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher’s exact tests) when C_trough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. Conclusions: The population pharmacokinetic model described the interindividual variability and identified C_trough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

Introduction: Dalbavancin (DAL) is a long-acting lipoglycopeptide active against Gram-positive bacteria, including multidrug-resistant isolates. A growing body of evidence supports its efficacy in various difficult-to-treat infections. DAL shows time-dependent bactericidal activity in vitro at free drug concentrations equal to 4×MIC values. However, the optimal dosing scheme for achieving the PK/PD target in multidose treatment has not been fully established. Methods: Pharmacokinetic analysis was based on a nonlinear mixed effects modelling approach performed in NONMEM v7.5/Pirana, while R was used for data management and graphical summaries. Final model parameters were used to simulate the plasma disposition of DAL by Monte Carlo simulations to determine the multidose DAL regimen associated with a 90% target attainment of 100% fT > 4×MIC. Results: A two-compartmental model with first-order elimination and allometric-scaled bodyweight best described DAL disposition in patients with CLcr > 30 mL/min. Monte Carlo simulations showed that two 1500 mg DAL doses 7 days apart granted an optimal PTA > 90% of 100% fT > 4×MIC up to 5, 4, and 3 weeks in patients weighting from 40–80 kg, 80–120 kg and 120–200 kg, respectively. An additional third 1500 mg dose at the above time points by weight bands may extend the optimal PTA up to 9, 7, and 6 weeks of total treatment. Conclusions: Two 1500 mg DAL doses administered 7 days apart could be a valuable starting strategy for patients of all weight classes with CLcr > 30 mL/min. In patients requiring long-term DAL treatment, the optimal timing of additional administrations should be guided by routine TDM or empirically through patients’ total body weight when TDM is unavailable.