CYP2D6 and CYP2C8 pharmacogenetics and pharmacological interactions to predict imatinib plasmatic exposure in GIST patients

Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure

FARMAPRICE: A Pharmacogenetic Clinical decision support system for precise and Cost-Effective Therapy

Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available

Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial

Background Results from small randomised trials on tamoxifen in the treatment of hepatocellular carcinoma (HCC) are conflicting, We studied whether the addition of tamoxifen to best supportive care prolongs survival of patients with HCC. Methods Patients with any stage of HCC were eligible, irrespective of locoregional treatment. Randomisation was centralised, with a minimisation procedure accounting for centre, evidence of disease, and time from diagnosis. Patients were randomly allocated best supportive care alone or in addition to tamoxifen, Tamoxifen was given orally, 40 mg per day, from randomisation until death. Results 496 patients from 30 institutions were randomly allocated treatment from January, 1995, to January, 1997. Information was available for 477 patients. By Sept 15, 1997, 119 (50%) of 240 and 130 (55%) of 237 patients had died in the control and tamoxifen arms, respectively. Median survival was 16 months and 15 months (p=0.54), respectively, No differences were found within subgroups defined by prognostic variables. Relative hazard of death for patients receiving tamoxifen was 1.07 (95% CI 0.83-1.39). Interpretation Our findings show that tamoxifen is not effective in prolonging survival of patients with HCC

Studio retrospettivo epidemiologico e chirurgico dell’entropion nel cane, mediante approccio orientato alle razze (BOA)

Scopo: effettuare uno studio retrospettivo volto a valutare in maniera sistematica i dati relativi all’epidemiologia e alle caratteristiche peculiari dell’entropion anatomico nelle razze canine di maggiore diffusione nel nostro territorio, fornendo utili indicazioni per la correzione chirurgica più adeguata nelle differenti anomalie tipiche di ogni razza. Materiali e metodi: Sono state esaminate le cartelle cliniche relative ai casi di entropion anatomico riscontrati nel cane, dal gennaio 2000 al dicembre 2008, valutando, per ogni singola razza, l’esistenza di una predisposizione a contrarre tale affezione. E’ stata valutata, inoltre, la presenza di caratteristiche peculiari delle anomalie palpebrali in ciascuna razza e l’influenza di tali peculiarità sulla scelta dell’opzione terapeutica e i risultati della tecnica chirurgica attuata. Risultati: sono stati valutati 253 casi di entropion anatomico nel cane, evidenziando caratteri differenti nelle specifiche razze esaminate. La scelta della tecnica chirurgica si è basata sui caratteri peculiari delle anomalie palpebrali. L’approccio chirurgico è stato risolutivo in tutti i soggetti sottoposti a intervento. Conclusioni: nelle razze di maggiore diffusione nel nostro territorio è possibile individuare alcune peculiarità che caratterizzano l’entropion e che devono essere prese in considerazione nel trattamento chirurgico della patologia

A rapid, simple and sensitive LC-MS/MS method for lenvatinib quantification in human plasma for therapeutic drug monitoring

Lenvatinib (LENVA) is an oral antineoplastic drug used for the treatment of hepatocellular carcinoma and thyroid carcinoma. LENVA therapeutic drug monitoring (TDM) should be mandatory for a precision medicine to optimize the drug dosage. To this end, the development of a sensitive and robust quantification method to be applied in the clinical setting is essential. The aim of this work was to develop and validate a sensitive, rapid, and cost-effective LC-MS/MS method for the quantification of LENVA in human plasma. On this premise, sample preparation was based on a protein precipitation and the chromatographic separation was achieved on a Synergi Fusion RP C18 column in 4 min. The method was completely and successfully validated according to European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines, with good linearity in the range of 0.50–2000 ng/mL (R≥0.9968). Coefficient of variation (CV) for intra- and inter-day precision was ≤11.3% and accuracy ranged from 96.3 to 109.0%, internal standard normalized matrix effect CV% was ≤2.8% and recovery was ≥95.6%. Successful results were obtained for sensitivity (signal to noise (S/N) ratio >21) and selectivity, dilution integrity (CV% ≤ 4.0% and accuracy 99.9–102%), and analyte stability under various handling and storage conditions both in matrix and solvents. This method was applied to quantify LENVA in patient’s plasma samples and covered the concentration range achievable in patients. In conclusion, a sensitive and robust quantification method was developed and validated to be applied in the clinical setting

Simultaneous quantification of palbociclib, ribociclib and letrozole in human plasma by a new LC-MS/MS method for clinical application

A novel LC-MS/MS method was developed for the quantification of the new cyclin dependent kinase inhibitors (CDKIs) palbociclib and ribociclib and the aromatase inhibitor letrozole used in combinatory regimen. The proposed method is appropriate to be applied in clinical practice due to the simple and fast sample preparation based on protein precipitation, the low amount of patient sample necessary for the analysis (10 \u3bcL) and the total run time of 6.5 min. It was fully validated according to FDA and EMA guidelines on bioanalytical method validation. The linearity was assessed (R2 within 0.9992\u20130.9983) over the concentration ranges of 0.3\u2013250 ng/mL for palbociclib, 10\u201310000 ng/mL for ribociclib and 0.5\u2013500 ng/mL for letrozole that properly cover the therapeutic plasma concentrations. A specific strategy was implemented to reduce the carryover phenomenon, formerly known for these CDKIs. This method was applied to quantify the Cmin of palbociclib, ribociclib and letrozole in plasma samples from patients enrolled in a clinical study. The same set of study samples was analysed twice in separate runs to assess the reproducibility of the method by means of the incurred samples reanalysis. The results corroborated the reliability of the analyte concentrations obtained with the bioanalytical method, already proved by the validation process. The percentage differences were always within \ub110% for all the analytes and the R2 of the correlation graph between the two quantifications was equal to 0.9994

Cisti lacrimale congiuntivale (Dacryops) in un Golden Retriever

Presupposti: l’insorgenza di dilatazioni cistiche a carico del tessuto lacrimale (dacryops) rappresenta un raro riscontro nel cane. Obiettivo dello studio: descrivere un caso di cisti lacrimale localizzata sulla congiuntiva della palpebra inferiore in un Golden Retriever. Metodologia: un Golden Retriever maschio di 5 mesi, è stato riferito in quanto presentava una tumefazione cistica a carico della congiuntiva della palpebra inferiore dell’occhio sinistro. La lesione, di dimensioni 1x 0,5 cm, è stata asportata chirurgicamente e sottoposta ad esame istologico. Il contenuto della cisti, 0,15 ml di fluido chiaro, è stato prelevato e sottoposto ad esame citologico e colturale. Risultati: L’esame citologico del fluido ha evidenziato la presenza di materiale proteinaceo basofilo amorfo sul fondo e poche cellule dell’epitelio ghiandolare normali caratterizzate da citoplasma schiumoso e nuclei piccoli. L’esame colturale è risultato negativo. L'esame istologico della cisti ha mostrato una parete composta da cellule in singolo e doppio strato. Le cellule apparivano cubiche, non-ciliate, con lieve infiltrato infiammatorio della sottomucosa rappresentato da linfociti, plasmacellule e rari macrofagi e circondate da un rivestimento connettivale. In alcune zone si osservano lobuli di tessuto ghiandolare acinare. L’escissione in toto della cisti è stata risolutiva e, a un follow up di 6 mesi, non è stata riscontrata alcuna recidiva. Conclusioni: la localizzazione della cisti e la giovane età del soggetto in esame suggeriscono l’insorgenza di un dacryops da tessuto ghiandolare lacrimale eterotopico