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

Guide-wire replacement of a mini-midline catheter with a central venous catheter: A retrospective study on 63 cases

Background: Achieving a reliable venous access in a particular subset of patients and/or in emergency settings can be challenging and time-consuming. Furthermore, many hospitalized patients do not meet the criteria for central venous catheter positioning, unless an upgrade of the treatment is further needed. The mini-midline catheter has already showed to be reliable and safe as a stand-alone device, since it is easily and rapidly inserted and can indwell up to 1 month. Methods: In this further case series, we retrospectively evaluated data from 63 patients where a previously inserted mini-midline catheter was upgraded to a central venous catheter (the devices inserted in the arm replaced by peripherally inserted central catheter and others inserted “off-label” in the internal jugular replaced by single lumen centrally inserted central catheter), being used as introducer for the Seldinger guidewire. Results: The guidewire replacement was been made even early (after 1 day) or late (more than 10 days), usually following a need for an upgrade in treatment. No early or late complications were reported. Conclusion: According to the preliminary data we collected, this converting procedure seems to be feasible and risk-free, since neither infectious nor thrombotic complications were reported

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study

Purpose: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. Methods: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January\u2013February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. Results: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). Conclusions: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management

Clonal selection of a novel deleterious TP53 somatic mutation discovered in ctDNA of a KIT/PDGFRA wild-type gastrointestinal stromal tumor resistant to imatinib

The standard of care for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) is represented by imatinib, which is given daily at a standard dosage until tumor progression. Resistance to imatinib commonly occurs through the clonal selection of genetic mutations in the tumor DNA, and an increase in imatinib dosage was demonstrated to be efficacious to overcome imatinib resistance. Wild-type GISTs, which do not display KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations, are usually primarily insensitive to imatinib and tend to rapidly relapse in course of treatment. Here we report the case of a 53-year-old male patient with gastric GIST who primarily did not respond to imatinib and that, despite the administration of an increased imatinib dose, led to patient death. By using a deep next-generation sequencing barcodeaware approach, we analyzed a panel of actionable cancer-related genes in the patient cfDNA to investigate somatic changes responsible for imatinib resistance. We identified, in two serial circulating tumor DNA (ctDNA) samples, a sharp increase in the allele frequency of a never described TP53 mutation (c.560-7_560-2delCTCTTAinsT) located in a splice acceptor site and responsible for a protein loss of function. The same TP53 mutation was retrospectively identified in the primary tumor by digital droplet PCR at a subclonal frequency (0.1%). The mutation was detected at a very high allelic frequency (99%) in the metastatic hepatic lesion, suggesting a rapid clonal selection of the mutation during tumor progression. Imatinib plasma concentration at steady state was above the threshold of 760 ng/ml reported in the literature for the minimum efficacious concentration. The de novo TP53 (c.560-7_560-2delCTCTTAinsT) mutation was in silico predicted to be associated with an aberrant RNA splicing and with an aggressive phenotype which might have contributed to a rapid disease spread despite the administration of an increased imatinib dosage. This result underlies the need of a better investigation upon the role of TP53 in the pathogenesis of GISTs and sustains the use of next-generation sequencing (NGS) in cfDNA for the identification of novel genetic markers in wild-type GISTs

Digestibilidade de nutrientes em rações de frangos de corte suplementadas com promotores de crescimento

Um experimento foi realizado para avaliar o efeito da utilização de diferentes promotores de crescimento sobre o metabolismo de frangos de corte em crescimento. Foram avaliadas duas dietas, uma atendendo às exigências nutricionais de frangos de corte (normal) e uma dieta reduzida, com 5% a menos da exigência nutricional (reduzida), suplementadas ou não com antibióticos e prebióticos. Foram utilizados 180 pintos de corte criados em galpão convencional, com cama de maravalha, até os 21 dias de idade. Em seguida, foram divididos em 36 gaiolas, distribuídos em delineamento experimental inteiramente ao acaso, utilizando método tradicional de coleta de excretas. Houve interação (P<0,05) entre dieta e promotores de crescimento para os coeficientes de digestibilidade ileal da matéria seca (CDIMS), da proteína bruta (CDIPB) e do extrato etéreo (CDIEE). A dieta reduzida contendo antibiótico apresentou menor CDIMS. A dieta normal contendo antibiótico apresentou maior CDIPB (P<0,05), enquanto a dieta reduzida contendo prebiótico apresentou melhor CDIPB e CDIEE (P<0,05). Os valores dos coeficientes de digestibilidade total da matéria seca (CDTMS), da proteína bruta (CDTPB) e do extrato etéreo (CDTEE) apresentaram interação (P<0,05) entre dietas e promotores de crescimento, em que a dieta reduzida contendo antibiótico apresentou menor CDTMS e CDTEE. A dieta normal apresentou maiores valores de energia metabolizável aparente (EMA) e EMA corrigida para balanço de nitrogênio (EMAn) (P<0,05). Concluiu-se que, ao se reduzir a exigência nutricional da ração, a digestibilidade dos nutrientes foi reduzida, no entanto os óleos essenciais promoveram aumento nos coeficientes de digestibilidade ileal da matéria seca, da proteína bruta e do extrato etéreo