Adverse Drug Reactions And Kinetics Of Cisplatin Excretion In Urine Of Patients Undergoing Cisplatin Chemotherapy And Radiotherapy For Head And Neck Cancer: A Prospective Study

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Cisplatin is a high-potency anticancer agent; however, it causes significant adverse drug reactions (ADRs). Potential pharmacokinetic markers must be studied to predict or prevent cisplatin-induced ADRs and achieve better prognosis. This study was designed to investigate the relationship between ADRs and kinetics of cisplatin excretion in the urine of patients undergoing high-dose cisplatin chemotherapy and radiotherapy for head and neck cancer. Methods: Outpatients with head and neck cancer received a first cycle of high-dose cisplatin chemotherapy (80-100 mg/m(2)) concurrent to radiotherapy. ADRs (haematological, renal, and gastrointestinal reactions) were classified based on severity by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4, grade 0-4). The kinetics of cisplatin excretion in urine was evaluated by high-performance liquid chromatography over three time periods: 0-12, 12-24, and 24-48 h after the administration of cisplatin. Spearman Correlation test and regression analysis were performed to assess the relationship between ADRs and cisplatin excretion in the urine. Results: In total, 59 patients with a mean age of 55.6 +/- 9.4 years were analysed; most patients were male (86.4%), white (79.7%), and with pharyngeal tumours in advanced stages (66.1%). The most frequently observed ADRs were anaemia (81.4%), lymphopenia (78%), and nausea (64.4%); mostly grades 1 and 2 of toxicity. The mean cisplatin excretion was 70.3 +/- 64.4, 7.3 +/- 6.3, and 5 +/- 4 mu g/mg creatinine at 0-12, 12-24, and 24-48 h, respectively. Statistical analysis showed that the amount of cisplatin excreted did not influence the severity of ADRs. Conclusions: The most frequent ADRs were anaemia, lymphopenia, and nausea. Grades 1 and 2 were the severities for most ADRs. The period over which the highest cisplatin excretion observed was 0-12 h after chemotherapy, and cisplatin excretion could not predict toxicity.25Sao Paulo Research Foundation (FAPESP) [2012/01807-2, 2014/18294-3, 2014/04744-7]Coordination for the Improvement of Higher Level Personnel (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Do Genetic Polymorphisms Modulate Response Rate And Toxicity Of Cisplatin Associated With Radiotherapy In Laryngeal Squamous Cell Carcinoma? A Case Report

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Cisplatin (CDDP) plus radiotherapy (RT) has been used to treat advanced laryngeal squamous cell carcinoma (LSCC) patients. Single nucleotide polymorphisms (SNPs) may be responsible for differences in chemo/radiosensitivity and side effects in those patients. We reported an advanced LSCC patient, who obtained durable complete response and unexpected pronounced toxicity during CDDP and RT, possibly due to SNPs in genes that modulate the effects of this therapeutic modality. Case presentation: A 30-year-old man with advanced LSCC obtained durable complete response and severe alopecia and pancytopenia after standard and reduced doses of CDDP and RT. Analyses of SNPs revealed that the patient presented GSTT1 deletion, variant MSH3 1045ThrThr, wild GSTP1 105IleIle, and wild BAX -248GG genotypes, which were previously described in association with abnormal detoxification, DNA repair, and damaged cell apoptosis, respectively. Seven other advanced LSCC patients with GSTT1 gene, MSH3 AlaAla or AlaThr, GSTP1 IleVal or ValVal, and BAX GA or AA genotypes served as controls of the study. Only 1 control presented complete response; the other 6 controls obtained partial response of short duration. Four and 3 controls presented grade 1 or 2 and grade 3 anemia or leukopenia during treatment, respectively. The CDDP level in urine collected after CDDP infusion in the reported patient was lower than the median value obtained in controls, suggesting a higher amount of intracellular CDDP in the reported case. The data suggest, for the first time, that inherited abnormalities in intracellular detoxification of CDDP, DNA repair of lesions induced by CDDP and RT, and damaged cell apoptosis may alter treatment response and toxicity in LSCC, but should be confirmed by large pharmacogenomic studies.9416Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2012/01807-2

High 15-f-2t-isoprostane Levels In Patients With A Previous History Of Nonmelanoma Skin Cancer: The Effects Of Supplementary Antioxidant Therapy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Background. Phase I of this study was aimed at comparing the profiles of oxidative stress biomarkers in patients with history of nonmelanoma skin cancer (NMSC), previously treated with surgery, to the healthy subjects. Phase II aimed to evaluate the effects of supplementary antioxidant therapy on the levels of biomarkers in the case group. Materials and Methods. In Phase I, oxidative stress biomarkers were measured in blood samples obtained from 24 healthy subjects and 60 patients with history of NMSC previously treated with surgery. In Phase II, the 60 patients with history of NMSC were randomized into two subgroups, one receiving placebo (n = 34) and the other (n = 26) receiving vitamin C, vitamin E, and zinc supplementation for 8 weeks, followed by reevaluation of biomarkers. Results. In Phase I, patients with history of NMSC showed increased plasma concentrations of all biomarkers, but only 15-F-2t-isoprostane was significantly higher than in the healthy subjects. Risk of NMSC increased by 4% for each additional 1 pg/mL increase in 15-F-2t-isoprostane. In Phase II, supplementation did not significantly reduce levels of oxidative stress biomarkers. Conclusion. Patients with history of NMSC had significantly high 15-F-2t-isoprostane plasma levels; supplementation did not result in significant reduction of oxidative stress biomarkers. This trial was registered with ClinicalTrials.gov (ID NCT02248584).Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq [482958/2011-1

High 15-f-2t-isoprostane levels in patients with a previous history of nonmelanoma skin cancer: the effects of supplementary antioxidant therapy

Phase I of this study was aimed at comparing the profiles of oxidative stress biomarkers in patients with history of nonmelanoma skin cancer (NMSC), previously treated with surgery, to the healthy subjects. Phase II aimed to evaluate the effects of supplementary antioxidant therapy on the levels of biomarkers in the case group. In Phase I, oxidative stress biomarkers were measured in blood samples obtained from 24 healthy subjects and 60 patients with history of NMSC previously treated with surgery. In Phase II, the 60 patients with history of NMSC were randomized into two subgroups, one receiving placebo (n = 34) and the other (n = 26) receiving vitamin C, vitamin E, and zinc supplementation for 8 weeks, followed by reevaluation of biomarkers. Results. In Phase I, patients with history of NMSC showed increased plasma concentrations of all biomarkers, but only 15-F-2t-isoprostane was significantly higher than in the healthy subjects. Risk of NMSC increased by 4% for each additional 1 pg/mL increase in 15-F-2t-isoprostane. In Phase II, supplementation did not significantly reduce levels of oxidative stress biomarkers. Patients with history of NMSC had significantly high 15-F-2t-isoprostane plasma levels; supplementation did not result in significant reduction of oxidative stress biomarkers. This trial was registered with ClinicalTrials.gov (ID NCT02248584)2015CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP482958/2011-1sem informaçã

Role of epigenetic mechanisms in cisplatin-induced toxicity

Cisplatin (CDDP) is a highly effective antineoplastic agent, widely used in the treatment of various malignant tumors. However, its major problems are side effects associated to toxicity. Considerable inter-individual differences have been reported for CDDP-induced toxicity due to genetic and epigenetic factors. Genetic causes are well described; however, epigenetic modifications are not fully addressed. In the last few years, many evidences were found linking microRNA to the development of CDDP-mediated toxicity, particularly nephrotoxicity. In this review, we described how genetic and epigenetic modifications can be important determinants for the development of toxicity in patients treated with CDDP, and how these alterations may be interesting biomarkers for monitoring toxicity induced by CDDP. Considering the validation in different studies, we suggest that miR-34a, -146b, -378a, -192, and -193 represent an attractive study group to evaluate potential biomarkers to detect CDDP-related nephrotoxicity137131142FAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2017/02338-0; 2017/11329-

The State of the Art of Artificial Intelligence Applied in Health Technology Assessment: a Scoping Review

This project provides an overview of the current uses of Artificial Intelligence in the field of Health Technology Assessment, future perspectives and barriers for its broad implementation

Colistin and polymyxin B for treatment of nosocomial infections in intensive care unit patients: pharmacoeconomic analysis

The emergence and rapid spread of multidrug-resistant gram-negative bacteria related to nosocomial infections is a growing worldwide problem, and polymyxins have become important due to the lack of new antibiotics. To evaluate the outcomes and pharmacoeconomic impact of using colistin and polymyxin B to treat nosocomial infections. Setting Neurosurgical, cardiovascular, or transplantation intensive care unit (ICU) at the Clinical Hospital of the University of Campinas (SAo Paulo, Brazil). A retrospective cohort study was conduct in patients in the ICU. The renal function was determined daily during treatment by measuring the serum creatinine. A cost minimization analysis was performed to compare the relative costs of treatment with colistin and polymyxin B. Main outcomes measure The outcomes were 30-day mortality and frequency and onset of nephrotoxicity after beginning treatment. Fifty-one patients treated with colistin and 51 with polymyxin B were included. 30-day mortality was observed in 25.49% and 33.33% of patients treated with colistin and polymyxin B, respectively; Nephrotoxicity was observed in 43.14% and 54.90% of patients in colistin and polymyxin B groups, respectively; and onset time of nephrotoxicity was 9.86 +/- 13.22days for colistin and 10.68 +/- 9.93days for polymyxin B group. Colistin treatment had a lower cost per patient compared to the cost for polymyxin B treatment (USD $13,389.37 vs. USD$13,639.16, respectively). We found no difference between 30-day mortality and nephrotoxicity between groups; however, colistin proved to be the best option from a pharmacoeconomic point of view4117480CAPES - Coordenação de Aperfeiçoamento de Pessoal e Nível SuperiorCNPQ - Conselho Nacional de Desenvolvimento Científico e Tecnológico164796/2014-2; 02P4353/2015Sem informaçã

GSTP1 c.313A>G, XPD c.934G>A, XPF c.2505T>C and CASP9 c.-1339A>G polymorphisms and severity of vomiting in head and neck cancer patients treated with cisplatin chemoradiation

Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.−93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937_-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as anti-emetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45 and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, is capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive pre-emptive anti-emetic therapy1216520525FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2012/01807-