Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide

BACKGROUND: Doxorubicin and cyclophosphamide (AC) therapy is an effective treatment for early-stage breast cancer. Doxorubicin is a substrate for ABCB1 and SLC22A16 transporters. Cyclophosphamide is a prodrug that requires oxidation to 4-hydroxy-cyclophosphamide, which yields a cytotoxic alkylating agent. The initial oxidation is catalysed by cytochrome P450 enzymes including CYP2B6, CYP2C9, CYP2C19 and CYP3A5. Polymorphic variants of the genes coding for these enzymes and transporters have been identified, which may influence the systemic pharmacology of the two drugs. It is not known whether this genetic variation has an impact on the efficacy or toxicity of AC therapy. METHODS: Germ line DNA samples from 230 patients with breast cancer on AC therapy were genotyped for the following SNPs: ABCB1 C1236T, G2677T/A and C3435T, SLC22A16 A146G, T312C, T755C and T1226C, CYP2B6*2, *8, *9, *3, *4 and *5, CYP2C9*2 and *3, CYP3A5*3 and CYP2C19*2. Clinical data on survival, toxicity, demographics and pathology were collated. RESULTS: A lower incidence of dose delay, indicative of less toxicity, was seen in carriers of the SLC22A16 A146G, T312C, T755C variants. In contrast, a higher incidence of dose delay was seen in carriers of the SLC22A16 1226C, CYP2B6*2 and CYP2B6*5 alleles. The ABCB1 2677A, CYP2B6*2, CYP 2B6*8, CYP 2B6*9, CYP 2B6*4 alleles were associated with a worse outcome. CONCLUSION: Variant alleles in the ABCB1, SLC22A16 and CYP2B6 genes are associated with response to AC therapy in the treatment of breast cancer

Evaluation of prognostic risk models for postoperative pulmonary complications in adult patients undergoing major abdominal surgery: a systematic review and international external validation cohort study

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society

Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

Ruris d.o.o. Županja posluje od 1992. godine kada otvara svoju prvu poljoprivrednu apoteku. Bave se proizvodnjom poljoprivrednih kultura (rajčice) te prodajom raznog repromaterijala za poljoprivrednu proizvodnju, prodajom i otkupom poljoprivrednih proizvoda te su trenutno nalaze među vodećim proizvođačima rajčice u RH. Na temelju financijskih izvještaja poduzeća za 2018. i 2019. godinu napravljena je analiza financijskih izvještaja tvrtke Ruris d.o.o. Županja i to bilance i računa dobiti i gubitka gdje su vidljive promjene prihoda, rashoda, imovine, obveza i kapitala kroz dvije godine. Također, napravljene su horizontalna i vertikalna analiza bilance i računa dobiti i gubitka gdje je vidljivo povećanje prihoda od 17,18% u 2019. godini i povećanje rashoda od 18,16% u odnosu na 2018. godinu. U radu je napravljena i SWOT analiza poduzeća kojom su prikazane snage, slabosti, prilike i prijetnje poduzeća. Analizom financijskih pokazatelja uspješnosti poslovanja utvrđeno je da poduzeće posluje ekonomično i profitabilno završavajući svaku godinu s ostvarenom dobiti odnosno pozitivnim financijskim rezultatom.Ruris d.o.o. Županja has been in business since 1992 when it opened its first agricultural pharmacy. They are engaged in the production of agricultural crops (tomatoes) and the sale of various raw materials for agricultural production, sale and purchase of agricultural products and are currently among the leading producers of tomatoes in the Republic of Croatia. Based on the financial statements of the company for 2018 and 2019, an analysis of the financial statements of balance sheets and income statements showed changes in income, expenses, assets, liabilities and capital in a period of two years. Also, horizontal and vertical analysis of the balance sheet and income statement was made, showing an increase in revenue of 17.18% in 2019 and an increase in expenditure of 18.16% compared to 2018. This BSc Thesis also provides a SWOT analysis of the company, which shows the strengths, weaknesses, opportunities and threats of the company. The analysis of financial indicators showed that the company operates economically and profitably, ending each year with a profit or a positive financial result

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.

PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. EXPERIMENTAL DESIGN: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. RESULTS: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. CONCLUSIONS: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Supplementary Figures 1 and 2 from Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System

Supplemental Figure 1. MALDI FTICR mass spectra selected from a pixel with maximum intensity in the MS images of liver (A) and flank tumor (B) sections showing the two first isotopes of rucaparib (peaks labelled 1 and 2, respectively). (C) MALDI FTICR mass spectrum selected from a pixel located in the orthotopic tumor area in the MS images of the brain section. No peak was detected for rucaparib. Black dotted lines in each H/E stained sister section delineate the MS images displayed in the figure. Supplemental Figure 2: Efficacy of rucaparib and temozolomide in orthotopic xenograft studies. Mice with established orthotopic xenografts from GBM14, GBM43 and GBM59 were randomized and treated with placebo, rucaparib 1 mg/kg/day, Days 1-5 every 28 days × 3 cycles, TMZ 50 mg/kg/day, Days 1-5 every 28 days × 3 cycles, or the combination.</p