Summary
What is known and objective
Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the ...information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity.
Methods
A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity.
Results and discussion
A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1‐5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C‐reactive protein >100 mg/dL was associated with supra‐therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity.
What is new and conclusions
There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.
The administration of intravenous voriconazole in critically ill patients is associated with a wide variability of concentrations. Bilirubin and C‐Reactive protein are associated with high concentrations of voriconazole, and, therefore, at the risk of toxicity.
The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after ...failure of first-line, platinum-based chemotherapy.
Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment.
Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone.
When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.
To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using ...DTIC alone as a control arm.
Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months.
From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio HR, 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects.
The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.
Background
Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This ...study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors.
Methods
Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient‐derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line.
Results
Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ‐H2AX. Inhibition of autophagy also increased ROS and γ‐H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy.
Conclusions
PARP inhibitor–induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild‐type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.
The data presented in this article show that poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors induce autophagy in 6 BRCA wild‐type ovarian cancer cells, which provides an adaptive mechanism of drug resistance. A combination of PARP inhibitors and autophagy inhibitors can overcome resistance and improve survival in different experimental models of ovarian cancer. These findings provide evidence of unique combinations of therapy for improving drug therapeutic efficacy, decreasing resistance, and extending the use of PARP inhibitors in the clinic.
Endometrial Cancer (EC) is one of the most common malignancies in women in developed countries. Molecular characterization of different biotypes may improve clinical management of EC. The Cancer ...Genome Atlas (TCGA) project has revealed four prognostic EC subgroups: POLE, MSI; Copy Number Low (CNL) and Copy Number High (CNH). The goal of this study was to develop a method to classify tumors in any of the four EC prognostic groups using affordable molecular techniques. Ninety-six Formalin-Fixed Paraffin-embedded (FFPE) samples were sequenced following a NGS TruSeq Custom Amplicon low input (Illumina) protocol interrogating a multi-gene panel. MSI analysis was performed by fragment analysis using eight specific microsatellite markers. A Random Forest classification algorithm (RFA), considering NGS results, was developed to stratify EC patients into different prognostic groups. Our approach correctly classifies the EC patients into the four TCGA prognostic biotypes. The RFA assigned the samples to the CNH and CNL groups with an accuracy of 0.9753 (p < 0.001). The prognostic value of these groups was prospectively reproduced on our series both for Disease-Free Survival (p = 0.004) and Overall Survival (p = 0.030).Hence, with the molecular approach herein described, a precise and suitable tool that mimics the prognostic EC subtypes has been solved and validated. Procedure that might be introduced into routine diagnostic practices.
Scedosporium is an important pathogen in cystic fibrosis (CF) and post‐transplantation, but it rarely causes invasive infection. Treatment remains challenging, particularly due to the inherent ...resistance to multiple antifungal agents. We present 3 complicated invasive tracheobronchial and lung Scedosporium apiospermum infections following lung transplantation. In 2 of 3 cases, the infection was clinically and radiologically cured with frequent cleansing bronchoscopies, combining triazole with terbinafine therapy and nebulized posaconazole. These cases highlight the importance of adjunctive nebulized therapy in addition to prolonged triazole treatment to manage complex invasive Scedosporium infections in immunosuppressed patients. Posaconazole (PSZ) was delivered during the bronchoscopy procedure through intrabronchial administration, whereas an eFlow rapid® device was used for nebulized therapy. Topical posaconazole was well tolerated in 2 patients, with only a slight cough during administrations; the third patient had local irritation with poor tolerance, which led to its withdrawal. This is the first report on compassionate use of topical PSZ as salvage therapy for resistant mold infections in lung transplant recipients. These 3 cases represent the entire experience using this approach; no additional patients have received this therapy due to there not having been any additional cases of Scedosporium tracheobronchitis presented.
This report describes the successful use of topical posaconazole as salvage therapy for tracheobronchial and lung Scedosporium invasive infections in lung transplant recipients. See the editorial by Thompson III and Patterson on page 287.
Objectives: The aim was to determine the direct impact of the COVID-19 pandemic on Spain's health budget. Methods: Budget impact analyses based on retrospective data from patients with suspected ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) admitted to a Spanish hospital between February 26 and May 21, 2020. Direct medical costs from the perspective of the hospital were calculated. We analyzed diagnostic tests, drugs, medical and nursing care, and isolation ward and ICU stays for three cohorts: patients seen in the emergency room only, hospitalized patients who tested positive for SARS-CoV-2, and patients who tested negative. Results: The impact on the hospital's budget for the 3 months was calculated at €15,633,180, 97.4% of which was related to health care and hospitalization. ICU stays accounted for 5.3% of the total costs. The mean cost per patient was €10,744. The main costs were staffing costs (10,131 to 11,357 €/patient for physicians and 10,274 to 11,215 €/patient for nurses). Scenario analysis showed that the range of hospital expenditure was between €14,693,256 and €16,524,924. The median impact of the pandemic on the Spanish health budget in the sensitivity analysis using bootstrapped individual data was €9357 million (interquartile range IQR, 9071 to 9689) for the conservative scenario (113,588 hospital admissions and 11,664 ICU admissions) and €10,385 million (IQR, 110,030 to 10,758) for the worst-case scenario (including suspected cases). Conclusion: The impact of COVID-19 on the Spanish public health budget (12.3% of total public health expenditure) is greater than multiple sclerosis, cancer and diabetes cost.
Summary Background Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits ...angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2 ) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , NCT01204749 , and is no longer accruing patients. Findings 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months 5·8–7·4 vs 5·4 months 95% CI 4·3–5·5, respectively, hazard ratio 0·66, 95% CI 0·57–0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 54% of 452 patients in the placebo group vs 258 56% of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 17% patients vs 27 6%, respectively) and higher incidences of oedema (294 64% patients had any-grade oedema in the trebananib group vs 127 28% patients in the placebo group). Grade 3 or higher adverse events included ascites (34 8% in the placebo group vs 52 11% in the trebananib group), neutropenia (40 9% vs 26 6%), and abdominal pain (21 5% vs 22 5%). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 17% vs 46 10%). Interpretation Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Funding Amgen.
Abstract Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. In spite of high response rates to the standard front-line treatment for advanced disease with ...cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse developing drug-resistant disease. Owing to the molecular heterogeneity, genetic instability and mutagenicity of OC, increases in survival might be achieved by translating recent insights at the morpho-molecular levels to individual therapeutic strategies. Several emerging treatments have been shown to be active in platinum-sensitive (PS) recurrent OC (ROC), but an optimal strategy still has not been established. Based on the recent results, it is likely that the introduction of novel non-platinum based chemotherapies and molecular targeted therapies will have a major impact on the management of ROC. Some current strategies are focused on the extension of platinum-free interval (PFI) in patients with PS, particularly in those with partially PS disease. Apparently, the PFI extension by an effective non-platinum intervention, such as trabectedin plus pegylated liposomal doxorubicin (PLD), may reduce cumulative platinum-induced toxicities leading to longer survival after the reintroduction of subsequent platinum. The introduction of novel therapies, such as the antiangiogenic monoclonal antibody bevacizumab, opens a new field of targeted therapies in this indication. In this review, we aim to outline the therapeutic potential of new emerging approaches, particularly the role of non-platinum therapy with trabectedin in combination with PLD in patients with PS ROC.
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