Fatal outcome of a hypersensitivity reaction to paclitaxel: a critical review of premedication regimens

Hypersensitivity reactions (HSRs) to paclitaxel are frequently encountered in patients receiving this antitumour drug. Administration of histamine H1- and H2-receptor antagonists and corticosteroids has been shown to reduce significantly the risk of developing an HSR in patients receiving taxanes. In this case report, we describe the fatal outcome of an HSR in a patient receiving paclitaxel despite short-course premedication. The level of evidence supporting the short-course i.v. premedication schedule is challenged, as it is not compatible with the pharmacokinetic properties of dexamethasone

A phase I and pharmacokinetic study of NK105, a paclitaxel-incorporating micellar nanoparticle formulation

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m−2, and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m−2. No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m−2 (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m−2. A partial response was observed in one patient with pancreatic cancer. The maximum concentration (Cmax) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m−2 was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m−2 every 3 weeks. The results of this phase I study warrant further clinical evaluation

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward

Comorbidity in Patients With Small-Cell Lung Cancer: Trends and Prognostic Impact

The present study is the first on the trends in comorbidity among patients with small-cell lung cancer. In particular, hypertension and pulmonary, cardiac, and vascular disease have become more common. Multimorbidity and cardiac and digestive disease have affected survival in those with limited-stage disease, and cardiac and cerebrovascular disease have decreased the survival of patients with extensive disease. These data are relevant for treatment decisions and patient communication in daily clinical practice. Introduction: We evaluated the trends in the prevalence of comorbidity and its prognostic impact in a cohort of unselected patients with small-cell lung cancer (SCLC). Patients and Methods: All patients (n = 4142) diagnosed with SCLC from 1995 to 2012 were identified from the population-based Netherlands Cancer Registry in the Eindhoven region. Results: The prevalence of comorbidity increased from 55% in 1995 to 1998 to 76% in 2011 to 2012 and multimorbidity (ie, >= 2 concomitant diseases) from 23% to 51%. The prevalence of a comorbidity increased with age. Among the men, hypertension, cardiac disease, and diabetes, in particular, became more common (increased from 11% to 35%, from 19% to 36%, and from 7% to 18%, respectively). In the women, the rate of pulmonary disease, hypertension, and cardiac disease increased the most (increased from 18% to 30%, from 12% to 28%, and from 11% to 24%, respectively). Multimorbidity was associated with a slightly increased hazard of death, independent of treatment in those with limited-stage SCLC (hazard ratio [HR] for >= 2 comorbidities vs. no comorbidities, 1.2; 95% confidence interval [CI], 1.0-1.4). The prognostic effects of multimorbidity resulted from treatment in those with extensive-stage SCLC (HR for >= 2 comorbidities vs. no comorbidities, final model, 1.2; 95% CI, 1.0-1.2). The prognostic impact of the specific comorbidities varied, with digestive disease reducing the hazard and cardiac disease increasing the hazard in those with limited-stage SCLC (HR for digestive disease vs. no digestive disease, 0.7 [95% CI, 0.5-0.9], and HR for cardiac vs. no cardiac disease, 1.2 [95% CI, 1.0-1.3]). Also, cardiac and cerebrovascular disease increased the hazard in those with extensive-stage SCLC (HR 1.2 [95% CI, 1.0-1.3] and HR 1.3 [95% CI, 1.1-1.6], respectively). Conclusion: Comorbidity among patients with SCLC is very common and has been increasing. Multimorbidity was associated with a slightly increased hazard of death in those with limited-stage SCLC, independent of treatment. However, the prognostic effects in those with advanced-stage SCLC resulted from treatment. Digestive disease favorably affected survival and cardiac disease negatively affected the prognosis for those with limited-stage SCLC, and cardiac and cerebrovascular diseases had a negative prognostic effect for those with extensive-stage SCLC. With the burden of comorbidities in patients with SCLC increasing, more attention to individualized treatment approaches is needed. (C) 2015 Elsevier Inc. All rights reserved

Improvement in population-based survival of stage IV NSCLC due to increased use of chemotherapy

This study aimed to investigate which factors were associated with the administration of chemotherapy for patients with stage IV non-small cell lung cancer (NSCLC), and their relation to survival at a population-based level. All patients with NSCLC stage IV from 2001 to 2012 were identified in the Netherlands Cancer Registry in the Eindhoven area (n=5,428). Chemotherapy use and survival were evaluated by logistic and Cox regression analyses, respectively. The proportion of patients receiving chemotherapy increased from 30% in 2001 to 48% in 2012. Higher rates were found among younger patients [multivariable odds ratio (OR64_vs._75_years): 1.8 (95%CI 1.6-2.1)], high socioeconomic status [ORhigh_vs._low: 1.8 (95%CI 1.6-2.2)], no comorbidity [OR0_vs._2: 1.5 (95%CI 1.3-1.8)], diagnosed in recent years [OR2010-2012_vs._2001-2003: 2.0 (95%CI 1.6-2.3)] and adenocarcinoma [ORsquamous_vs._adenocarcinoma: 0.8 (95%CI 0.6-0.9)]. Having liver metastasis was associated with reduced odds (ORliver_vs._brain: 0.8 (95%CI 0.7-1.0). The variation between hospitals was large, up to OR 2.0 (95%CI 1.5-2.6). Median survival increased from 18 weeks in 2001-2003 to 21 weeks in 2010-2012 (log-rank p=0.007), and was 35 weeks in patients with and 10 weeks without chemotherapy. The multivariable hazard of death reduced significantly over time [HR2001-2003_vs._2010-2012: 1.1 (95%CI 1.0-1.2), HR2004-2005_vs._2010-2012: 1.2 (95%CI 1.1-1.3)] and only remained significant for 2004-2006 after additional adjustment for chemotherapy [final multivariable model, HR2004-2006_vs._2010-2012: 1.1 (95%CI 1.0-1.2)]. Besides, prognostic factors were having chemotherapy [final multivariable model: HR 0.4 (95%CI 0.4-0.4)], female sex [HRmale_vs._female: 1.1 (95%CI 1.0-1.1)], socioeconomic status [HRintermediate_and_high_vs._low both 0.9 (95%CI 0.9-1.0)], comorbidity [HRunknown_vs._2: 1.3 (95%CI 1.2-1.5)], histology [HRother_vs._adenocarcinoma: 1.1 (95%CI 1.1-1.2)], and location of metastasis [range: 1.2 (HRlymph_nodes_vs._brain) - 1.6 (HRliver_vs._brain)]. In conclusion, population-based survival increased due to increasing administration rates of chemotherapy. The administration of chemotherapy was affected by hospital of diagnosis and both patient and tumour characteristics. Identifying patients who benefit from chemotherapy should become a key issue. What's new? The addition of chemotherapy to supportive care can improve survival in patients with metastatic (stage IV) non-small cell lung cancer (NSCLC). But certain factors, such as socioeconomic status and patient age, may dictate whether patients with advanced disease use chemotherapy. This population-based study shows that chemotherapy use in stage IV NSCLC is affected by a variety of patient and tumor characteristics. Hospital of diagnosis is also a factor, with significant differences in chemotherapy use observed among hospitals. Increasing administration rates of chemotherapy over the period 2001 to 2012 resulted in an extension of median survival by three weeks

Rat cytomegalovirus replication in the salivary glands is exclusively confined to striated duct cells

The salivary gland is the preferred organ for cytomegalovirus (CMV) replication and viral persistence. In order to identify the nature of infected cells and to study viral replication in more detail, several experiments were conducted. Using the rat CMV (RCMV) model, acutely infected young adult rats (6 weeks of age) and new-born rats (3 days of age) were infected, and submandibular, parotid and sublingual glands were harvested at different time points after infection. For identification of the nature of infected cells, immunohistochemistry, in situ hybridisation and electron microscopic techniques were used. In young adult animals, the submandibular gland was the preferred organ for RCMV replication. The parotid and sublingual glands contained fewer viruses than the submandibular gland. In contrast, in new-born rats, the main site of RCMV replication was the sublingual gland, while the submandibular and parotid glands contained low amounts of virus. No virus could be detected in the parotid glands. In all glands of RCMV-infected animals, the infection was exclusively confined to striated duct cells. Infection resulted in a cellular inflammatory response which was mostly located in the interlobular duct region, whereas only few inflammatory cells were found in the neighbourhood of infected striated duct cells. This phenomenon may contribute to the long persistence of the virus in this organ