Adriamycin-loaded albumin-heparin conjugate microspheres for intraperitoneal chemotherapy

Adriamycin-loaded albumin-heparin conjugate microspheres (ADR-AHCMS) were evaluated as possible intraperitoneal (i.p.) delivery systems for site-specific cytotoxic action. The biocompatibility of the microspheres after intraperitoneal injection was tested first. 1 day after i.p. administration of empty as well as drug-loaded AHCMS to male Balb/c mice, only a moderate increase in i.p. neutrophils was measured. 3 days after injection neutrophil levels were comparable with the controls. No significant increases in the numbers of other cell types were observed, indicating an acute inflammatory response which can be considered to be mild. Antitumour efficacy was tested in an L1210 tumour-bearing mouse model and in a CC531 tumour-bearing rat model. The use of ADR-AHCMS leads to longer survival times of mice and improved tumour growth delay in rats, as compared with untreated controls and free drug treated animals. In both animal models higher adriamycin doses were initially tolerated if the drug was formulated in microspheres, although long-term adriamycin toxicity effects were evident in all treated groups. Doses and dosage schedules may be optimized to further reduce the toxic effects of the drug

The association between distal findings and proximal colorectal neoplasia: a systematic review and meta-analysis

Objectives: Whether screening participants with distal hyperplastic polyps (HPs) detected by flexible sigmoidoscopy (FS) should be followed by subsequent colonoscopy is controversial. We evaluated the association between distal HPs and proximal neoplasia (PN)/advanced proximal neoplasia (APN) in asymptomatic, average-risk patients. Methods: We searched Ovid Medline, EMBASE, and the Cochrane Library from inception to 30 June 2016 and included all screening studies that examined the relationship between different distal findings and PN/APN. Data were independently extracted by two reviewers with disagreements resolved by a third reviewer. We pooled absolute risks and odds ratios (ORs) with a random effects meta-analysis. Seven subgroup analyses were performed according to study characteristics. Heterogeneity was characterized with theI2 statistics. Results: We analyzed 28 studies (104,961 subjects). When compared with normal distal findings, distal HP was not associated with PN (OR=1.16, 95% confidence interval (CI)=0.89–1.51,P=0.14,I2=40%) or APN (OR=1.09, 95% CI=0.87–1.36,P=0.39,I2=5%), while subjects with distal non-advanced or advanced adenoma had higher odds of PN/APN. Higher odds of PN/APN were observed for more severe distal lesions. Weaker association between distal and proximal findings was noticed in studies with higher quality, larger sample size, population-based design, and more stringent endoscopy quality-control measures. The Egger’s regression tests showed allP>0.05. Conclusions: Distal HP is not associated with PN/APN in asymptomatic screening population when compared with normal distal findings. Hence, the presence of distal HP alone detected by FS does not automatically indicate colonoscopy referral for all screening participants, as other risk factors of PN/APN should be considered

Essential Role for Macrophage Migration Inhibitory Factor in Gastritis Induced by Helicobacter pylori

Macrophage migration inhibitory factor (MIF) is an upstream regulator of immune and inflammatory responses; however, its role in Helicobacter pylori (HP)-associated gastritis remains unknown. We infected MIF knockout (KO) and wild-type mice with SS1 HP and found that 2 weeks after infection, MIF and its receptor CD74 were markedly up-regulated in wild-type mice. This up-regulation preceded the up-regulation of both tumor necrosis factor-α and intercellular adhesion molecule-1, as well as the development of moderate gastritis at 8 weeks, as determined by a significant infiltration of neutrophils, T cells, and macrophages. In contrast, KO mice were protected against HP-induced gastritis by preventing the up-regulation of CD74 and Th1-mediated immune injury, including a reduction in the Th1 transcriptional factor T-bet and the expression of interferon-γ. Additionally, inhibition of skin delayed type hypersensitivity reactions to HP antigens in KO mice also suggested a critical role for MIF in cell-mediated injury. A regulatory role for MIF in Th1-immune responses was further demonstrated by the finding that antigen-primed CD4+ T cells lacking MIF failed to differentiate into the Th1 phenotype; these cells were instead promoted to Th2 differentiation after challenge with HP antigen in vitro. Results from this study indicated that inhibition of HP-induced innate immune responses and Th1-mediated immune injury may be the key mechanisms by which KO mice failed to develop gastritis after HP infection

Randomized phase III study of docetaxel versus docetaxel plus intercalated erlotinib in patients with relapsed non-squamous non-small cell lung carcinoma

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC). Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2–16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity. Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5–7.1) versus 1.9 months (95% CI 1.4–3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16–5.43). Corresponding median OS was 10.6 months (95% CI: 7.0–8.6) versus 4.7 months (95% CI: 3.2–8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46–9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia. Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice

Health-related quality of life in patients with adolescent idiopathic scoliosis after treatment: Short-term effects after brace or surgical treatment

For treatment of teenagers with progressive adolescent idiopathic scoliosis in an early stage, two options are generally considered: treatment with a brace or observation followed by surgery if necessary. Many doctors and patients prefer conservative treatment (i.e. brace treatment) to surgical treatment, because surgery of the spine is generally considered a drastic intervention. Because potential differences in health-related quality of life (HRQoL) after treatment between braced and surgically treated patients are not well explored, this study aimed to determine whether short-term differences exist in HRQoL between adolescents treated with a brace or treated surgically. A cross-sectional analysis of HRQoL was made of 109 patients with adolescent idiopathic scoliosis who, after completing treatment, filled out the Dutch SRS-22 Patient Questionnaire. All patients had been treated either with a brace or surgery, or with a brace followed by surgery. Patients treated surgically had significantly higher mean scores in the satisfaction with management domain than those treated with a brace. No other consistent differences in HRQoL were foun