The importance of jointly analyzing treatment administration and toxicity associated with targeted therapies: a case study of regorafenib in soft tissue sarcoma patients

Abstract

Background

Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting.

Patients and methods

The prevalence method estimates the probability of progression-free patients being in a particular health state (State 1: AEs with full dose, State 2: AEs with reduced dose, State 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib.

Results

Only 4.6% of progression-free patients developed mucositis/stomatitis (grade≥2) at three months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm.

Conclusion

This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score which incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit-risk ratio of therapies in their treatment choice.

Clinical trial

NCT01900743

Phase 3 Safety Study of Intravenous NEPA, a Novel Fixed Antiemetic Combination of Fosnetupitant and Palonosetron in Patients Receiving Highly Emetogenic Chemotherapy

Abstract

Background

NEPA, an oral fixed combination of the NK1RA netupitant (300mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given prior to AC and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days post-chemotherapy. The safety of NEPA was well-established in the Phase 2/3 clinical program in 1169 NEPA-treated patients. An intravenous (IV) formulation of the NEPA combination (fosnetupitant 235mg plus PALO 0.25mg) has been developed.

Patients and methods

This randomized, multinational, double-blind, stratified (by sex and country) Phase 3 study [NCT02517021] in chemotherapy-naïve patients with solid tumors assessed the safety of a single dose of IV NEPA infused over 30 minutes prior to initial and repeated cycles of HEC. Patients received either IV NEPA or oral NEPA, both with oral DEX on days 1-4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms

Results

A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% IV NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% IV NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to IV NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed.

Conclusions

IV NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC.

Divergent adaptation in thyroid cancers

Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial—PRODIGE 20 study results

Ann Oncol 2018; 29: 127–132 (doi: 10.1093/annonc/mdx529)

Linear Cutaneous Erythema in a Patient With Amyotrophic Lateral Sclerosis

(See pages 1637–8 for the Answer to the Photo Quiz.)

In the Literature

News

Linear Cutaneous Erythema in a Patient With Amyotrophic Lateral Sclerosis

larva currensstrongyloidiasisStrongyloidescorticosteroidBaërmann

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Biochemical and life cycle effects of triclosan chronic toxicity to earthworm Eisenia fetida

Abstract

The study aimed at determining the response of adult Eisenia fetida earthworms to chronic exposure to triclosan (TCS) (10–750 mg kg⁻¹) in soil. TCS life cycle toxicity was evaluated by the means of survival, growth rate, and reproduction assessment. Biochemical responses including changes in the activity of antioxidative enzymes (catalase, superoxide dismutase, and glutathione reductase) and concentration of malondialdehyde (MDA) were determined. Significant reduction in the earthworm survival was observed only if the exposure to TCS was longer than 4 weeks. TCS reduced the growth rate of E. fetida; the weight of the fastest growing control individuals exceeded that for the slowest growing by factor of 2.56. Reproduction was the most sensitive life cycle parameter and was affected at the very low levels of TCS in the soil. The results showed that chronic exposure to TCS levels in the soil induced a significant increase in the activity of antioxidative enzymes and MDA concentration. Present study revealed that an integrated approach combining biochemical and life cycle endpoints would provide a more comprehensive assessment of the ecological effects of chronic TCS exposure on earthworms.

Prenatal exposure to perfluorooctanoic acid induces nerve growth factor expression in cerebral cortex cells of mouse offspring

Abstract

Previous studies have showed perfluorooctanoic acid (PFOA) inducing cytotoxicity in an organ. In addition, epidemiological data show that high level of PFOA in cord blood of a pregnant woman is detected. Therefore, we extrapolate that circulating PFOA may affect organogenesis in offspring, such as the brain. In this study, intrauterine exposure to PFOA in mice was used to characterize the potential impacts of prenatal PFOA exposure on cerebral cortex cells of postnatal 21 (PND21) offspring. In an ex vivo cell model, PND21-based cortex cells were exposed to PFOA or/and nerve growth factor (NGF)-specific inhibitor before further biochemical assays. As results, biochemical data showed increased trends of liver metabolic enzymes in sera of PFOA-treated PND21 mice. Interestingly, PFOA-treated PND21 mice resulted in increased levels of NGF in sera and cortex cells. In addition, PFOA-exposed cerebral cortex cells induced NGF and proliferating cell nuclear antigen (PCNA) expressions, while exposure to PFOA/NGF-specific inhibitor downregulated expressions of NGF and PCNA. In addition, Nissl-labeled, NGF-positive cells, and NGF protein expression in cortex cells of PFOA-treated PND21 mice were upregulated, respectively. Further, immunoblotting assays showed that intracephalic poly (ADP-ribose) polymerase (PARP) and p42/44 mitogen-activated protein kinase (MAPK) proliferation-regulated protein levels were elevated in PFOA-treated cortex cells. Taken together, our current findings indicate that the prenatal PFOA exposure may induce proliferation of cerebral cortex cells in PND21 mice through promoting intracephalic NGF expression in the cortex.

Status, sources, and risk assessment of polycyclic aromatic hydrocarbons in urban soils of Xi’an, China

Abstract

To identify status, source of polycyclic aromatic hydrocarbons (PAHs) in urban soils and to assess soil environmental quality in Xi'an City, China, total 45 soil samples were collected from surface layer (0–10 cm) in different functional areas. Total concentrations of 16 US EPA priority PAHs ranged from 149.9 to 5770 μg kg⁻¹, with a mean of 1246 μg kg⁻¹. High molecular weight (HMW) PAHs accounted for the majority (42.4–72.2%) of the total PAHs in the urban soils, and phenanthrene (Phe), fluorene (Flo), pyrene (Pyr), benzo(b)fluoranthene (BbF), and chrysene (Chr) were the major compounds. Concentrations of PAHs varied among different functional areas. High level of PAHs was particularly apparent in industrial zones and city road overpass, while low level was recorded in scenic spots and campus. The integration of isomer ratios, principal component analysis (PCA), and positive matrix factor (PMF) indicated that the sources of PAHs in Xi'an urban soils were mainly derived from vehicle emissions and coal combustion. Based on incremental lifetime cancer risks (ILCR) model, the urban soils from the three functional areas (industrial zone, urban road, and city road overpass) posed potential cancer risk, and the cancer risks of direct ingestion for children were apparently higher than that for adolescence and for adult, respectively. Therefore, attention should be paid to the health risk for children exposed to PAHs in the urban soils.

Effect of compost tea containing phosphogypsum on potato plant growth and protection against Fusarium solani infection

Abstract

Three composts made of industrial wastes were prepared by mixing olive oil mill waste water (OMW), olive pomace, coffee grounds, and phosphogypsum (0, 10, and 30%). Potato plants (Solanum tuberosum) cultivated in a greenhouse were used to screen compost tea suppressive ability. All compost tea treatments inhibited Fusarium solani growth and improved plant growth and response to F. solani infection. The antagonistic effects of the different treatments were associated with a marked increase of the antioxidant enzymes and PR (pathogenesis related) protein expression and a decrease of disease severity. These results also showed that plant growth and disease suppression were improved by application of phosphogypsum-supplemented compost teas (A10 and A30). This enhancement can be attributed to the influence of phosphogypsum on nutrient elements and microbial diversity in the resulting compost teas.

Hybrid cardiac imaging using PET/MRI: a joint position statement by the European Society of Cardiovascular Radiology (ESCR) and the European Association of Nuclear Medicine (EANM)

Abstract

Positron emission tomography (PET) and magnetic resonance imaging (MRI) have both been used for decades in cardiovascular imaging. Since 2010, hybrid PET/MRI using sequential and integrated scanner platforms has been available, with hybrid cardiac PET/MR imaging protocols increasingly incorporated into clinical workflows. Given the range of complementary information provided by each method, the use of hybrid PET/MRI may be justified and beneficial in particular clinical settings for the evaluation of different disease entities. In the present joint position statement, we critically review the role and value of integrated PET/MRI in cardiovascular imaging, provide a technical overview of cardiac PET/MRI and practical advice related to the cardiac PET/MRI workflow, identify cardiovascular applications that can potentially benefit from hybrid PET/MRI, and describe the needs for future development and research. In order to encourage its wide dissemination, this article is freely accessible on the European Radiology and European Journal of Hybrid Imaging web sites.

Key Points

• Studies and case-reports indicate that PET/MRI is a feasible and robust technology.

• Promising fields of application include a variety of cardiac conditions.

• Larger studies are required to demonstrate its incremental and cost-effective value.

• The translation of novel radiopharmaceuticals and MR-sequences will provide exciting new opportunities.

International Comparison of Abdominal Fat Distribution Among Four Populations: The ERA-JUMP Study

Metabolic Syndrome and Related Disorders, Volume 16, Issue 4, Page 166-173, May 2018.

Inverted Nipple Treatment and Poliglecaprone Spacer

Abstract

Introduction

Nipple inversion is defined as a non-projectile nipple. It is a frequent pathologic condition, in which the whole nipple, or a portion of its, is buried inward towards the lactiferous duct and lies below the plane of the areola. Numerous strategies have been described to correct nipple inversion. All the procedures have the purpose to give a good shape to the nipple, preserving its function and sensitivity, when it is possible. To avoid recurrences and to obtain good aesthetic results, we present a modified percutaneous technique.

Method

We performed a retrospective study between 2011 and 2016 and included all the cases of inverted nipples treated in our department. Our modified percutaneous technique consists of a minimal incision supported by a percutaneous suture as a temporary spacer to fill the defect caused by releasing the fibro-ductal bands.

Results

A total of 41 cases of inverted nipples were corrected in 32 patients. After 1 year of follow-up, no recurrence was observed and all nipples maintained complete eversion. There was only one case of partial unilateral necrosis in a patient who underwent tumorectomy and radiotherapy. All patients were satisfied with the aesthetic outcomes.

Conclusion

This is a simple, safe and cheap technique that should be considered as a reliable method for long-term correction of nipple inversion.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Trends in Rhinoplasty Research: A 20-Year Bibliometric Analysis

Abstract

Background

Rhinoplasty is a popular aesthetic and reconstructive surgical procedure. It is one of the top five surgical cosmetic procedures performed worldwide.

Objectives

To evaluate global trends in rhinoplasty research spanning 20 years between 1994 and 2013.

Methods

The top 15 plastic surgery and otolaryngology journals containing rhinoplasty research were determined using impact factors (IF). A database of rhinoplasty articles from 1994 to 2013 was created to include the following classifications: IF, authors' geographic location, study design, level of evidence (LOE), and pertinence to aesthetic or reconstructive rhinoplasty. Productivity index and productivity share were calculated for each region.

Results

A total of 1244 rhinoplasty articles were included in the database. The mean IF among the 15 journals increased from 0.75 in 1994 to 1.90 in 2013 (p < 0.001). The majority of rhinoplasty publications were clinical in study design (91.0%) and were predominantly of weaker LOE (level IV: 42.4%; level V: 33.2%). The USA led in proportion of total rhinoplasty publications by volume and productivity index (37.9%, 41.2%), followed by Asia (29.1%, 28.2%) and Western Europe (18.8%, 18.2%). The majority of articles published were classified as aesthetic (60.4%), whereas 30.6% were reconstructive; there was a significant increase in the proportion of aesthetic rhinoplasty articles published per year (p = 0.009).

Conclusions

The USA has consistently been the most productive country in rhinoplasty research. However, its lead has diminished over the last 20 years. The trend in rhinoplasty research appears to be toward aesthetic rather than reconstructive topics. Attention should be given to producing stronger LOE studies.

Level of Evidence III

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Design of Ag/ and Pt/TiO 2 -SiO 2 nanomaterials for the photocatalytic degradation of phenol under solar irradiation

Abstract

The design of hybrid mesoporous TiO₂-SiO₂ (TS1) materials decorated with Ag and Pt nanoparticles was performed. The photocatalytic degradation of phenol under artificial solar irradiation was studied and the activity and selectivity of the intermediate products were verified. TiO₂-SiO₂ was prepared by sol-gel method while Ag- and Pt-based photocatalysts (TS1-Ag and TS1-Pt) were prepared by photodeposition of the noble metals on TS1. Two series of photocatalysts were prepared varying Ag and Pt contents (0.5 and 1.0 wt%). An increase in the photocatalytic activity up to two and five times higher than TS1 was found on TS1-Ag-1.0 and TS1-Pt-1.0, respectively. Changes in the intermediate products were detected on Ag- and Pt-based photocatalysts with an increase in the catechol formation up to 3.3 and 6.6 times higher than that observed on TS1, respectively. A two-parallel reaction mechanism for the hydroquinone and catechol formation is proposed. A linear correlation between the photocatalytic activity and the surface concentration of noble metals was found indicating that the electron affinity of noble metals is the driven force for both the increase in the photoactivity and for the remarkable changes in the selectivity of products.