Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Noninvasive Tracking of Patient's Head Movements During Computer-Assisted Intranasal Microscopic Surgery

A noninvasive system designed for patient tracking during image-guided intranasal sinus surgery is described. It is based on optical digitizing with a custom-made registration and reference system, locatable surgical instruments, and a self-localizing operating microscope. Experimental and clinical results reveal a high degree of accuracy for the system. A mean spatial error of 0.82 ± 0.31 mm was determined for repositioning of the reference system in a plastic model of the skull. For the positioning of the microscope, a mean error of 2.3 ± 0.83 mm was calculated. Measurements of repositioning accuracy in 24 patients who received surgery for various sinus diseases had a mean spatial error of 1.56 ± 0.76 mm. The 95% error interval for locating intranasal structures using the surgical instrument was 2.05 mm, and it was 4.92 mm using the microscope. These results suggest that the use of our noninvasive registration and reference system may be effective, accurate, and useful for noninvasive tracking of patient movements in computer-assisted intranasal surgery.     

A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults’ trials

BackgroundDose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).MethodsPhase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials.ResultsFifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population.ConclusionsThese data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.     

Maternal Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Male Reproductive Function in Young Adulthood: Combined Exposure to Seven PFAS

Background: Concerns remain about the human reproductive toxicity of the widespread per- and polyfluoroalkyl substances (PFAS) during early stages of development.Objectives: We examined associations between maternal plasma PFAS levels during early pregnancy and male offspring reproductive function in adulthood.Methods: The study included 864 young men (age range:18.9–21.2 y) from the Fetal Programming of Semen Quality (FEPOS) cohort established between 2017 and 2019. Plasma samples from their mothers, primarily from the first trimester, were retrieved from the Danish National Biobank and levels of 15 PFAS were measured. Seven PFAS had detectable levels above the limit of detection in >80% of the samples and were included in analyses. Semen quality, testicular volume, and levels of reproductive hormones and PFAS were assessed in the young men. We used weighted quantile sum (WQS) regression to estimate the associations between combined exposure to maternal PFAS and reproductive function, and negative binomial regression to estimate the associations of single substances, while adjusting for a range of a priori–defined fetal and postnatal risk factors.Results: By a 1-unit increase in the WQS index, combined maternal PFAS exposure was associated with lower sperm concentration (−8%; 95% CI: −16%, −1%), total sperm count (−10%; 95% CI: −17%, −2%), and a higher proportion of nonprogressive and immotile sperm (5%; 95% CI: 1%, 8%) in the young men. Different PFAS contributed to the associations with varying strengths; however, perfluoroheptanoic acid was identified as the main contributor in the analyses of all three outcomes despite the low concentration. We saw no clear association between exposure to maternal PFAS and testicular volume or reproductive hormones.Discussion: In a sample of young men from the general Danish population, we observed consistent inverse associations between exposure to maternal PFAS and semen quality. The study needs to be replicated in other populations, taking combined exposure, as well as emerging short-chain PFAS, into consideration. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10285","term_id":"372009670","term_text":"EHP10285"}}EHP10285     

以光学为基础的量化诊断初期龋的方法应用

定量诊断初期龋的先进方法,近年来受到了高度重视。相对于传统的常规定性诊断方法来说,一些先进的定量诊断方法能检测到龋病的早期脱钙现象,这对于早期采取预防和控制措施都是非常重要的,一些技术现在已推向市场。随着龋病的预防和治疗技术的提高,在欧洲和北美发达国家龋病的患     

Intra-rater and inter-rater reliability of the standardized ultrasound protocol for assessing subacromial structures

Background: US-examinations related to shoulder impingement (SI) often vary due to methodological differences, examiner positions, transducers, and recording parameters. Reliable US protocols for examination of different structures related to shoulder impingement are therefore needed. Objectives: To investigate the intra- and inter-rater reliability of the existing ultrasound (US) examinations of the subacromial space, the subacromial-subdeltoid bursa, and the supraspinatus tendon. Method: In a three-phased design, two physiotherapists using a standardized US protocol examined the thickness of the supraspinatus tendon (SUPRA) and subacromial subdeltoid (SASD) bursa in two imaging positions, and the acromial humeral distance (AHD) in one position. Additionally, agreement on dynamic impingement (DI) examination was performed. The intra- and inter-rater reliability was carried out on the same day. Participants: Forty-six sports active participants with a mean age of 37 years (range 18–57) participated. Twenty-two had SI and pain within previous week and 24 did not have SI or pain within previous week. Results: Intra- and inter-rater reliability ICC (2,3) models were all above 0.80 (range 0.82–0.99) with no systematic bias (Bland Altman plots). For the DI examination, the overall agreement was 98% and 93%, with Kappa of 0.96 and 0.82, for intra- and inter-rater reliability, respectively. Conclusion: The reliability of the current standardized protocol for US examination of SI was excellent and considered feasible for clinical practice.