Supervised clustering of peripheral immune cells associated with clinical response to checkpoint inhibitor therapy in patients with advanced melanoma.

Background and purpose: Immune therapy with checkpoint inhibitors (CPIs) is a highly successful therapy in many cancers including metastatic melanoma. Still, many patients do not respond well to therapy and there are no blood-borne biomarkers available to assess the clinical outcome. Materials and methods: To investigate cellular changes after CPI therapy, we carried out flow cytometry-based immune monitoring in a cohort of 90 metastatic melanoma patients before and after CPI therapy using the FlowSOM algorithm. To evaluate associations to the clinical outcome with therapy, we divided the patients based on progression-free survival. Results: We found significant associations with CPI therapy in both peripheral blood mononuclear cell and T-cell subsets, but with the most pronounced effects in the latter. Particularly CD4+ effector memory T-cell subsets were associated with response with a positive correlation between CD27+HLA-DR+CD4+ effector memory T cells in a univariate (odds ratio: 1.07 [95% confidence interval 1.02-1.12]) and multivariate regression model (odds ratio: 1.08 [95% confidence interval 1.03-1.14]). We also found a trend towards stronger accumulation of CD57+CD8+ T cells in non-responding patients. Conclusion: Our results show significant associations between immune monitoring and clinical outcome of therapy that could be evaluated as biomarkers in a clinical setting.

It's all about timing, early treatment with hyperbaric oxygen therapy and corticosteroids is essential in acute acoustic trauma.

BACKGROUND: Acute acoustic trauma (AAT) is an acute hearing impairment caused by intense noise-impact. The current management strategy for AAT with substantial hearing loss in the Dutch military is the combination therapy with corticosteroids and hyperbaric oxygen therapy (HBOT). In a previous study, early initiation of the combination therapy was associated with better outcomes. Therefore, we performed a new analysis to assess the difference in hearing outcome between patients in whom combination therapy was started within two days, versus after more than two days. METHODS: A retrospective analysis was performed on military patients diagnosed with AAT with substantial hearing loss who presented between February 2018 and March 2020. Absolute and relative hearing improvement between first and last audiograms were calculated for all affected frequencies (defined as loss of ≥20 dB on initial audiogram). We also determined the amount of patients who recovered to the level of Dutch military requirement, and performed speech discrimination tests. RESULTS: In this analysis, 30 male patients (49 ears) with AAT were included. The median age was 24.5 years (IQR 23-29). The median time to initiation of therapy with corticosteroids and HBOT were one and two days, respectively. HBOT was started within two days in 31 ears, and after more than two days in 18 ears. The mean absolute and relative hearing gains were 18.8 dB (SD 14.6) and 46.8% (SD 31.3) on all affected frequencies. The 100% discrimination/speech perception level improved from 64.0 dB to 51.7 dB (gain 12.3 dB ± 14.1). There was significantly more improvement in absolute and relative hearing improvement when HBOT was started in ≤2 days, compared to >2 days. CONCLUSION: Our analysis shows results in favor of early initiation (≤2 days) of the combination treatment of HBOT and corticosteroids in patients with AAT.

Subclinical effects of adapalene-benzoyl peroxide: a prospective in vivo imaging study on acne micromorphology and transfollicular delivery.

BACKGROUND: Adapalene-benzoyl peroxide (A-BPO) is a first-line topical treatment for acne vulgaris. In vivo reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) detect micromorphological changes over time and visualize transfollicular delivery. OBJECTIVES: To visualize temporal, subclinical effects of A-BPO on acne micromorphology using RCM and OCT, and evaluate their impact on transfollicular delivery of microparticulate carrier systems. METHODS: Fifteen patients with mild to moderate acne received a 6-week course of A-BPO. Micromorphological changes were evaluated at time 0, 3 and 6 weeks with RCM (n = 1190 images) and OCT (n = 210 scans). Transfollicular delivery of microparticles was assessed at baseline and week 6. RESULTS: In vivo imaging visualized steady normalization of skin micromorphology in response to A-BPO over 6 weeks, including decreased hyperkeratinization of follicular borders (RCM median decrease -71.2%, P < 0.05), reduced intrafollicular keratinous content (RCM median decrease -47.7%, P < 0.05) and increased epidermal thickness (OCT median increase of 25.25%, P < 0.05). Imaging visualized microparticles in the follicular unit. Despite a visible reduction in keratin and sebum, transfollicular microparticle delivery appeared unaffected. CONCLUSIONS: Reflectance confocal microscopy and OCT detect A-BPO-induced changes in micromorphology and visualize transfollicular microparticle delivery. Keratolysis and sebolysis did not have a measurable effect on transfollicular delivery of microparticles.

Effect of hyperbaric oxygen therapy and corticosteroid therapy in military personnel with acute acoustic trauma.

INTRODUCTION: Acute acoustic trauma (AAT) is a sensorineural hearing impairment due to exposure to an intense impulse noise which causes cochlear hypoxia. Hyperbaric oxygen therapy (HBO) could provide an adequate oxygen supply. The aim was to investigate the effectiveness of early treatment with combined HBO and corticosteroid therapy in patients with AAT compared with corticosteroid monotherapy. METHODS: A retrospective study was performed on military personnel diagnosed with AAT between November 2012 and December 2017. Inclusion criteria for HBO therapy were hearing loss of 30 dB or greater on at least one, 25 dB or more on at least two, or 20 dB or more on three or more frequencies as compared with the contralateral ear. RESULTS: Absolute hearing improvements showed significant differences (independent t-test) between patients receiving HBO and the control group at 500 Hz (p=0.014), 3000 Hz (p=0.023), 4000 Hz (p=0.001) and 6000 Hz (p=0.01) and at the mean of all frequencies (p=0.002). Relative hearing improvements were significantly different (independent t-test) at 4000 Hz (p=0.046) and 6000 Hz (p=0.013) and at all frequencies combined (p=0.005). Furthermore, the percentage of patients with recovery to the functional level required by the Dutch Armed Forces (clinical outcome score) was higher in the HBO group. CONCLUSIONS: Early-stage combination therapy for patients with AAT was associated with better audiometric results at higher frequencies and better clinical outcome score.

Mucocele formation after frontal sinus obliteration.

BACKGROUND: A possible complication of frontal sinus obliteration with fat is the formation of mucoceles. We studied the prevalence of mucoceles as well as and the need for revision surgery. METHODS: Retrospective case review of forty consecutive patients undergoing frontal sinus obliteration from September 1995 to February 2012 for chronic rhinosinusitis (26), frontal mucocele (12) or frontal osteoma (2) with an average follow up of 80 months (range 15-218). MRI of the paranasal sinuses was performed in all. Outcome measures included MRI signs of mucocele formation in the obliterated frontal sinus, revision surgery, symptom burden. RESULTS: Magnetic resonance imaging (MRI) showed potential postoperative frontal sinus mucoceles in 6/40 patients. In 3 patients (7.5%) a revision operation was performed, revealing mucoceles in two cases. A wait and scan-policy in the other 3 patients confirmed the presence of a mucocele in 1 of these patients. The majority of patients (33/40, 83%) was asymptomatic at the last follow up. CONCLUSION: The prevalence of mucoceles and revision rate in this series was 7.5% (3/40). MRI can improve detection rate and reduce / avoid unnecessary revision surgery after frontal sinus obliteration.

Complications of acute rhinosinusitis in The Netherlands.

BACKGROUND: Despite the evidence demonstrating that antibiotics are of little benefit in acute rhinosinusitis (ARS), GPs continue to prescribe them, possibly in an attempt to prevent potentially dangerous complications. In this study, we present epidemiological data about the incidence, course and severity of such complications in the Netherlands. METHODS: This retrospective cohort study included all patients hospitalized in The Netherlands in 2004 with a complication of ARS. Records were made of the symptoms of ARS and the complication, demographics, medical history, medical treatment preceding hospitalization, diagnostic techniques, therapeutic management, course and outcome. RESULTS: Forty-seven patients with 48 complications (16 intracranial and 32 orbital) were included. In the intracranial group (mean age 35.9 years), six patients had been treated with oral antibiotics prior to hospitalization. While hospitalized, all patients were treated with intravenous antibiotics and 15 underwent surgery. Eight patients recovered fully after treatment, three patients had residual symptoms and three patients died (missing data: 2). Of the 31 patients with orbital complications (mean age 17.4 years), 14 received oral antibiotics before admission. While hospitalized, all patients were treated with intravenous antibiotics and 13 underwent surgery. Twenty-seven patients recovered fully and two had residual symptoms (missing data: 2). CONCLUSIONS: Severe ARS complications occur in an otherwise healthy population in an estimated 1:12,000 paediatric and 1:32,000 adult cases in the Netherlands. Our study suggests that antibiotic treatment of ARS in general practice does not play a role in preventing complications.

Preliminary efficacy of fluticasone delivered by a novel device in recalcitrant chronic rhinosinusitis.

OBJECTIVE: To assess whether delivery of fluticasone propionate using a novel bi-directional delivery device (Opt-FP) offers therapeutic benefits in patients with chronic rhinosinusitis (CRS). METHODS: A prospective, single centre, randomized, double-blind, placebo (PBO)-controlled, parallel group study was conducted in adult subjects (n=20) with CRS without nasal polyps or only cobblestoned mucosa. Subjects received Opt-FP 400 µg or placebo twice daily for 12 weeks (n=10/group). Outcome measures included symptom scores, RSOM-31, CRS VAS, nasendoscopy, peak nasal inspiratory flow (PNIF) and magnetic resonance imaging (MRI). RESULTS: Endoscopy score for oedema showed a highly significant and progressive improvement (12 weeks (median scores): Opt-FP -4.0, PBO -1.0, p=0.015). PNIF increased significantly during Opt-FP treatment compared to placebo (4 weeks: p=0.006; 8 weeks: p=0.03). After 12 weeks MRI scores in the Opt-FP group improved against baseline (p=0.039) and a non-significant trend was seen versus placebo. The nasal RSOM-31 subscale was significantly improved with Opt-FP treatment (4 weeks: p<0.009, 8 weeks: p<0.016, 12 weeks: NS). Sense of smell, nasal discomfort and combined score were all significantly improved (p<0.05). The Opt-FP was well tolerated. CONCLUSIONS: The OptiNose breath-actuated bi-directional delivery device administering fluticasone propionate (400 µg b.i.d.) is an effective and well tolerated treatment for recalcitrant CRS.