Adopting Integrated Care Pathways in Non–Small-Cell Lung Cancer: From Theory to Practice

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Theory and Practice of Glucocorticoids in COVID-19: Getting to the Heart of the Matter-A Critical Review and Viewpoints

Prolonged, low-dose glucocorticoids (GCs) have shown the highest efficacy among pharmacological and non-pharmacological treatments for COVID-19. Despite the World Health Organization's recommendation against their use at the beginning of the pandemic, GCs at a dose equivalent to dexamethasone 6 mg/day for 10 days are now indicated in all COVID-19 cases who require respiratory support. However, the efficacy of the intervention depends on the timing of initiation, the dose, and other individual factors. Indeed, patients treated with similar GC protocols often experience different outcomes, which do not always correlate with the presence of comorbidities or with the severity of respiratory involvement at baseline. This prompted us to critically review the literature on the rationale, pharmacological principles, and clinical evidence that should guide GC treatment. Based on these data, the best treatment protocol probably involves an initial bolus dose to saturate the glucocorticoid receptors, followed by a continuous infusion to maintain constant plasma levels, and eventually a slow tapering to interruption. Methylprednisolone has shown the highest efficacy among different GC molecules, most likely thanks to its higher ability to penetrate the lung. Decreased tissue sensitivity to glucocorticoids is thought to be the main mechanism accounting for the lower response to the treatment in some individuals. We do not have a readily available test to identify GC resistance; therefore, to address inter-individual variability, future research should aim at investigating clinical, physiological, and laboratory markers to guide a personalized GC treatment approach

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Background: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking. Methods: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction (P aO2 /F IO2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14. Results: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO2 /F IO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points. Conclusion: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking

Effect of the combination of basic fibroblast growth factor and cysteine on corneal epithelial healing after photorefractive keratectomy in patients affected by myopia

Background: This study sought to evaluate the effect of basic fibroblast growth factor eye drops and cysteine oral supplements on corneal healing in patients treated with photorefractive keratectomy (PRK). Materials and Methods: One hundred and twenty patients treated bilaterally with PRK for myopia were enrolled at one of two eye centers (Clinica Santa Lucia, Bologna, Italy and Department of Ophthalmology, University of Magna Graecia, Catanzaro, Italy) and were treated at the former center. Sixty patients included in the study group (Group 1) were treated postoperatively with topical basic fibroblast growth factor plus oral L-cysteine supplements, whereas 60 subjects included in the control group (Group 2) received basic fibroblast growth factor eye drops. We recorded the rate of corneal re-epithelialization and patients were followed-up every 30 days for 6 months. Statistical analyses were performed on the collected data. Results: The eyes in Group 1 demonstrated complete re-epithelialization at Day 5, whereas the eyes in Group 2 achieved this status on Day 6. No side-effects were reported. Conclusions : Patients treated with basic fibroblast growth factor eye drops and L-cysteine oral supplements benefit from more rapid corneal re-epithelialization. In human eyes, this combination treatment appeared to be safe and effective in accelerating corneal surfacing after surgery. Financial Disclosure: No author has any financial or proprietary interest in any material or method used in this study. Trial Registration: Current Controlled Trials ISRCTN73824458. © 2005 - Indian Journal of Ophthalmology

WAMD: from pathophysiology to therapeutic treatments

Age-related macular degeneration (AMD) is referred to as the leading cause of irreversible visual loss in developed countries, with a profound effect on the quality of life. The neovascular form of AMD is characterized by the formation of subretinal choroidal neovascularization, leading to sudden and severe visual loss [1]. Aging of the eye is accompanied by the buildup of uncleared cellular debris that originates from the retinal pigment epithelium (RPE) and accumulates where the RPE interfaces with Bruch’s membrane and the neurosensory retina. These deposits, known as drusen, are typically the first ophthalmoscopic sign of AMD, appearing before visual function is appreciably affected. Drusen are composite structures, primarily consisting of lipids as well as proteins and carbohydrates that can be visualized as small white or yellowish deposits on the macula [2]. Drusen deposition in Bruch’s membrane concomitant with other structural and biochemical changes associated with AMD pathogenesis (including persistent activation of the complement cascade and inflammation) lead to thickening and decreased permeability of the membrane [3]. This obstructs both nutrient transport to the retina and waste exchange to the choroid and is accompanied by the thinning of the choroidal vasculature. These steps, combined with neurodegenerative changes within the photoreceptor–RPE complex, result in pigmentary abnormalities of the RPE, including hypo- or hyperpigmentation, in early or intermediate stages of disease [4

In vivo confocal microscopy: qualitative investigation of the conjunctival and corneal surface in open angle glaucomatous patients undergoing the XEN-Gel implant, trabeculectomy or medical therapy

Purpose Assessing the quality of the ocular surface by in vivo scanning laser confocal microscopy (IVCM) in primary open angle glaucoma (POAG) patients treated by Xen 45 Gel Stent, medical therapy and trabeculectomy. Methods Retrospective, single-center, single-masked, comparative study including 60 eyes of 30 patients (mean age 61.16 +/- 10 years) affected by POAG. Eyes were divided into 3 groups: Group 1 eyes underwent the Xen 45 Gel Stent procedure, Group 2 eyes were under medical therapy, Group 3 eyes were surgically treated by trabeculectomy. All patients underwent HRT II IVCM analysis of cornea, limbus, conjunctiva, sub-tenionian space and sclera. Results The Xen 45 Gel stent, if properly positioned in the sub-conjunctival space preserves goblet cells and limits ocular surface inflammation. Regular corneal epithelial cells with micro-cysts, and normo-reflective sub-epithelial nerve plexus are documented by IVCM. In sub Tenon's implants an alternative lamellar intra-scleral filtration is detectable. Combined surgical procedures show a noticeable number of inflammatory cells with rare micro-cysts. Post-trabeculectomy inflammatory reaction is more evident than Xen 45 Gel Stent associated surgical procedures, but less than medical therapy where a conspicuous presence of Langerhans cells, peri-neural infiltrates, marked loss of goblet cells and fibrosis is visible. Conclusion Ocular surface inflammation was more notable in topical therapy than after trabeculectomy, which itself causes more inflammation than XEN Gel stents

Accelerated 15 mW pulsed-light crosslinking to treat progressive keratoconus: Two-year clinical results

Purpose To assess the clinical and microstructural results of accelerated 15 mW pulsed-light corneal crosslinking (CXL) to treat progressive keratoconus. Setting Siena Crosslinking Center, Siena, Italy. Design Prospective case series. Methods After epithelium removal (with Epi-Clear) and 10 minutes stromal soaking with riboflavin 0.1% hydroxypropyl methylcellulose solution, all eyes had 15 mW/cm2pulsed-light epithelium-off accelerated CXL for 6 minutes of ultraviolet-A (UVA) irradiation (1 second on/1 second off), maintaining a total UVA exposure of 12 minutes at a fluence of 5.4 J/cm2. The 2-year follow-up examination included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, Scheimpflug tomography, in vivo confocal microscopy (IVCM), and spectral-domain optical coherence tomography (SD-OCT). Results The study comprised 132 eyes of 96 patients (mean age 23.7 years ± 4.3 [SD]) with stage II keratoconus. The change in UDVA and CDVA was statistically significant, from 0.51 ± 0.106 logarithm of the minimum angle of resolution (logMAR) at baseline to 0.309 ± 0.074 logMAR (P =.0001) and 0.271 ± 0.144 logMAR at baseline to 0.135 ± 0.100 logMAR (P =.0023), respectively. Coma values measured by Scheimpflug analysis showed a statistically significant improvement beginning with the first postoperative month (P =.0004). The IVCM scans documented basal epithelial healing occurring 72 hours after treatment associated with the presence of subepithelial nerves. The SD-OCT scans performed in the central 6.0 mm of corneal diameter documented a demarcation line at a mean depth of 280 ± 32 μm. Conclusion The 15 mW/cm2pulsed-light epithelium-off accelerated CXL was effective and safe, stabilizing keratoconus progression through 2 years of follow-up

Fixation stability measurements in patients with neovascular age-related macular degeneration treated with ranibizumab

Objective: To evaluate which of 2 measuring units (bivariate contour ellipse area [BCEA] vs Fujii) yields more accurate measurements of fixation stability, obtained using the MP-1 device, in patients with neovascular age-related macular degeneration (nAMD) treated with intravitreal injections of ranibizumab, during a 12-month follow-up period. Design: Small retrospective, noncomparative, interventional case series. Participants: A total of 25 eyes in 25 patients (13 males, 12 females; mean age 71.72 +/- 7.98 years). Methods: All participants were older than 50 years, diagnosed with active subfoveal choroidal neovascularization, had best corrected visual acuity (BCVA) values above 20/100, and all lesion types were included. All patients underwent a loading phase with 3 consecutive intravitreal injections of 0.05 mg ranibizumab at monthly intervals. Patients were retreated after the third injection if they exhibited a 100-mu m increase in macular thickness or evidence of intraretinal and/or subretinal fluid and new subretinal hemorrhage, observed with spectral-domain optical coherence tomography and fluorescein angiography. The data collected included BCVA and mean macular sensitivities, BCEA, and fixation patterns, performed at baseline and at months 4 and 12, using the MP-1 device. Results: The mean total injection number was 5.92 +/- 1.18 (minimum 3, maximum 8). Mean BCVA at baseline was 0.55 +/- 0.28 logMAR and increased significantly to 0.50 +/- 0.33 logMAR. Mean macular sensitivity at baseline was 7.06 +/- 4.59 dB and increased significantly to 8.40 +/- 4.82. Mean BCEA was 2.19 +/- 1.38 deg(2) and decreased significantly to 1.68 +/- 1.43 deg(2). Fixation stability patterns, according to the protocol set out by Fujii, did not change significantly during follow-up. Conclusions: Compared with Fujii fixation stability patterns, BCEA correlated better with variations in macular sensitivity and BCVA. BCEA can be added to the traditional parameters used to evaluate the efficacy of intravitreal injections in patients with nAMD