Search

Introduction: Cancer-related fatigue (CRF) is a common symptom in patients with metastatic breast cancer (MBC), who receive taxane-based chemotherapy, and is associated with poor outcomes. Current guidelines recommend regular screening for fatigue from the time of cancer diagnosis, during treatment, and after treatment is completed to identify CRF early, lessen its negative impact on quality of life, and prevent potential treatment interruptions. Fatigue is a subjective symptom and is assessed through patient questionnaires such as the FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) survey. However, there is currently no gold standard or recommended survey to assess CRF. Methods: A prospective, non-interventional, multicenter trial is ongoing to validate the FACIT-Fatigue scale in patients with locally advanced or metastatic breast cancer who are eligible to receive taxane-based chemotherapy. Adult patients who have documented locally advanced or metastatic breast cancer (not amenable to surgical resection), and mild-to-moderate CRF indicated by a score of 1 to 6 on a scale from 0 to 10 (10 being most severe), who are candidates to receive cycle one of taxane chemotherapy will be included. Patients who are unable to take oral medications, have other cancer-related causes of fatigue, are using oral morphine ≥60 mg/day, or are participating in another clinical trial will be excluded. The primary objective is to evaluate the change in FACIT-Fatigue scores at baseline and at the end of the study (16 weeks). Secondary endpoints include evaluation of quality-of-life outcomes. A subgroup of patients will participate in a phone-based cognitive interview at the end of study visit or within 2 weeks of this visit to explore fatigue factors deemed important to patients. Results: The total planned sample size is estimated to be 60 patients to allow for a minimum clinically important difference (MCID) with a minimum precision of 1.9 points, and standard deviation of 3 points. The qualitative assessment will be conducted as part of a substudy inclusive of data from 30 patients. Conclusions: This study is currently ongoing to determine the MCID in FACIT-Fatigue scores in patients with locally advanced or MBC receiving treatment with taxane-based chemotherapy. Contact usmedinfo@dompe.com for information related to clinical trial sites and this study. Citation Format: Alessandra Fabi, Steven Hager, Laura Lourdes, Rebecca Pedersini, Paola Malaguti, Elizabeth M. Gavioli, Renuka Wakade, Pier Adelchi Ruffini, Francesco Sergio, Manuela Leone, Flavio Mantelli, Marcello Allegretti, Anne Blaes. Trial In Progress: An Evaluation of FACIT-Fatigue in Patients with Locally Advanced or Metastatic Breast Cancer receiving Treatment with Taxane-based Chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-16-01.

Introduction: Fatigue is a debilitating and persistent condition of exhaustion that interferes with usual functioning. It is the most reported symptom across all cancer patients, and when related to the malignancy itself or to the neoplastic treatment, is referred to as cancer-related fatigue (CRF). Fatigue occurs in nearly all patients with metastatic breast cancer and is associated with poor clinical outcomes and worse quality-of-life. It is subjective and can be assessed from patient self-reports, such as the FACIT-Fatigue scale or Brief Fatigue Inventory, with no current gold-standard, which may lead to under reporting and lack of treatment intervention. Only since 2016, fatigue has been considered as a syndrome and included in the International Statistical Classification of Diseases, 10th edition, Clinical Modification (ICD-10-CM) according to specific criteria. The aim of this real-world data analysis was to describe the prevalence of fatigue, as reported by physicians using ICD-10-CM codes, in patients with locally advanced (Adv) or metastatic (Mtx) breast cancer (BC) undergoing single-agent taxane-based chemotherapy (CT), and to assess whether relapsed subjects had a higher prevalence versus those diagnosed de novo at an advanced stage. Methods: Electronic health records (EHR) were analyzed from TriNetX, a global research network containing real-world data from approximately 150 million patients in 115 Health Care Organizations (72 in the United States and 42 in the European Union). Using ICD-10-CM codes and structured data only (no medical notes), subjects were identified with a diagnosis of Adv-Mtx BC who underwent CT with single-agent taxane in 2020, 2021 and 2022 (first quarter). After splitting the cohort based on “relapsed” (second- or further line treatment) vs “de novo” (first-line treatment), we assessed the prevalence of fatigue (any type, R53.x) and CRF (R53.0) within the first 3 months after initiation of taxanes. Results: Among 379,880 BC patients under follow-up in 2021 across the 115 sites, 50,490 (13%) had Adv-Mtx BC, of whom 16,170 (32%) were diagnosed de novo and 34,330 (68%) experienced relapse. The proportion of patients undergoing single-agent taxane-based CT was 7.5% (1,220) and 13.4% (4,590), respectively. Almost one third (28%) of relapsed patients had previously received taxanes. The prevalence of fatigue (any type) and CRF was similar between the “de novo” and “relapsed” groups (24.6% vs 25.7% and 6.6% vs 5.4%, respectively). Overall, 27% and 21% of all fatigue was coded as CRF in the “de novo” and “relapsed” groups, respectively. No relevant differences were observed between 2020, 2021 and 2022 results. Conclusions: This real-world analysis reveals that at least one in four patients with Adv-Mtx BC undergoing taxane based CT suffer from fatigue, independent of disease history and other factors. Fatigue is an unmet medical need in patients with BC, particularly in patients receiving taxanes. Table. Fatigue prevalence (as per ICD-10-CM codes) within the first 3 months of single-agent taxane-based CT in patients with locally advanced or metastatic BC diagnosed “de novo” or relapsed in 2021 Citation Format: Anne Blaes, Elizabeth M. Gavioli, Renuka Wakade, Santiago Miracle, Giovanna DiTuri, Maria DePizzol, Pier Adelchi Ruffini, Francesco Sergio, Manuela Leone, Flavio Mantelli, Marcello Allegretti, Alessandra Fabi. Fatigue in patients with locally advanced or metastatic breast cancer undergoing single-agent taxane-based chemotherapy: de novo versus relapsed [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-07-09.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by triggering the formation of neutrophil extracellular traps (NETs), producing cytokines including interleukin-8 (CXCL8), and mediating the recruitment of other immune cells to regulate processes such as acute and chronic inflammation, which can lead to ARDS. CXCL8 is involved in the recruitment, activation, and degranulation of neutrophils, and therefore contributes to inflammation amplification and severity of disease. Furthermore, activation of neutrophils also supports a prothrombotic phenotype, which may explain the development of immunothrombosis observed in COVID-19 ARDS. This review aims to describe hyperinflammatory ARDS due to SARS-CoV-2 infection. In addition, we address the critical role of polymorphonuclear neutrophils, inflammatory cytokines, and the potential targeting of CXCL8 in treating the hyperinflammatory ARDS population.

Patients with rheumatoid arthritis (RA) or other rheumatic diseases say that pain and stiffness are symptoms affecting their quality of life. Ketoprofen and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammation and manage mild-to-moderate pain. The aim of this new systematic review of the literature and meta-analysis of randomized controlled trials (RCTs) was to compare the clinical efficacy of ketoprofen and ibuprofen in patients with RA. The MEDLINE and EMBASE scientific databases were systematically searched from their inception to November 2020 to identify RCTs directly comparing the recommended therapeutic doses of oral ketoprofen (50–200 mg/day) with ibuprofen (600–1800 mg/day) for RA pain relief. The meta-analysis was made using the standardized mean differences (SMD) of each of the identified RCTs using a fixed effects model. Four RCTs involving 456 patients met the inclusion criteria. The results of the meta-analysis showed a statistically significant difference in efficacy in favor of ketoprofen (0.33, 95% CI 0.14–0.52, p = 0.0005) at all point-estimates of the mean-weighted size effect. The heterogeneity test for the efficacy outcome (the hypothesis was χ2 = 3.57%, df = 3, p value = 0.31 and the chance of a test effect was 3.49, p = 0.0005) was not significant, and this was confirmed by a Higgins percentage of 16%. The studies included in the meta-analysis did not reveal any significant differences between the two drugs in terms of tolerability or safety. The result of this meta-analysis shows that ketoprofen is more effective than ibuprofen in managing RA pain at therapeutic doses, thus supporting its use in clinical practice.

AIM: To evaluate the ability of ladarixin (LDX, 400 mg twice-daily for three cycles of 14 days on/14 days off), an inhibitor of the CXCR1/2 chemokine receptors, to maintain C-peptide production in adult patients with newly diagnosed type 1 diabetes. MATERIALS AND METHODS: A double-blind, randomized (2:1), placebo-controlled study was conducted in 45 males and 31 females (aged 18-46 years) within 100 days of the first insulin administration. The primary endpoint was the area under the curve (AUC) for C-peptide in response to a 2-hour mixed meal tolerance test (AUC[0-120 min] ) at week 13 ± 1. Secondary endpoints included C-peptide AUC(15-120 min) , HbA1c, daily insulin requirement, severe hypoglycaemic events (SHE), the proportion of subjects achieving HbA1c less than 7.0% without SHE and maintaining a residual beta cell function. Follow-up assessments were scheduled at weeks 13 ± 1, 26 ± 2 and 52 ± 2. RESULTS: In total, 26/26 (100%, placebo) and 49/50 (98%, LDX) patients completed week 13. The mean change from baseline to week 13 in C-peptide AUC(0-120 min) was -0.144 ± 0.449 nmol/L with placebo and 0.003 ± .322 nmol/L with LDX. The difference was not significant (0.149 nmol/L, 95% CI -0.04 to 0.33; P = .122). At week 26, the proportion of patients with HbA1c less than 7.0% without SHE was transiently higher in the LDX group (81% vs. 54%, P = .024). Otherwise, no significant secondary endpoint differences were noted. Transient metabolic benefit was seen at week 26 in favour of the LDX group in the prespecified subpopulation with fasting C-peptide less than the median value at screening. CONCLUSIONS: In newly diagnosed patients with type 1 diabetes, short-term LDX treatment had no appreciable effect on preserving residual beta cell function. ispartof: DIABETES OBESITY & METABOLISM vol:24 issue:9 pages:1840-1849 ispartof: location:England status: published

Introduction: Acute lung injury and acute respiratory distress syndrome are common complications in patients with coronavirus disease 2019 (COVID-19). Poor outcomes in patients with COVID-19 are associated with cytokine release syndrome. Binding of interleukin-8 (CXCL8/IL-8) to its chemokine receptors, CXCR1/2, may mediate this inflammatory process. The aim of this clinical trial was to determine if CXCR1/2 blockade with reparixin can improve clinical outcomes in hospitalized patients with severe COVID-19 pneumonia. The dose and safety of reparixin have been investigated in clinical trials of patients with metastatic breast cancer. Methods: This was a phase 2,open-label, multicenter, randomized study in hospitalized adult patients with severe COVID-19 pneumonia from May5, 2020 until November27, 2020. Patients were randomized 2:1 to receive 1200mg reparixin orally three times daily or standard of care (SOC) for up to 21days. The primary endpoint was defined as a composite of clinical events: use of supplemental oxygen, need for mechanical ventilation, intensive care unit admission, and/or use of rescue medication. Results: Fifty-five patients were enrolled between reparixin (n = 36) and SOC (n = 19). The rate of clinical events was statistically significantly lower in the reparixin group compared with the SOC group (16.7% [95%CI 6.4-32.8%] vs. 42.1% [95%CI 20.3-66.5%], P = 0.02). The sensitivity analysis based on the Cox regression model provided an adjusted hazard ratio of 0.33 with statistical significance lower than 0.05 (95%CI 0.11-0.99; P = 0.047). Reparixin treatment appeared to be well tolerated. Conclusion: In patients with severe COVID-19, reparixin led to an improvement in clinical outcomes when compared with the SOC. A larger phase3 clinical study is needed to confirm these results. Trial registration: EudraCT identifier, 2020-001645-40; registered May6, 2020 (retrospectively registered), and clinicaltrials.gov (NCT04794803) on March 8, 2021.

Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human cone-rod disorders, demonstrating that intravitreal (IV) administration of rhNGF can boost zebrafish retinal regeneration in this model. Adult zebrafish retinae exposed to 60 h of light irradiation (60 h LID) displayed evident reduction of outer nuclear layer (ONL) thickness and cell number with presence of apoptotic cells. Retinal histologic evaluation at different time points showed that IV therapeutic injection of rhNGF resulted in an increase of ONL thickness and cell number at late time points after damage (14 and 21 days post injury), ultimately accelerating retinal tissue recovery by driving retinal cell proliferation. At a molecular level, rhNGF activated the ERK1/2 pathway and enhanced the regenerative potential of Müller glia gfap- and vim-expressing cells by stimulating at early time points the expression of the photoreceptor regeneration factor Drgal1-L2. Our results demonstrate the highly conserved nature of NGF canonical pathway in zebrafish and thus support the use of zebrafish models for testing new compounds with potential retinal regenerative properties. Moreover, the pro-regenerative effects of IV-injected NGF that we observed pave the way to further studies aimed at evaluating its effects also in mammals, in order to expedite the development of novel rhNGF-based therapeutic approaches for ophthalmological disorders.

Current available therapeutic options for Coronavirus Disease-2019 (COVID-19) are primarily focused on treating hospitalized patients, and there is a lack of oral therapeutic options to treat mild to moderate outpatient COVID-19 and prevent clinical progression. Raloxifene was found as a promising molecule to treat COVID-19 due to its activity to modulate the replication of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and act as an immunomodulator to decrease proinflammatory cytokines.This was a phase 2 multicenter, randomized, placebo-controlled trial to evaluate the efficacy and safety of raloxifene in adult patients with mild to moderate COVID-19 between October 2020 to June 2021 in five centers located in Italy. This was a planned 2/3 adaptive study, but due to operational difficulties, the study was discontinued during the phase 2 study segment. Participants were randomized 1:1:1 to receive oral placebo, raloxifene 60 mg, or raloxifene 120 mg by self-administration for a maximum of two weeks. The primary outcomes were the proportion of patients with undetectable SARS-CoV-2 via nasopharyngeal swabs at day 7 and the proportion of patients who did not require supplemental oxygen therapy or mechanical ventilation on day 14. Safety was assessed. The trial is registered (EudraCT 2021-002,476-39, and ClinicalTrials.gov: NCT05172050).A total of 68 participants were enrolled and randomized to placebo (Raloxifene showed evidence of effect in the primary virologic endpoint in the treatment of early mild to moderate COVID-19 patients shortening the time of viral shedding. The safety profile was consistent with that reported for other indications. Raloxifene may represent a promising pharmacological option to prevent or mitigate COVID-19 disease progression.The study was funded by Dompé Farmaceutici SpA and supported by the funds from the European Commission - Health and Consumers Directorate General, for the Action under the Emergency Support Instrument- Grant to support clinical testing of repurposed medicines to treat SARS-COV-2 patients (PPPA-ESI-CTRM-2020-SI2.837140), and by the COVID-2020-12,371,675 Ricerca finalizzata and line 1 Ricerca Corrente COVID both funded by Italian Ministry of Health.

Purpose To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. Design Multicenter, randomized, double-masked, vehicle-controlled trial. Participants Patients with neurotrophic persistent epithelial defect with or without stromal thinning. Methods The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. Main Outcome Measures The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally ( Results Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%–66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%–73.1%; P Conclusions Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

Retinal disorders are leading causes of blindness and are due to an imbalance between reactive oxygen species and antioxidant scavenger (in favor of pro‐oxidant species) or a disruption of redox signaling and control. Indeed, it is well known that oxidative stress is one of the leading causes of retinal degenerative diseases. Different approaches using nutraceuticals resulted in protective effects in these disorders. This review will discuss the impact of oxidative stress in retinal neurodegenerative diseases and the potential strategies for avoiding or counteracting oxidative damage in retinal tissues, with a specific focus on taurine. Increasing data indicate that taurine may be effective in slowing down the progression of degenerative retinal diseases, thus suggesting that taurine can be a promising candidate for the prevention or as adjuvant treatment of these diseases. The mechanism by which taurine supplementation acts is mainly related to the reduction of oxidative stress. In particular, it has been demonstrated to improve retinal reduced glutathione, malondialdehyde, superoxide dismutase, and catalase activities. Antiapoptotic effects are also involved; however, the protective mechanisms exerted by taurine against retinal damage remain to be further investigated., Increasing data indicate that taurine supplement may be effective in slowing down the progression of retinal diseases (including glaucoma, AMD, and DR), thus suggesting that taurine can be a promising candidate for the prevention or as adjuvant treatment of these diseases. The mechanism by which taurine supplementation acts is mainly related to the reduction of oxidative stress. Antiapoptotic effects are also involved; however, the protective mechanisms exerted by taurine against retinal damage remain to be further investigated.

High levels of proinflammatory cytokines have been associated with a loss of tissue function in ocular autoimmune diseases, but the basis for this relationship remains poorly understood. Here we investigate a new role for tumor necrosis factor α in promoting N-glycan-processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes involved in the biosynthesis of N-glycans. Tumor necrosis factor α but not IL-1β had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including N-acetylglucosaminyltransferases 1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression was correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with ocular mucous membrane pemphigoid were characterized by marginal N-acetylglucosaminyltransferase expression and decreased N-glycan branching in the conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan-processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of ocular autoimmune diseases.

Increasing evidence suggests that nerve growth factor (NGF) exerts protective effects against retinal degeneration in animal models of retinitis pigmentosa (RP). This study aims at investigating the effects of intravitreal injection of recombinant human NGF (rhNGF) on retinal photoreceptors apoptosis in an animal model of RP, the Royal College of Surgeons (RCS) rats.Thirty-six RCS rats were treated with intravitreal injection of rhNGF or murine NGF (mNGF) or vehicle at 20 postnatal days (pd) and sacrificed at 40 pd. The eyes were enucleated and evaluated by histology, flow cytometric analysis for rhodopsin expression, Western blot for TrkA and activated (phosphorylated) TrkA (pTrkA) levels, and TUNEL assay for apoptosis' detection.RCS rats showed a significant retinal degeneration associated with cell apoptosis at 40 pd when compared to wild-type animals. Histology showed that rhNGF intravitreal treatment significantly increased retinal thickness when compared to untreated eyes. Photoreceptors' number evaluated by flow cytometry was significantly increased in both intravitreal rhNGF- and mNGF-treated groups when compared to untreated eyes. This protective effect was associated with an increase in TrkA and activated pTrkA levels and an inhibition of apoptosis. Intravitreal NGF injection was well tolerated and did not show clinical and histological signs of adverse effects.Intravitreal rhNGF injection proved safe and effective in favoring retinal cell survival in RCS rats. This is the first report showing that the novel rhNGF already proved safe in a phase I study exerts a biologic effect similar to the well-characterized mNGF-induced retinal protection. These results may trigger further studies to investigate rhNGF administration for the treatment of progressive degenerative retinal disorders such as retinitis pigmentosa.

BackgroundDry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.MethodsForty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.ResultsOf 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.ConclusionsThe data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.Trial registration numberNCT02101281.

To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy.Multicenter, randomized, double-masked, vehicle-controlled trial.Patients with neurotrophic persistent epithelial defect with or without stromal thinning.The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 μg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat.The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8.Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient.Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

The objective of this clinical trial (NCT02507934) was to assess the efficacy and safety of recombinant human lubricin as compared to a 0.18% sodium hyaluronate (HA) eye drop in subjects with moderate dry eye disease (DED).DEWS Grade 2-3 subjects were randomized to use lubricin (N=19, 51.9 ± 11.8 years) or HA (N=20, 61.8 ± 13.3 years). After a saline washout period, subjects administered BID therapy for 7 days, followed by instillation as needed (2-6 drops per eye) for 7 days. Visual analog scale (VAS) including foreign body sensation, burning/stinging, itching, pain, sticky feeling, blurred vision and photophobia were primary outcomes, with secondary endpoints of corneal fluorescein staining, Schirmer test, tear film breakup time (TFBUT), eyelid and conjunctival erythema and number of instillations compared at day 14.The primary endpoint was met. Lubricin supplementation achieved greater than a 72% reduction from baseline in foreign body sensation (P.013), burning/stinging, pain, sticky feeling (P.0432), blurred vision (P.0013), and photophobia (P.011) in at least one eye. Lubricin also showed significant improvement in fluorescein staining (OD/OS: 43.8%/50.0%, vs. 26.5%/23.3%, P.0398, P.0232), TFBUT (P.010), SANDE frequency (P.0435), eyelid erythema (P.004), conjunctival erythema (P.0013), and instillations (P.04) as compared to HA. No treatment-related adverse events occurred during the investigation.Recombinant human lubricin was shown to produce significant improvement in both signs and symptoms of dry eye disease as compared to HA.

Background Schoolchildren screening for allergic diseases may improve early identification and management of atopic children. The aim of this study was to perform a schoolchildren screening program for identification of children with allergic diseases. Methods All parents of children attending to 13 primary schools in the city of Rome were requested to fill in a demographic data form and the ChAt questionnaire. Allergological evaluation was performed in the children with suspect of allergy (ChAt score > 2). Ocular examination was performed to identify signs of allergic conjunctivitis. The presence of allergic symptoms was related to demographic and environmental variables. Results A total of 2667 children (mean age: 7.1 ± 1 years) were included, and 2489 (93.3%) parents completed the ChAt questionnaire. Results of ChAt questionnaire showed a previous diagnosis of allergic disease in 637 (25.6%) children and the potential presence of an allergic disease (ChAt score > 2) in 35.1%. Multivariate analysis showed that older age, male gender, and having less than two siblings were associated with higher risk of allergic disease. Visual screening showed the presence of clinical signs of allergic conjunctivitis in 2% of children. Allergologic evaluation in 334 children confirmed the diagnosis of allergic disease in 324 (97%) cases. Among them, 97 (29.9%) did not refer to a previous formal diagnosis of allergic condition. Conclusions This study confirmed that schoolchildren screening using ChAt questionnaire could represent a useful tool for early identification of yet undiagnosed atopic children.

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality in women of reproductive age. Although its clinical consequences have been known for a long time to extend beyond the reproductive system, with type-2 diabetes and obesity being the most common, the involvement of the ocular surface in PCOS has been described only more recently. The ocular surface is a morphofunctional unit comprising eyelid margin, tear film, cornea, and conjunctiva. Increasing evidence indicates that these structures are under a sex hormone control and relevant diseases such as ocular allergy and dry eye are often caused by alterations in circulating or local steroid hormones levels. Novel treatments targeting sex hormone receptors on ocular surface epithelial cells are also being developed. In this review we aim to describe the current knowledge on the effects of sex hormones at the ocular surface, with a special focus on the effects of androgen imbalance in PCOS.

PURPOSE: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from loss of corneal innervation. DESIGN: Phase II multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with stage II (moderate) or stage III (severe) NK in one eye. METHODS: The REPARO Phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10μg/ml, 20 μg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study drug, while efficacy was by intention to treat. MAIN OUTCOME MEASURES: Corneal healing (defined as

Neurotrophic keratitis/keratopathy (NK), a rare degenerative corneal disease, lacks effective pharmacologic therapies.1 Because NK pathology involves trigeminal nerve damage and loss of corneal innervation, nerve growth factor (NGF) is surmised to promote healing of NK.2 Preliminary studies with murine NGF demonstrated efficacy for treating corneal neurotrophic ulcers;3 however, the complex tertiary structure of NGF has complicated the production of recombinant human NGF (rhNGF) suitable for clinical development. To this end, we developed an Escherichia coli–derived rhNGF formulation that demonstrated to be well tolerated and safe for topical ophthalmic use in a phase I study in healthy volunteers.4 We report phase I results of topical rhNGF for patients with moderate-to-severe NK.

Introduction: Nerve growth factor (NGF) is a pleiotropic neurotrophin that extends its biological activity from the CNS and peripheral nervous system to the immune, endocrine and visual systems. A recombinant human NGF (rhNGF) was developed for systemic administration in diabetic and HIV-related neuropathy but it did not reach the market due to the failure of a Phase III study. More recently, experimental and clinical data showed that NGF eye drop treatment may be effective in several ophthalmic diseases, and clinical trials with a new rhNGF eye drops are currently ongoing.Areas covered: rhNGF produced in Escherichia coli was approved in Europe and in the United States for use in clinical trials in ophthalmic diseases. A Phase I study showed that rhNGF eye drops are safe and well tolerated. rhNGF has recently obtained Orphan Drug Designation for retinitis pigmentosa (RP) and neurotrophic keratopathy and Phase II clinical trials on these conditions are currently ongoing. The authors examine preclinical, ph...

We report the case of a 29-year-old female patient who presented with an acute onset of anisocoria, blurred vision, nausea and severe left-sided headache. There was no history of trauma, drug abuse, or instillation of topical mydriatic compounds. The ocular history was negative for similar events. On presentation, her visual acuity was 0.2 in the left and 1.0 in the right eye with a +2.5 dpt sph. correction. Slit-lamp examination demonstrated a shallow anterior chamber as well as the presence of iris nodules in both eyes. These nodules were identified as Lisch nodules as the patient referred to the previous diagnosis as being neurofibromatosis type 1. A third nerve palsy was considered, but a brain MRI showed normal results. Her ocular motility was normal, but the left pupil was mydriatic and poorly reacting to light, with an associated raised intraocular pressure (IOP) of 38 mm Hg. An examination of the fellow eye was normal, with the IOP measuring 18 mm Hg. Gonioscopy of the right eye showed a narrow angle. On further anamnestic investigation, the patient revealed that the pain and the blurred vision begun in the morning while she was helping her mother in the garden. Finally, after showing the patient a picture of Datura flowers, which she recognized immediately, we made the unusual diagnosis of angle closure glaucoma by Datura, a well-known toxic plant with mydriatic properties. The patient was successfully treated with systemic acetazolamide and topical pilocarpine.

Nerve growth factor (NGF) is an endogenous neurotrophin involved in the development, maintenance and regeneration of mammalian sympathetic and sensory neurons. Additionally, NGF is known to have trophic and differentiating activity on several populations of cholinergic neurons of the central nervous system (CNS), and to act as a differentiation factor in the development of the visual cortex. The paramount functions of NGF in the visual system are also highlighted by the presence of this neurotrophin and both its receptors TrkA and p75 in most intra-ocular tissues, including lens, vitreous, choroid, iris, and trabecular meshwork. In the retina, NGF is produced and utilized specifically by retinal ganglion cells (RGC), bipolar neurons and glial cells, and is thought to have crucial protective effects in several disease states. Studies on the role of NGF on RGCs survival following optic nerve transection, ischemic injury, ocular hypertension and glaucoma are discussed in this review.

Aims Topical ciclosporin A (CsA) is a therapeutic option for dry eye disease (DED) to control ocular surface inflammation and improve tear function. The aim of this study is to systematically review data from randomised clinical trials (RCTs) evaluating efficacy and safety of topical CsA treatment for DED. Methods Articles published up to December 2012 were identified from Medline, Embase and the Cochrane Controlled Trials Register. A total of 18 RCTs that evaluated the efficacy and safety of different topical CsA formulations for the treatment of DED were selected according to the set criteria. The Jadad score was calculated to assess RCT quality. Results The mean Jadad score of the included RCTs was 2.8±0.6. All CsA formulations proved safe for the treatment of DED. Symptoms improved in 100% (9/9) RCTs, tear function improved in 72% (13/18) RCTs and ocular surface damage was ameliorated in 53% (9/17) RCTs in patients with DED. No improvements with CsA treatment versus control were observed in DED resulting from surgical procedures, contact lens use and thyroid orbitopathy. Statistical comparison of CsA efficacy through a meta-analysis of data was not possible due to a lack of standardised criteria and comparable outcomes among studies. Conclusions Although topical CsA appears to be a safe treatment for DED, evidence emerging from RCTs is limited, and this affects the strength of recommendations to healthcare providers and policymakers for optimal management. Standardised diagnostic criteria to assess the efficacy of topical CsA are recommended to improve the design of future RCTs in DED.

In this review, we aim to summarize the currently available compounds targeting the different components of the inflammatory cascade triggered by an ocular allergic reaction, from mast cells to eosinophils and lymphocytes, with a special focus on specific signs and symptoms that are related to them.The article gives a review of topical therapies utilized to treat the various forms of allergic conjunctivitis, starting from the first drugs developed in the 1980s up to the new compounds that are currently being developed. These include antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory agents, and topical immunosuppressants.The treatment options that have been developed for allergic conjunctivitis in the past 30 years are the result of a better understanding of the pathogenic mechanisms involved in the initiation and perpetuation of the ocular allergic reaction, which is guiding us toward a more specific treatment approach.Several reports and literature reviews have demonstrated that a better knowledge of the immunopathogenesis of the different types of ocular allergy has improved the treatment choice resulting in better clinical outcomes for ocular allergy sufferers. Specifically, the development of novel compounds targeting specific cells and/or cytokines involved in the ocular immune reaction provided safer and more tolerated drugs for both mild-to-moderate and severe forms of allergic conjunctivitis. The correlation of clinical responses to drugs with what we understand about the molecular mechanisms involved could possibly prove useful for developing more standardized treatments in the near future.

Dry eye is a complex disease characterized by changes in the ocular surface epithelia related to reduced quality and/or quantity of tears, inflammatory reaction, and impairment of ocular surface sensitivity. It has recently been proposed that increased tear osmolarity represents a main trigger to the altered cellular mechanisms leading to epithelial damage in dry eye. However, dry eye pathogenesis is multifactorial, with cytotoxic inflammatory mediators, altered lacrimal gland secretion and nerve function, squamous metaplasia of the conjunctival epithelium and decrease of goblet cells density, all playing a role in a detrimental loop that perpetuates and worsens damage to the corneal and conjunctival epithelia. Current topical treatments for dry eye patients include the use of lubricants and anti-inflammatory drugs. However, lubricants only improve symptoms temporarily, and chronic use of topical steroids is associated to severe ocular side effects such as cataract and glaucoma. The deeper understanding of the cellular mechanisms that are altered in dry eye is opening novel perspectives for patients and physicians, who are seeking treatments capable not only of improving symptoms but also of restoring the homeostasis of the ocular surface. In this review, we will focus on novel anti-inflammatory agents and on nerve growth factor, a neurotrophin that is altered in dry eye and has been suggested as a main player in the neuroimmune cross-talk of the ocular surface as well as in the stimulation of corneal sensitivity, epithelial proliferation and differentiation, and stimulation of mucin production by goblet cells. J. Cell. Physiol. 228: 2253-2256, 2013. © 2013 Wiley Periodicals, Inc.

To analyze the clinical characteristics of patients with ocular prosthesis to assess the causes of eye loss in the different genders and age groups, and their incidence over the years. We retrospectively examined the rates of ocular prosthesis application and related causes in the period from 1927 to 2011 in a referral center in Rome, Italy, and compared them over time. We also compared the results within the population in terms of age and gender. Of 8018 ocular prosthesis wearers, 63% were males and 37% were females, with a mean age of 29 years. The most frequent cause of ocular prosthesis application was a traumatic event (54%), with work-related eye injuries being the most frequent single cause of ocular trauma reported. Other frequent causes were end-stage ocular diseases, tumors, and malformations, without significant differences in gender. Tumors and malformations showed a slight increasing trend over time, while end-stage ocular diseases and work-related injuries remained unchanged, and other traumatic events decreased. The constantly high frequency of ocular prosthesis application for work-related injuries and end-stage ocular diseases suggests that preventive measures for these events have not been addressed accordingly, and might represent a neglected public-health issue.

To describe an 8-year-old girl with diagnosis of Sturge-Weber syndrome (SWS) presenting with glaucoma, abnormal iris vessels, diffuse choroidal hemangioma, and small white dot-shaped "microdrusen-like" alterations of the retina in the right eye.Complete ophthalmological examination was performed with slit-lamp anterior segment assessment and fundus ophthalmoscopy. Near infrared reflectance (NIR) and enhanced depth imaging (EDI) spectral domain optical coherence tomography (SD-OCT) were carried out.Microdrusen-like retinal alterations observed with fundus ophthalmoscopy appeared as multiple hyperreflective dots surrounded by a hyporeflective ring on NIR. EDI SD-OCT showed increased choroidal thickness exceeding 1000 μm. B-scan cross-sectional examination on the hyperreflective dots revealed focal alterations of the retinal pigment epithelial (RPE)-photoreceptor layer.The increase of the choroidal thickness due to the diffuse choroidal hemangioma caused alterations of the RPE-photoreceptor layer similar to reticular pseudodrusen or pachychoroid pigment epitheliopathy.

To describe the changes of the ocular surface following chronic use of eye drop therapies. The possible pathogenetic mechanisms responsible for specific signs and symptoms are described and discussed.Topical treatments for ocular diseases may trigger an inflammatory response in predisposed patients, with local activation of immune cells and ocular surface damage. The resulting clinical picture may vary substantially, from mild to severe, sharing a red eye as a hallmark presentation. Recent in-vitro, in-vivo, and clinical data suggest that these detrimental effects are not solely related to eye drop preservatives and may be caused by the medication itself, especially for patients with preexisting ocular diseases. However, no specific tests are currently available to make a clear cut diagnosis between what is caused by the disease and what is the effect of its therapy. Patients' history and clinical features remain essential to hypothesize the underlying pathogenetic mechanism.Topical therapies may induce ocular surface allergic reactions, dry eye-like reactions, and epithelial damage. Patients in need of chronic therapies are at higher risk of facing these detrimental effects of eye drop therapies and should be treated with unpreserved compounds.

Purpose In the present study, we investigated lacrimal function and presence of the neurotrophin nerve growth factor (NGF) and its receptors in the lacrimal gland (LG) of normal rats and rats with inherited retinitis pigmentosa (IRP). Materials and methods After anesthesia, modified Schirmer tests were performed on IRP rats and Sprague Dawley (SD) rats to measure tear function. LGs of developing and adult IRP and SD rats were removed and used for histological, immunohistochemical, and biochemical analyses. Results The results showed that basal tear secretion is reduced in IRP rats as compared with SD rats. NGF and NGF receptors are expressed in the LG of both rat strains. In SD rats, these NGF markers are low during early life and more elevated in adult life. Conversely in rats with IRP, NGF and its receptors decreased in adult life. Conclusions The role of NGF in maintaining ocular surface integrity is well known. The observations of this study further support the hypothesis that neurotrophins play a role in modulating tear secretion and probably in preventing the deleterious effects of dry eye. This hypothesis is presented and discussed.

Maintenance of an intact mucosal barrier is critical to preventing damage to and infection of wet-surfaced epithelia. The mechanism of defense has been the subject of much investigation, and there is evidence now implicating O-glycosylated mucins on the epithelial cell surface. Here we investigate a new role for the carbohydrate-binding protein galectin-3 in stabilizing mucosal barriers through its interaction with mucins on the apical glycocalyx. Using the surface of the eye as a model system, we found that galectin-3 colocalized with two distinct membrane-associated mucins, MUC1 and MUC16, on the apical surface of epithelial cells and that both mucins bound to galectin-3 affinity columns in a galactose-dependent manner. Abrogation of the mucin-galectin interaction in four different mucosal epithelial cell types using competitive carbohydrate inhibitors of galectin binding, beta-lactose and modified citrus pectin, resulted in decreased levels of galectin-3 on the cell surface with concomitant loss of barrier function, as indicated by increased permeability to rose bengal diagnostic dye. Similarly, down-regulation of mucin O-glycosylation using a stable tetracycline-inducible RNA interfering system to knockdown c1galt1 (T-synthase), a critical galactosyltransferase required for the synthesis of core 1 O-glycans, resulted in decreased cell surface O-glycosylation, reduced cell surface galectin-3, and increased epithelial permeability. Taken together, these results suggest that galectin-3 plays a key role in maintaining mucosal barrier function through carbohydrate-dependent interactions with cell surface mucins.

Sturge-Weber syndrome has been included in the group of phakomatoses that is characterized by hamartomas involving the brain, skin, and eyes. The characteristic facial port-wine stain, involving the first branch of the trigeminal nerve and the embryonic vasculature distribution in this area, leads to several ocular complications of the anterior segment and can involve the eyelids and conjunctiva. The posterior segment of the eyes is also affected with diffuse choroidal hemangiomas. However, the most frequent ocular comorbidity is glaucoma with a prevalence rate ranging from 30%-70%. Glaucoma is related to anterior chamber malformations, high episcleral venous pressure (EVP), and changes in ocular hemodynamics. Glaucoma can be diagnosed at birth, but the disease can also develop during childhood and in adults. The management of glaucoma in Sturge-Weber syndrome patients is particularly challenging because of early onset, frequently associated severe visual field impairment at the time of diagnosis, and unresponsiveness to standard treatment. Several surgical approaches have been proposed, but long-term prognosis for both intraocular pressure control and visual function remains unsatisfactory in these patients. Choroidal hemangiomas may also lead to visual impairment thorough exudative retinal detachment and macular edema. Treatment of exudative hemangioma complications is aimed at destructing the tumor or decreasing tumor leakage.

Full-term neonates produce tears normally, but neonatal tear film is modified to resist evaporation with a thick lipid layer that allows lower spontaneous blink rates. This adaptation presumably prevents drying of the ocular surface during long inter-blink periods. However, tear-film stability is not only based on the integrity of the lipid layer, but also reflects properties of the underlying mucus layer. Characteristics of the neonatal mucus tear-film layer have not yet been described.Tear samples were obtained from eight full-term healthy neonates (four males, four females, mean age 1.7 +/- 0.5 days) and eight healthy adult controls (four males, four females, mean age 26.3 +/- 2.5 years). Characterization of tear samples' total proteins was obtained by spectrophotometry. Western blot for major secretory mucin MUC5AC was performed on the samples. Blink rate in the neonates and adults enrolled in the study was also observed and recorded.Using the same procedure, the amount of tears collected was significantly greater in adults than in neonates (p.01). Western Blot performed on neonatal tear samples showed a significant 76.8% increase in the expression of major secretory mucin MUC5AC as compared to healthy adult controls (p.001). Mean blink rate recorded in neonates was significantly lower than in adults (p.001), with a mean 1.6 +/- 0.5 blinks per minute and a mean interblink time of 33 +/- 9 seconds.As far as we are aware this is the first description of the mucus tear-film layer in neonates. The greater tear-film stability in neonates has been so far attributed to a thicker lipid layer. In our study, we show that a concomitant increase in MUC5AC protein expression in tears is present and may contribute to this greater stability; therefore, both mucus and lipid layer should be considered while evaluating tear film stability in neonates.

This special issue is focused on the current approaches used to identify and manage rare diseases of the anterior segment of the eye, which range from congenital to acquired disorders that are caused by ocular or systemic conditions and often have consequences that extend beyond the anterior segment of the eye. Specifically, the groups of Dr. R. Cascella et al. and Dr. G. L. Scuderi et al. provided a complete overview on primary congenital glaucoma and pediatric glaucoma, respectively, from diagnosis to treatment outcomes; the groups of Dr. D. Dobrowolski et al. and Dr. B. E. Ramirez et al. described the use of oral mucosa and stem cell therapy, respectively, for ocular surface reconstruction in rare diseases such as aniridia; Dr. F. Mantelli and colleagues reviewed the diagnosis and management of congenital corneal anesthesia and neurotrophic keratitis; Dr. A. K. Nowinska and colleagues compared different tomographic approaches to evaluate rare corneal dystrophies; the groups of Dr. M. Oldak and Dr. S. P. Patel explained the pathophysiology of Fuchs endothelial corneal dystrophy and congenital hereditary endothelial corneal dystrophy, respectively; Dr. M. Sacchetti and colleagues provide a guide to diagnose and manage the iridocorneal endothelial (ICE) syndrome; Dr. S. Abdolrahimzadeh and colleagues described a series of rare diseases and ophthalmic alterations that may lead to glaucoma; Dr. M. F. Suarez et al. described how environmental agents can influence a rare corneal disease, climatic droplet keratopathy. As can be seen from the variety of topics presented in this special issue, the disorders grouped under the umbrella term of rare diseases of the anterior segment of the eye can be considered quite heterogenous and numerous and, in turn, represent a substantial clinical burden on a worldwide basis [1]. In fact, although single disorders are rarely encountered in clinical practice, when taken together, they are not seldom seen. In addition, these diseases often represent a clinical challenge due to the paucity of specific diagnostic criteria and the lack of specific treatments. In fact, rare disorders tend to remain orphan drug indications due to the difficulty of running clinical trials, and surgical approaches are often inadequate due to concomitant anatomical and congenital anomalies. To make the clinical picture of the rare diseases of the anterior segment of the eye even more difficult to manage, they often have consequences that extend beyond the anterior segment and can severely impair vision. Specifically, while corneal opacities and iris anomalies may directly affect visual function, several diseases such as iridocorneal angle anomalies may induce glaucoma with consequent damage to the optic nerve. In addition, several congenital diseases of the anterior segment of the eye are also associated with facial anomalies and other malformations of intraocular structures, making this group of disorders particularly complex for the ophthalmologist, who encounters obstacles in patients' management from diagnosis to treatment [2]. The recent advances in translational research, which are reshaping modern ophthalmology, allowed identifying the link between different clinical phenotypes and specific mutations in genes regulating the normal formation and maturation of the anterior segments of the eye [3]. In turn, our ability to understand the pathogenesis of rare and complex ophthalmic diseases has improved and, recently, novel treatments are being proposed for selected disorders of the anterior segment. For instance, biotechnology approaches for the pharmaceutical development of recombinant human molecules as well as novel procedures for ex vivo expansion of limbal stem cells may soon open novel therapeutic perspectives for patients with previously untreatable corneal disorders [4, 5]. Similarly, pre- and posttest genetic counseling plays an essential role in the achievement of an appropriate management of congenital glaucoma, in terms of medical, social, and psychological impact of the disease [6]. Nevertheless, due to the complexity of most of the rare anterior segment disorders of the eye, ranging from corneal disorders such as corneal dystrophies, neurotrophic keratitis, iridocorneal anomalies, and congenital glaucoma, further progress is mandatory to exert a significant impact on the natural history of the diseases [7–10]. Hopefully, the constant growth of novel diagnostic tools, accompanied by a better understanding of the disease pathophysiology, will also foster more preclinical and clinical research in this area of high medical need. Alessandro Lambiase Flavio Mantelli Marta Sacchetti Siavash Rahimi Giacomina Massaro-Giordano