Allergic conjunctivitis: current concepts on pathogenesis and management.

Allergic conjunctivitis (AC) includes a wide spectrum of clinical entities characterized by different incidence, age of onset, natural course, clinical outcome and response to treatment. Taken together, they represent one of the most frequent ocular surface diseases affecting more than 30% of the young-adult population and show an increasing incidence over the years. Moreover, comorbidities with other systemic atopic conditions such as asthma, atopic dermatitis and rhinitis require a multidisciplinary approach. Recent advances in the knowledge of the pathogenic mechanism overcome the classic role of type I hyper-sensitivity and mast cells’ activation, demonstrating an involvement of innate immunity and neuroinflammation in the pathogenesis of the most severe forms such as atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). Ocular itching, swelling and tearing are the most frequent symptoms complained by patients with all forms of AC, while photophobia and pain are typical of the most severe forms, such as VKC and AKC, due to the frequent corneal involvement. Upper tarsal papillary reaction represents the main clinical sign of AC associated with conjunctival hyperemia and mucous secretion. Diagnosis is based on clinical history and eye evaluation and can be confirmed through allergological tests. Additional ocular exams include specific allergen conjunctival provocation tests and the presence of eosinophils in the conjunctival scraping. Current treatments of AC include the use of antiallergic eye drops for mild forms, while recurrences of ocular surface inflammations with corneal involvement in severe forms require the use of topical steroids to avoid visual impairment. Novel steroid sparing therapies such as Cyclosporine A eye drops or topical Tacrolimus have been proposed to improve VKC and AKC management.

Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.

BACKGROUND: NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol). METHODS: Four patients entered each of 12 dose levels (n=48; 60-325 µg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment. RESULTS: Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival. CONCLUSION: asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.

Phase II study of NGR-hTNF in combination with doxorubicin in relapsed ovarian cancer patients.

BACKGROUND: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. METHODS: Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 µg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. RESULTS: A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). CONCLUSION: Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.

Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies.

BACKGROUND: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose-response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 µg/m(2) as optimal biological and maximum-tolerated dose, respectively. PATIENTS AND METHODS: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 µg/m(2) in combination with capecitabine-oxaliplatin (XELOX). RESULTS: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3-4 NGR-hTNF-related toxicities were observed. Grade 1-2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression-free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy. CONCLUSIONS: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low-dose NGR-hTNF.

Clinical trials in allergic conjunctivits: a systematic review.

BACKGROUND: Ocular allergy represents one of the most common conditions encountered by allergists and ophthalmologists. However, there is wide variability of study designs in clinical trials of allergic conjunctivitis, which results in conflicting evidence on their optimal management. We conducted a systematic review of clinical trials to critically evaluate their quality and to highlight biases to be avoided in future clinical research in ocular allergy. METHODS: Clinical trials in allergic conjunctivitis performed since 1965 were retrieved, and data on patients, interventions, comparison of interventions, and outcomes were extracted. Four authors independently assessed articles for inclusion in the systematic review and assessed trials' quality using the Jadad scale. RESULTS: Three hundred and sixty-two trials were included in the study. Only a minority of trials fulfilled all the criteria of proper clinical trial design. In most of the studies, there was a very limited use of objective (quantifiable) parameters for both patients' selection and evaluation of drug efficacy and safety. Several outcomes of primary importance, such as disease relapses and recurrence rate, were omitted in clinical trials of allergic conjunctivitis. CONCLUSIONS: Evidence coming out of clinical trials in ocular allergy is limited, and this affects the strength of recommendations to health care providers and policy makers for optimal management. Standardized diagnostic criteria for patient selection and quantifiable primary outcomes are recommended to improve the design of future clinical trials in allergic conjunctivitis.

Achromobacter xylosoxidans respiratory tract infection in cystic fibrosis patients.

The aims of this study were to evaluate the frequency of Achromobacter xylosoxidans infection in a cohort of cystic fibrosis patients, to investigate antimicrobial sensitivity, to establish possible clonal likeness among strains, and to address the clinical impact of this infection or colonization on the general outcome of these patients. The study was undertaken between January 2004 and December 2008 on 300 patients receiving care at the Regional Cystic Fibrosis Center of the Naples University "Federico II". Sputum samples were checked for bacterial identification. For DNA fingerprinting, pulsed-field gel electrophoresis (PFGE) was carried out. Fifty-three patients (17.6%) had at least one positive culture for A. xylosoxidans; of these, 6/53 (11.3%) patients were defined as chronically infected and all were co-colonized by Pseudomonas aeruginosa. Of the patients, 18.8% persistently carried multidrug-resistant isolates. Macrorestriction analysis showed the presence of seven major clusters. DNA fingerprinting also showed a genetic relationship among strains isolated from the same patients at different times. The results of DNA fingerprinting indicate evidence of bacterial clonal likeness among the enrolled infected patients. We found no significant differences in the forced expiratory volume in 1 s (FEV(1)) and body mass index (BMI) when comparing the case group of A. xylosoxidans chronically infected patients with the control group of P. aeruginosa chronically infected patients.

Ectropion Uveae in neurofibromatosis type 1: a new manifestation.

Abstract: Neurofibromatosis type 1 (NF1) is a rare genetic disorder with an autosomal dominant transmission and an estimated incidence of 1:2500-3500 live birth. Penetrance is virtually 100%, but the expression is highly variable and almost every organ can be affected. Diagnosis of NF1 is made with at least two of the following diagnostic criteria: six or more cafè-au-lait spots, two neurofibromas or one plexiform neurofibroma, axillary or groin freckling, optic glioma, two Lisch nodules, bone dysplasia and first-degree relative with NF1. Other ocular manifestations include orbital neurofibromas, cafè-au-lait spots on the eyelids, congenital dysplasia of the sphenoids wing and con-genital glaucoma and choroidal abnormalities. Congenital Ectropion Uveae (CEU) is a rare, non-progressive anomaly characterized by the presence of iris pigment epithelium on the anterior surface of the iris stroma, resulting from its proliferation. CEU probably depends on embryological disorders in neural cells and/or neuroectoderm of the optic cell. In this paper the authors describe three patients with CEU and NF1 found in 243 consecutive NF1 patients.

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels. METHODS: Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 microg m(-2) once every 3 weeks. The primary aim of the study was progression-free survival (PFS). RESULTS: No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months. CONCLUSION: NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest.

Perineal ultrasound evaluation of urethral mobility after the TVT-O procedure.

AIMS: The aim of study was to assess, by means of perineal ultrasound (US), women treated with the trans-obturator suburethral sling procedure for urinary stress incontinence (USI). METHODS: Twelve women with USI and urethral hypermobility were enrolled. Static and dynamic perineal US of urethral mobility was performed before and after tension-free vaginal tape opturator (TVT-O) procedure: US parameters evaluated were pubis-urethra distance and inclination angle of the urethral axis. RESULTS: The Valsalva stress US evaluation showed a return to normal range of the pubic urethral distance in all cases (p = 0.0001); also a correction of the angle of inclination of the urethral axis occurred in all patients (p < 0.0001). CONCLUSIONS: Our results propose the use of perineal US for patients with USI as an additional diagnostic tool and a means for postsurgical follow-up.

Impact of COVID-19 pandemic on otolaryngology, ophthalmology and dental clinical activity and future perspectives.

OBJECTIVE: Since the COVID-19 outbreak, otolaryngologists, ophthalmologists and dentists have been severely affected, both for the transmission routes and for the diagnostical and therapeutic procedures typical of these disciplines. MATERIALS AND METHODS: In this article, we discuss the transmission routes, the potential risk of contagion for patients and healthcare providers during procedures, and comment on the changes that will affect head and neck clinical practice in the future of outpatient and surgical activities. RESULTS: Otolaryngologists, ophthalmologists and dentists are at high risk for infection contagion and spread because they perform diagnostic and therapeutic procedures that generate aerosol and droplets thus facilitating virus transmission. Furthermore, examination involves close doctor-patient contact and otolaryngologists and dentists have to remove patient's protective devices during the visit. CONCLUSIONS: Special attention to prevention protocols for diagnostic and therapeutic procedures and the use of protective equipment is of utmost importance to limit contagion and prevent a new virus spread in the near future.

Clinical and Epidemiological Study on Tubercular Uveitis in a Tertiary Eye Care Centre in Italy.

PURPOSE: To describe frequency, clinical characteristics, and visual prognosis of tubercular uveitis (TBU) in a nonendemic country. METHODS: We retrospectively reviewed 3743 charts of patients with endogenous uveitis visited from 2008 to 2018 at a tertiary referral centre in Rome, Italy. We included immunocompetent patients with diagnosis of TBU. Patients were divided in two groups: patients with history of uveitis without a previous diagnosis of TBU (group A) and patients at their first episode of TB uveitis (group B). RESULTS: TBU was diagnosed in 28 (0.75%) out of 3743 patients. Twelve (42.9%) patients came from tuberculosis endemic areas. All patients received specific antitubercular treatment (ATT) and were evaluated for a mean follow-up of 3.2 ± 2.9 years. Group A showed a greater number of ocular complications when compared with group B. ATT was effective in reducing the frequency of recurrences of uveitis in patients of group B. CONCLUSION: Intraocular inflammation can be the first manifestation of tuberculosis. Our data highlight that early diagnosis and specific treatment of TBU may allow to decrease recurrences and to improve visual outcomes.

Phase Ib study of NGR-hTNF, a selective vascular targeting agent, administered at low doses in combination with doxorubicin to patients with advanced solid tumours.

BACKGROUND: Asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF) is a vascular targeting agent exploiting a tumour-homing peptide (NGR) that selectively binds to aminopeptidase N/CD13, overexpressed on tumour blood vessels. Significant preclinical synergy was shown between low doses of NGR-TNF and doxorubicin. METHODS: The primary aim of this phase I trial was to verify the safety of low-dose NGR-hTNF combined with doxorubicin in treating refractory/resistant solid tumours. Secondary objectives included pharmacokinetics (PKs), pharmacodynamics, and clinical activity. In all 15 patients received NGR-hTNF (0.2-0.4-0.8-1.6 microg m(-2)) and doxorubicin (60-75 mg m(-2)), both given intravenously every 3 weeks. RESULTS: No dose-limiting toxicity occurred and the combination was well tolerated. Around two cases of neutropenic fevers, lasting 2 days, and two cases of cardiac ejection-fraction drops, one asymptomatic and the other symptomatic, were registered. Only 11% of the adverse events were related to NGR-hTNF and were short-lasting and mild-to-moderate in severity. There was no apparent PK interaction and the shedding of soluble TNF-receptors did not increase to 0.8 microg m(-2). One partial response (7%), at dose level 0.8 microg m(-2), and 10 stable diseases (66%), lasting for a median duration of 5.6 months, were observed. CONCLUSIONS: NGR-hTNF plus doxorubicin was administered safely and showed promising activity in patients pre-treated with anthracyclines. The dose level of 0.8 microg m(-2) NGR-hTNF plus doxorubicin 75 mg m(-2) was selected for phase II development.

Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface.

We have analyzed the proliferative and differentiation potential of human ocular keratinocytes. Holoclones, meroclones, and paraclones, previously identified in skin, constitute also the proliferative compartment of the ocular epithelium. Ocular holoclones have the expected properties of stem cells, while transient amplifying cells have variable proliferative potential. Corneal stem cells are segregated in the limbus, while conjunctival stem cells are uniformly distributed in bulbar and forniceal conjunctiva. Conjunctival keratinocytes and goblet cells derive from a common bipotent progenitor. Goblet cells were found in cultures of transient amplifying cells, suggesting that commitment for goblet cell differentiation can occur late in the life of a single conjunctival clone. We found that conjunctival keratinocytes with high proliferative capacity give rise to goblet cells at least twice in their life and, more importantly, at rather precise times of their life history, namely at 45-50 cell doublings and at approximately 15 cell doublings before senescence. Thus, the decision of conjunctival keratinocytes to differentiate into goblet cells appears to be dependent upon an intrinsic "cell doubling clock. " These data open new perspectives in the surgical treatment of severe defects of the anterior ocular surface with autologous cultured conjunctival epithelium.

A characteristic type of retinal microvascular abnormalities in a patient with Neurofibromatosis type 1.

This study aims to describe a typical retinal microvascular abnormality in patients with neurofibromatosis type 1 (NF-1). A 64-year-old man with diagnosis of NF-1 was evaluated by complete ophthalmological examination, including fluorescein angiography and spectral Domain OCT in Near-Infrared (NIR-OCT) modality. Slit lamp exam showed the presence of more than 10 Lisch nodules for each eye. Ophthalmic examinations and NIR-OCT scans showed the presence of retinal tortuous vessels ending in a 'puff of smoke' arrangement. The clinical significance as diagnostic and prognostic factor of this novel type of retinal microvascular abnormality in NF-1 should be further investigated.

Radiological-Pathological Correlation in Plasmablastic Lymphoma in an Immunocompromised Patient.

Plasmablastic lymphoma (PBL) is a malignant, rare, and aggressive form of non-Hodgkin's lymphoma with poor response to treatment that most commonly involves the oral mucosa of immunodeficient patients. The orbit might be primarily or secondarily involved; on the other hand other pathological conditions, i.e., fungal infections, may localize in the orbit in both immunocompromised patients and drug user, which might have similar radiological features. We describe the clinical, radiological, and pathological features of an orbital plasmablastic lymphoma (PBL) in an immunocompromised HIV positive drug user patient.

Corneal ulcer as an atypical presentation of ocular cicatricial pemphigoid.

PURPOSE: To describe three patients, each presenting noninfective corneal epithelial damage as first manifestation of ocular cicatricial pemphigoid (OCP). METHODS: Case report. RESULTS: Patients 1 and 2 were referred to the authors' clinic for corneal ulcer while Patient 3 for relapsed epithelial defects. All patients had negative history for systemic diseases and microbiological tests were negative. Topical steroid treatment induced the complete resolution of corneal damage. During the follow-up period, the onset of mild conjunctival fibrosis in the lower fornix allowed the authors to suspect OCP, confirmed by conjunctival biopsy. CONCLUSIONS: In the three patients corneal damage was an early sign of OCP, in the absence of typical signs of conjunctival fibrosis. The authors thus suggest considering conjunctival biopsy as a useful additional test in the management of idiopathic corneal ulcers.

Cenegermin for the treatment of neurotrophic keratitis.

The trigeminal nerve provides corneal sensitivity and trophic supply to corneal tissues. The impairment of corneal innervation leads to development of neurotrophic keratitis (NK). NK is a rare, degenerative corneal disease characterized by corneal hypo/anesthesia and development of nonhealing corneal epithelial defects and ulcers. NK is a challenging condition with high medical need due to the lack of approved treatments that can restore corneal integrity. Current treatment of NK aims at stimulating corneal healing and preventing disease progression. Cenegermin is a recombinant human nerve growth factor that was safe and well tolerated in preclinical and clinical studies. Cenegermin eye drops were safe and effective in restoring corneal integrity in two phase II clinical trials in patients with NK. The European Commission granted a full marketing authorization to cenegermin eye drops for the treatment of moderate to severe NK in July 2017.

Involvement of the Anterior Segment of the Eye in Patients with Mucopolysaccharidoses: A Review of Reported Cases and Updates on the Latest Diagnostic Instrumentation.

Mucopolysaccharidoses (MPS) are a heterogeneous group of rare inherited disorders, characterized by the lack or malfunction of lysosomal enzymes necessary for glycosaminoglycan (GAGs) catabolism, and their subsequent accumulation in many tissues and organs throughout the body. An overview of the current knowledge of corneal and anterior segment manifestations in patients with MPS was provided and clinical guidelines for their diagnosis and management were furnished. The anterior segment of the eye is usually involved in every subtype of MPS, with major complications including varying degrees of corneal opacification and raised intraocular pressure (IOP) with development of glaucoma. Their recognition and management can be very useful in the diagnosis of MPS. Novel techniques are available to objectively measure the grade and extent of corneal clouding and give information about the anatomy of the anterior chamber and the structures of the angle beyond the clouded cornea. It is advisable to take advantage of this new instrumentation in order to obtain thorough information on the ocular involvement and its related anterior chamber complications for a better management of patients with MPS, both in terms of visual prognosis and therapeutic outcome.

Allergy and infections: long-term improvement of vernal keratoconjunctivitis following viral conjunctivitis.

PURPOSE: Vernal keratoconjunctivitis (VKC) is a severe, chronic allergic inflammatory disease of the ocular surface poorly responsive to antiallergic treatments and possibly leading to permanent visual impairment. VKC, because of mast cell, eosinophil, and Th2-type inflammation, polyclonal IgE activation, and tissue remodeling, is considered to be a typical Th2- driven disease. Viral infection stimulates a Th1 type immune response, potentially attenuating allergen-induced inflammation. The purpose of this report is to describe the effect of viral keratoconjunctivitis in a patient with VKC. METHODS: The authors report on a patient with a severe form of VKC, poorly responsive to antiallergic treatments, who developed a viral keratoconjunctivitis. Signs, symptoms, and cytologic findings were recorded during the 5-year follow-up period. RESULTS: The authors observed a prompt and permanent improvement of signs and symptoms of the allergic condition after the viral infection. Conjunctival scraping confirms that the inhibition of the eosinophilic inflammation lasts at least for 5 years. CONCLUSIONS: In this case, the viral infection seemed to induce a clinical recovery of allergic disease, suggesting that an immune deviation induced by Th1-polarizing agents may revert an ongoing Th2 inflammation.

Conjunctival papilloma and human papillomavirus: identification of HPV types by PCR.

PURPOSE: To report the identification of human papillomavirus types in four cases of conjunctival papillomas and to review the literature regarding human conjunctival papillomavirus (HPV). METHODS: Specimens from conjunctival papillomas of four patients were analyzed for the presence of HPV by polymerase chain reaction and subsequent filter hybridization. HPV types 6, 11, 16, 18, 31, and 33 were investigated. Histologic sections were analyzed for the presence of koilocytosis. RESULTS: Histologic examination confirmed HPV infection in all cases. HPV type 11 was detected in all specimens. CONCLUSIONS: HPV is frequently implicated in the pathogenesis of proliferative squamous lesions. HPV type 11 was the most frequently found in benign conjunctival lesion in this study.