Publications by authors named "Steffen Heegaard"

257 Publications

Investigation of the correlation between diabetic retinopathy and prevalent and incident migraine in a national cohort study.

Sci Rep 2022 Jul 20;12(1):12443. Epub 2022 Jul 20.

Department of Ophthalmology, Odense University Hospital, Odense, Denmark.

Migraine is a disease characterized by cerebral vasodilation. While diabetes has previously been associated with a lower risk of migraine, it is not known if diabetic retinopathy (DR), a retinal peripheral vascular occlusive disease, is a potential biomarker of protection against migraine. Therefore, we aimed to examine diabetic retinopathy as a marker of prevalent and 5-year incident migraine. In a national cohort, we compared patients with diabetes attending DR screening from The Danish National Registry of Diabetic Retinopathy (cases, n = 205,970) to an age- and gender-matched group of patients without diabetes (controls, n = 1,003,170). In the cross-sectional study, a multivariable model demonstrated a lower prevalence of migraine among cases compared with controls (OR 0.83, 95% CI 0.81-0.85), with a lower risk in cases with DR than in those without (OR 0.69, 95% CI 0.65-0.72). In the prospective study, a lower risk of incident migraine was found in a multivariable model in cases (HR 0.76, 95% CI 0.70-0.82), but this did not depend upon the presence of DR. To conclude, in a national study of more than 1.2 million people, patients screened for DR had a lower risk of present migraine, but DR was not a protective marker of incident migraine.
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http://dx.doi.org/10.1038/s41598-022-16793-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9300720PMC
July 2022

NK- and T-cell lymphoma of the nasal cavity and paranasal sinuses in Denmark 1980-2017: a nationwide cohort study.

Leuk Lymphoma 2022 Jun 14:1-10. Epub 2022 Jun 14.

Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Compared to Asian and Latin American populations, sinonasal NK- or T-cell lymphoma is rare in Europe. All patients with sinonasal NK- or T-cell lymphoma in Denmark from 1980 to 2017 were validated histologically, and the disease behavior and demographics were extracted from medical records and national registries. Prognostic factors associated with mortality were determined using survival statistics. We included 56 patients: 40 extranodal NK/T-cell lymphoma (nasal type) (ENKTCL) and 16 peripheral T-cell lymphoma (not otherwise specified) (PTCL). The median age was 66, and most patients were male (72%). The ENKTCL and PTCL 5-year overall survival was 48% and 50%, respectively; progression-free survival was 38% for both. With ENKTCL, stage and performance status increased mortality significantly (HR = 8.6;  < 0.001 and HR = 4.23;  = 0.04). In conclusion, disseminated disease had a dismal outcome and the onset of ENKTCL in this ethnically homogeneous European cohort was about a decade later than reported in Asian populations.
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http://dx.doi.org/10.1080/10428194.2022.2087069DOI Listing
June 2022

An Evaluation of the Physicochemical Properties of Preservative-Free 0.005% (/) Latanoprost Ophthalmic Solutions, and the Impact on In Vitro Human Conjunctival Goblet Cell Survival.

J Clin Med 2022 May 31;11(11). Epub 2022 May 31.

Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.

Purpose: To examine the physicochemical properties of five preservative-free (PF) 0.005% latanoprost ophthalmic products; Monoprost, Latanest, Gaap Ofteno, Xalmono, and Xaloptic Free. Furthermore, the study investigated the mucin production and cell survival of primary cultured human conjunctival goblet cells when treated with PF eye drops.

Method: The pH value, osmolality, and surface tension were examined. Cell survival was analyzed using lactate dehydrogenase and tetrazolium dye colorimetric assays. Mucin production was analyzed with immunohistochemical staining.

Results: Monoprost (pH value 6.84 ± 0.032) had a pH value closest to the pH value of tear fluid (pH value 7.4-7.6), whereas Gaap Ofteno (pH value 6.34 ± 0.004) and Latanest (pH value 6.33 ± 0.003) had the lowest pH values. Gaap Ofteno (325.9 ± 2.9 mosmol/kg) showed iso-osmolar probabilities, whereas the other products were hypo-osmolar. Gaap Ofteno (60.31 ± 0.35 mN/m) had a higher surface tension compared to the tear fluid (40 to 46 mN/m), as described in the literature. No significant differences in goblet cell survival or mucin release were observed between the treatments and control.

Conclusion: Significant differences in pH value, osmolality, and surface tension were observed. However, this did not affect the viability of the goblet cells or the release of mucin. Clinical studies are required to evaluate the long-term effects of use on efficacy and safety.
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http://dx.doi.org/10.3390/jcm11113137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181163PMC
May 2022

A rare case of lacrimal sac angioleiomyoma managed with dacryocystectomy and turbinectomy.

Orbit 2022 Jun 9:1-4. Epub 2022 Jun 9.

Deparment of Ophthalmology and Pathology, Rigshospitalet, University of Copenhagen, Copenhagem, Denmark.

We report a rare case of a lacrimal sac angioleiomyoma. A 56-year-old woman complained of pain in the right medial canthal region over a period of 2 years. There were no complaints of epiphora or ocular infection, and no visible or palpable masses in the medial canthal region. Computed tomography scan revealed a solid tumor of the lacrimal sac expanding to the nasolacrimal duct and protruding under the inferior turbinate. The tumor was removed by external dacryocystectomy combined with endonasal, endoscopic anterior turbinectomy, and nasal mucosal resection. Histological and immunohistological findings were consistent with an angioleiomyoma of the venous type. There was no recurrence of the tumor at the three-year follow-up. Angioleiomyomas should be included in the differential diagnosis of lacrimal sac tumors. The definitive diagnoses rely on histology and immunohistological reactions. The treatment is complete surgical resection.
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http://dx.doi.org/10.1080/01676830.2022.2085306DOI Listing
June 2022

Mutation of KRAS in colorectal adenocarcinoma in Greenland.

APMIS 2022 Aug 20;130(8):493-497. Epub 2022 Jun 20.

Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

KRAS mutation is one of the most frequent driver mutations in colorectal cancer (CRC) and is also a prognostic biomarker. The aim of the present study was to determine the frequency of KRAS mutations over time in the Greenlandic population diagnosed with CRC. In total, 578 patients with the diagnosis of adenocarcinoma between 1988 and 2017 were identified. The status of KRAS and the mutational subtypes of KRAS mutations were determined in 102 representative samples by the Idylla™ platform in the time periods 1988-1990, 2002-2004, and 2015-2017. The results showed that the frequency of the KRAS mutations increased significantly, from 27% in 1988-1990 to 43% in 2015-2017 (p < 0.001). Furthermore, the most frequent subtypes of KRAS mutations in Greenland were G12D (c.35G > A) with 14%, G12V (c.35G > T) with 7%, and G13D (c.38G > A) with 6%. In conclusion, this study showed that the frequency of KRAS mutations in CRC has been increasing in recent decades in the specific population of Greenland. The results of this study may be used in initiatives related to targeted therapy of CRC in specific ethnicities and in investigations focusing on the environmental factors of cancer-related somatic mutations.
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http://dx.doi.org/10.1111/apm.13254DOI Listing
August 2022

Viral and Genomic Drivers of Squamous Cell Neoplasms Arising in the Lacrimal Drainage System.

Cancers (Basel) 2022 May 23;14(10). Epub 2022 May 23.

The Eye Pathology Section, Department of Pathology, Copenhagen University Hospital Rigshospitalet, DK-2100 Copenhagen, Denmark.

The pathogenesis of squamous cell neoplasms arising in the lacrimal drainage system is poorly understood, and the underlying genomic drivers for disease development remain unexplored. We aimed to investigate the genomic aberrations in carcinomas arising in the LDS and correlate the findings to human papillomavirus (HPV) status. The HPV analysis was performed using HPV DNA PCR, HPV E6/E7 mRNA in-situ hybridization, and p16 immunohistochemistry. The genomic characterization was performed by targeted DNA sequencing of 523 cancer-relevant genes. Patients with LDS papilloma ( = 17) and LDS carcinoma ( = 15) were included. There was a male predominance (68%) and a median age at diagnosis of 46.0 years (range 27.5-65.5 years) in patients with papilloma and 63.8 years (range 34.0-87.2 years) in patients with carcinoma. Transcriptional activity of the HPV E6/E7 oncogenes was detected in the whole tumor thickness in 12/15 (80%) papillomas (HPV6, 11, 16) and 10/15 (67%) squamous cell carcinomas (SCC) (HPV11: 3/15 (20%) and HPV16: 7/15 (47%)). Pathogenic variants in , , , and , wildtype , p16 overexpression, and deregulated high-risk E6/E7 transcription characterized the HPV16-positive SCC. The deregulated pattern of HPV E6/E7 expression, correlating with HPV DNA presence and p16 positivity, supports a causal role of HPV in a subset of LDS papillomas and carcinomas. The viral and molecular profile of LDS SCC resembles that of other HPV-driven SCC.
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http://dx.doi.org/10.3390/cancers14102558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140041PMC
May 2022

Adverse Effects and Safety in Glaucoma Patients: Agreement on Clinical Trial Outcomes for Reports on Eye Drops (ASGARD)-A Delphi Consensus Statement.

Am J Ophthalmol 2022 May 18;241:190-197. Epub 2022 May 18.

From the Department of Drug Design and Pharmacology, University of Copenhagen (A.-S.T., A.H., M.K.), Copenhagen, Denmark; Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet (A.H., S.H., M.K.), Glostrup, Denmark. Electronic address:

Purpose: The purpose of this study is to establish consensus among experts on outcomes and methods to be used in clinical trials to assess adverse effects of anti-glaucomatous eye drops.

Design: Modified Delphi method.

Methods: Clinical experts from Europe, North America, South America, the Middle East, and Asia were invited to participate in 2 sequential web-based surveys administered from June 27 to August 29, 2021. A total of 91 clinical experts were invited to participate. Of these, 71 (78%) experts from 23 different countries accepted the invitation and answered the first questionnaire. The importance of items was ranked using a 10-point scale (1 as not important, 10 as very important).

Results: A total of 84 items were rated in round one by 71 participants. Of these, 68 (81%) reached consensus. In round 2, 19 items, including 3 additional items, were rated by 53 (75%) participants. Consensus was reached in 98% of investigated items. Eight outcomes were agreed as important to assess when conducting future trials: ocular surface, dryness, epithelial damage, local adverse effects related to eye drops as reported by patients, periocular surroundings and eyelids, quality of life questionnaires, hyperemia, visual acuity, tear film, and anterior chamber inflammation.

Conclusion: We propose a consensus-based series of outcomes and assessment methods to be used in clinical trials assessing adverse effects of antiglaucomatous eye drops. This, we hope, will improve the comparability of results from future trials and thus facilitate meta-analyses and progress in this field.
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http://dx.doi.org/10.1016/j.ajo.2022.05.007DOI Listing
May 2022

Nationwide Incidence of Thyroid Eye Disease and Cumulative Incidence of Strabismus and Surgical Interventions in Denmark.

JAMA Ophthalmol 2022 07;140(7):667-673

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Importance: Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce.

Objective: To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED.

Design, Setting, And Participants: A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 107 person-years (women, 4.18 × 107 person-years; men, 4.04 × 107 person-years).

Main Outcome Measures: The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age.

Results: A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P < .001).

Conclusions And Relevance: This study in Denmark provides nationwide empirical incidence of TED and strabismus and surgical interventions after TED that required inpatient or outpatient hospital treatment, and might be used for patient information and health care planning.
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http://dx.doi.org/10.1001/jamaophthalmol.2022.1002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9121304PMC
July 2022

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

Acta Ophthalmol 2022 May 8. Epub 2022 May 8.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Purpose: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics.

Methods: The effect of travoprost eye drops was evaluated on GC cultures. Cell viability was assessed through lactate dehydrogenase (LDH) and tetrazolium dye (MTT) colorimetric assays. Mucin secretion was evaluated by immunohistochemical staining. Secretion of interleukin (IL)-6 and IL-8 was measured using BD Cytometric Bead Arrays. pH, viscosity, droplet mass, osmolality and surface tension were measured for all included eye drops.

Results: In the LDH assay, BAK travoprost caused significant GC loss after 2 hrs of incubation compared to the control. PQ travoprost caused no GC loss at any time point. Both PQ- and BAK travoprost caused secretion of mucin to the cytoplasma. No difference in IL-6 and IL-8 secretion was identified compared to controls. The pH values for the generics were lower (pH 6.0) than the pH value for Travatan (pH 6.7; p < 0.0001). The viscosity was lowest for Travatan, while the mean droplet mass was higher for Travatan (35 mg) than the generics (28-30 mg; p ≤ 0.0318). The osmolality and surface tension did not differ between the eye drops investigated.

Conclusion: BAK travoprost caused GC loss, indicating that PQ preservation may be preferable in treatment of glaucoma. Furthermore, physicochemical properties of branded and generic travoprost eye drops can not be assumed to be identical.
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http://dx.doi.org/10.1111/aos.15163DOI Listing
May 2022

Specific location of ocular adnexal lymphoma and mortality: an international multicentre retrospective study.

Br J Ophthalmol 2022 May 5. Epub 2022 May 5.

Eye Pathology Section, Department of Pathology, Rigshospitalet, Copenhagen, Denmark

Aims: To examine whether the specific location of ocular adnexal lymphoma (OAL) and the American Joint Committee on Cancer (AJCC) TNM tumour stage are prognostic factors for mortality in the main OAL subtypes.

Methods: Clinical and survival data were retrospectively collected from seven international eye cancer centres. All patients from 1980 to 2017 with histologically verified primary or secondary OAL were included. Cox regression was used to compare the ocular adnexal tumour locations on all-cause mortality and disease-specific mortality.

Results: OAL was identified in 1168 patients. The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n=688, 59%); follicular lymphoma (FL) (n=150, 13%); diffuse large B-cell lymphoma (DLBCL) (n=131, 11%); and mantle cell lymphoma (MCL) (n=89, 8%). AJCC/TNM tumour-stage (T-stage) was significantly associated with disease-specific mortality in primary ocular adnexal EMZL and increased through T-categories from T1 to T3 disease. No associations between AJCC/TNM T-stage and mortality were found in primary ocular adnexal FL, DLBCL, or MCL. EMZL located in the eyelid had a significantly increased disease-specific mortality compared with orbital and conjunctival EMZL, in both primary EMZL and the full EMZL cohort. In DLBCL, eyelid location had a significantly higher disease-specific mortality compared with an orbital or lacrimal gland location.

Conclusion: Disease-specific mortality is associated with AJCC/TNM T-stage in primary ocular adnexal EMZL patients. Lymphoma of the eyelid has the highest disease-specific mortality in primary EMZL, and in the full cohort of EMZL and DLBCL patients.
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http://dx.doi.org/10.1136/bjophthalmol-2021-320466DOI Listing
May 2022

IL-4 and IL-13 both contribute to the homeostasis of human conjunctival goblet cells in vitro.

Allergy 2022 Aug 6;77(8):2555-2558. Epub 2022 May 6.

Department of In Vitro Biology, Molecular Biomedicine, Research and Early Development, LEO Pharma A/S, Ballerup, Denmark.

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http://dx.doi.org/10.1111/all.15326DOI Listing
August 2022

Epidemiology and clinical characteristics of congenital choristomas in the ocular adnexa of pediatric patients.

Graefes Arch Clin Exp Ophthalmol 2022 Apr 21. Epub 2022 Apr 21.

Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Purpose: To investigate the epidemiology and clinical characteristics of infants presenting with conjunctival, palpebral, or orbital congenital choristomas (dermolipomas, epidermoids, and dermoid cysts) and children undergoing surgery for congenital choristomas in the ocular adnexa.

Methods: We reviewed the medical files of congenital choristomas in children seen in The Capital Region of Denmark during a 5-year period (2014-2018). Children (< 18 years) were divided into two groups: those referred < 1 year of age (Group I) and those undergoing surgery to remove the lesion (Group II). Group I was used to calculate a population-based incidence of congenital choristomas by comparing our data to birth statistics from the Danish Medical Birth Registry.

Results: A total of 97 children were included, 43 in Group I and 70 in Group II (including 16 patients from Group I). The total incidence of congenital choristomas was 1 in 2537 live born children. Most lesions were palpebral choristomas (27/43, 63%) located in the superotemporal region (17/27, 63%), followed by the superonasal region (7/27, 26%). The main reasons for surgical removal of a congenital choristoma were growth (28/70, 40%) or cosmesis (25/70, 36%).

Conclusion: The total incidence of congenital choristomas in the ocular adnexa of infants < 1 year of age, including both conjunctival and palpebral congenital choristomas, is about 1 in 2537 live born children in The Capital Region of Denmark. Hence, congenital choristomas are common masses found in the ocular adnexa.
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http://dx.doi.org/10.1007/s00417-022-05652-3DOI Listing
April 2022

Metachronous, non-pineal, trilateral retinoblastoma in a patient with a seemingly reduced-expressivity germline deletion.

Clin Case Rep 2022 Mar 18;10(3):e05498. Epub 2022 Mar 18.

Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark.

The clinical course of trilateral retinoblastoma can be unpredictable, and expressivity of germline variants may vary during development. We describe an unexpected fatal case of trilateral retinoblastoma with an intracranial tumor in an unusual location and discuss genetic copy number analyses as a useful diagnostic tool with therapeutic potential.
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http://dx.doi.org/10.1002/ccr3.5498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933631PMC
March 2022

Vaginal melanoma in Denmark from 1980 to 2018: A population-based study based on genetic profile and survival.

Gynecol Oncol 2022 04 3;165(1):53-59. Epub 2022 Feb 3.

Department of Pathology, Copenhagen University Hospital, Copenhagen, Denmark; Department of Ophthalmology, Copenhagen University Hospital, Copenhagen, Denmark. Electronic address:

Objective: To investigate the clinical, pathological, and genetic characteristics of patients with vaginal melanoma in a nationwide setting.

Materials/methods: All patients diagnosed with vaginal melanoma from 1980 to 2018 were collected by searching the digital archives of the Danish Registry of Pathology (Patobank). Patient specimens were examined, the histological diagnoses were validated, and targeted next-generation sequencing (NGS) of known frequent hot spots in 163 genes was performed.

Results: Fifty-two patients were included. The incidence for primary melanoma of the vagina in the Danish population (5.5 million people) was calculated to be 0.24 cases/million/year from 1980 to 2018. For all patients, the median OS was 17.5 months (95% CI: 13.0-24.0), and the 5-year OS was 19.4% (95% CI: 10.9-34.3). We identified frequent mutations in ATRX (7/25 cases) and TP53 (7/25 cases). Mutations found in TP53 were associated with a significant decrease in OS (p = 0.043), whereas mutations in the ATRX gene alone did not show a significant impact on OS (p = 0.3649). Patients who harbored co-mutations in both ATRX and TP53 showed a significant reduction in OS (p = 0.0081), with a median OS of 9.5 months compared to 20 months in those without the co-mutation.

Conclusions: Vaginal melanoma is a rare disease with a poor prognosis presumably due to vague symptoms and the anatomical location of the disease. Co-mutations in ATRX and TP53 and mutations in TP53 alone were associated with a poor prognosis, and these genes are potentially interesting targets for future therapy.
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http://dx.doi.org/10.1016/j.ygyno.2022.01.028DOI Listing
April 2022

Sinonasal B-cell lymphomas: A nationwide cohort study, with an emphasis on the prognosis and the recurrence pattern of primary diffuse large B-cell lymphoma.

Hematol Oncol 2022 Apr 6;40(2):160-171. Epub 2022 Feb 6.

Department of Otorhinolaryngology, Head and Neck Surgery & Audiology, Rigshospitalet, Copenhagen, Denmark.

Lymphomas of the nasal cavity and paranasal sinuses (NPS) are rare. Knowledge on sinonasal B-cell lymphoma (SNBCL) primarily comes from case series or single-center studies on small cohorts. We sought to determine the subtype distribution, clinical characteristics, disease behavior, and prognosis on a nationwide scale, with an emphasis on prognostic factors for the most common sinonasal lymphoma, primary sinonasal diffuse large B-cell lymphoma (PSDLBCL). We collated all data from medical records and national databases on patients registered with SNBCL from 1980 through 2018 in the national pathology registry and collected all tissue samples for validation of diagnosis. We included 205 patients and found 10 different subtypes of lymphoma. Diffuse large B-cell lymphoma (DLBCL) was the predominant subtype (80%). The incidence of SNBCL was 0.14/100,000 person-years. The five-year progression-free survival (PFS) and overall survival rates for PSDLBCL were 50% and 56%, respectively. For PSDLBCL, Rituximab showed a statistically significant effect (Hazard Ratio 0.22, p < 0.001), whereas consolidative radiotherapy combined with immunochemotherapy was of limited value (PFS, p = 0.93). When treatment failure occurred, DLBCL showed a distinct pattern of recurrence/dissemination to the NPS, skin, breast, central nervous system (CNS), and/or testis. Collectively, DLBCL comprised a clear majority of SNBCLs, although nine other subtypes were represented. Data showed that immunochemotherapy increased survival for PSDLBCL and that the addition of radiotherapy did not benefit patients. Furthermore, treatment failure for sinonasal DLBCL showed a possible common pathogenesis with primary extranodal lymphomas of specific locations (e.g., CNS, skin, breast, and testis).
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http://dx.doi.org/10.1002/hon.2968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303446PMC
April 2022

Comparison of temporal artery ultrasound versus biopsy in the diagnosis of giant cell arteritis.

Eye (Lond) 2022 Jan 29. Epub 2022 Jan 29.

Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Background/objectives: Giant cell arteritis (GCA) is a medical and ophthalmological emergency due to risk of stroke and sudden irreversible loss of vision. Fast and accurate diagnosis is important to prevent complications and long-term high dose glucocorticoids toxicity. Temporal artery biopsy is gold standard for diagnosing GCA. However, temporal artery ultrasound is a fast and non-invasive procedure which may provide a supplement or an alternative to biopsy. This study assesses the diagnostic performance of ultrasound and biopsy in the diagnosis of GCA.

Subjects/methods: Examination results of patients suspected of having GCA in the period from August 2018 to June 2019 were reviewed. Patients underwent clinical examination and blood tests. Within a few days of starting glucocorticoid treatment, temporal ultrasound and unilateral biopsy were performed. Experienced physicians established the final clinical diagnosis at 6-months follow-up.

Results: Seventy-eight patients underwent both ultrasound and biopsy. Thirty-five (45%) received the final clinical diagnosis of GCA. Compared with the final clinical diagnosis, biopsy had a sensitivity of 69% (51-83%) and a specificity of 100% (92-100%), and ultrasound a sensitivity of 63% (45-79%) and a specificity of 79% (64-94%). Area under the receiver operating characteristics curves were 0.84 and 0.71 for biopsy and ultrasound respectively (p = 0.048). False negative rate of ultrasound was 4 out of 78 (5%).

Conclusion: Sensitivity of ultrasound is almost on par with that of biopsy although the overall diagnostic accuracy of ultrasound was slightly lower. We find that ultrasound is a reliable tool for first line diagnosis of GCA.
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http://dx.doi.org/10.1038/s41433-022-01947-1DOI Listing
January 2022

Controlled Subretinal Injection Pressure Prevents Damage in Pigs.

Ophthalmologica 2022 24;245(3):285-294. Epub 2022 Jan 24.

Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Introduction: Administration of retinal gene and stem cell therapy in patients with retinal degenerative diseases is in many cases dependent on a subretinal approach. It has been indicated that manual subretinal injection is associated with outer retinal damage, which may be explained by a high flow rate in the injection cannula. In the present porcine study, we evaluated flow-related retinal damage after controlled subretinal injection at different flow rates.

Methods: The flow rate through a 41G cannula was estimated at different injection pressures (6-48 pounds per square inch [PSI]) in an in vitro setup. A linear correlation between the flow rate and injection pressure was found from 6 to 32 PSI. In full anesthesia, 12 pigs were vitrectomized and received a controlled subretinal injection of 300 μL balanced saline solution at injection pressures of 14, 24, and 32 PSI (four in each group). Prior to surgery and 2 and 4 weeks after surgery, the eyes were examined by multifocal electroretinogram (mfERG) and fundus photographs. At the end of follow-up, the eyes were enucleated for histology.

Results: The in vitro flow study determined that the flow in a 41G cannula shifts from laminar to turbulent at 32 PSI and that the manual injection flow is turbulent. In the porcine study, we showed a significant difference in retinal pigment epithelium (RPE) damage between the three pressure groups (p = 0.0096). There was no significant difference in damage to the outer retina (p = 0.1526), but the high-pressure group (32 PSI) had the most outer retinal damage. The middle-pressure group (24 PSI) showed minimum retinal damage. There was no significant change in the mfERG ratios during follow-up.

Discussion/conclusion: This study indicates that an injection pressure at approximately 24 PSI might be safe for subretinal delivery. Retinal damage at low injection pressures may be explained by mechanical damage to the RPE due to prolonged needle time in the subretinal space, while retinal damage at high pressures can be related to high flow in the injection cannula. Controlled subretinal injection pressure of 24 PSI showed minimum mechanical- and flow-related damage to the porcine retina.
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http://dx.doi.org/10.1159/000522110DOI Listing
June 2022

Diabetic Retinopathy Predicts Risk of Alzheimer's Disease: A Danish Registry-Based Nationwide Cohort Study.

J Alzheimers Dis 2022 ;86(1):451-460

Department of Ophthalmology, Odense University Hospital, Odense, Denmark.

Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD).

Objective: To investigate diabetes and DR as a risk marker of present and incident AD.

Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes.

Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59-0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81-0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08-1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18-1.53).

Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR.
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http://dx.doi.org/10.3233/JAD-215313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9028615PMC
April 2022

Risk of New Primary Cancer in Patients with Posterior Uveal Melanoma: A National Cohort Study.

Cancers (Basel) 2022 Jan 7;14(2). Epub 2022 Jan 7.

Department of Ophthalmology, University Hospital of Copenhagen, 2100 Copenhagen, Denmark.

Background: Studies on the risk of new primary cancer in patients with posterior uveal melanoma (UM) have produced conflicting results, and the role of socioeconomic status (SES) is unknown. The purpose of this population-based matched cohort study was to determine the risk of new primary cancer following the diagnosis of posterior UM.

Methods: 2179 patients with posterior UM 1968-2016 and 22,717 matched controls without cancer were included. Incidence and time-dependent hazard ratio (HR) of new primary cancer were described, and the effect of SES was emphasized in a sub-cohort.

Results: The incidence of new primary cancer was increased in patients with posterior UM, rate ratio (RR) 1.21 (95% CI: 1.08; 1.35), but the specific cancer types did not differ compared to the controls. The rate of new primary cancer following the diagnosis of posterior UM was significantly increased 2-5 years (HR 1.49 (95% CI: 1.23; 1.80)) and 11-15 years (HR: 1.49 (95% CI: 1.12; 1.99)), and adjusting for SES did not change the rate (HR 1.35 (95% CI:1.20; 1.55)).

Conclusions: Patients with posterior UM have an increased risk of new primary cancer independent of SES. No difference in incidence of specific cancer type was observed compared to the control group.
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http://dx.doi.org/10.3390/cancers14020284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773914PMC
January 2022

Ocular graft-versus-host disease and dry eye disease after paediatric haematopoietic stem cell transplantation - incidence and risk factors.

Bone Marrow Transplant 2022 03 18;57(3):487-498. Epub 2022 Jan 18.

Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Ocular graft-versus-host disease (oGVHD) contributes substantially to morbidity after allogeneic haematopoietic stem cell transplantation (HSCT) but is sparsely investigated in children. We assessed incidence and risk factors for oGVHD and dry eye disease (DED) in a nationwide, single-centre study of 484 consecutive children receiving HSCT during the period 1980-2016. Ophthalmological examinations were performed before and annually at least until five years after HSCT. Twenty-five patients had DED before transplantation (5.6%). The cumulative incidence was 1.9% for acute oGVHD, 6.0% for chronic oGVHD, 8.7% for new onset DED, and 12.7% for new onset Corneal Fluorescein Staining (CFS). In adjusted Fine-Gray regression models, the use of Busulfan was a risk factor for developing acute oGVHD (HR 5.01, p = 0.03), and malignant disease was a risk factor for developing CFS (HR 2.00, p = 0.047). Younger recipient age was associated with reduced risk of DED when comparing children aged 0-4 years with 10-16 years (HR 0.33, p = 0.03). These data underscore the need of attention to DED and oGVHD in relation to HSCT leading to our recommendation of performing ophthalmic examinations in all children before HSCT, and after HSCT when needed, in order to secure diagnosis and treatment of these complications.
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http://dx.doi.org/10.1038/s41409-022-01564-2DOI Listing
March 2022

Impact of benzalkonium chloride-preserved and preservative-free latanoprost eye drops on cultured human conjunctival goblet cells upon acute exposure and differences in physicochemical properties of the eye drops.

BMJ Open Ophthalmol 2021 20;6(1):e000892. Epub 2021 Dec 20.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Objective: To investigate the short-term impact on human conjunctival goblet cell (GC) survival and mucin release of acute exposure to benzalkonium chloride (BAK) preserved and preservative-free (PF) 0.005% (w/v) latanoprost (LT) eye drops, and to compare the eye drops' physicochemical properties.

Methods And Analysis: Primary GC cultures were established from human conjunctival donor tissue. The impact of eye drops on GC survival was assessed using a lactate dehydrogenase assay. Mucin release was evaluated through mucin-specific immunostaining. pH value, osmolality, drop mass and surface tension for all LT eye drops were measured.

Results: After application with PF-LT for 30 min (min), the GC survival was maintained compared with control (p=0.9941), while all BAK-LT eye drops reduced survival with approximately 30% (p<0.02). Following application with PF-LT for 30 min, mucin was found around the GC nucleus, as seen in the vehicle control, indicating no secretion. In contrast, BAK-LT caused diffuse staining of mucin, similar to the secretagogue histamine, indicating stimulation of secretion. The pH value of the BAK-LT and PF-LT eye drops were 6.0-6.9 and 6.8, respectively. The osmolality was 258-288 mOsm/kg for the BAK-LT eye drops and 276 for PF-LT eye drops. The mean drop mass was 26-31 mg for the BAK-LT eye drops and 30 mg for PF-LT. The surface tension was lower for all BAK-LT eye drops (31.1-32.1 mN/m) compared with PF-LT (42 mN/m).

Conclusion: PF-LT compared with various branded and generic LT preparations containing BAK are less cytotoxic when applied to cultured GCs.
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http://dx.doi.org/10.1136/bmjophth-2021-000892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689192PMC
December 2021

[Orbital cysticercosis].

Ugeskr Laeger 2021 12;183(51)

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December 2021

Diabetic retinopathy as a potential marker of Parkinson's disease: a register-based cohort study.

Brain Commun 2021 8;3(4):fcab262. Epub 2021 Nov 8.

Department of Ophthalmology, Odense University Hospital, 5000 Odense, Denmark.

Neurodegeneration is an early event in the pathogenesis of diabetic retinopathy, and an association between diabetic retinopathy and Parkinson's disease has been proposed. In this nationwide register-based cohort study, we investigated the prevalence and incidence of Parkinson's disease among patients screened for diabetic retinopathy in a Danish population-based cohort. Cases ( = 173 568) above 50 years of age with diabetes included in the Danish Registry of Diabetic Retinopathy between 2013 and 2018 were matched 1:5 by gender and birth year with a control population without diabetes ( = 843 781). At index date, the prevalence of Parkinson's disease was compared between cases and controls. To assess the longitudinal relationship between diabetic retinopathy and Parkinson's disease, a multivariable Cox proportional hazard model was estimated. The prevalence of Parkinson's disease was 0.28% and 0.44% among cases and controls, respectively. While diabetic retinopathy was not associated with present (adjusted odds ratio 0.93, 95% confidence interval 0.72-1.21) or incident Parkinson's disease (adjusted hazard ratio 0.77, 95% confidence interval 0.56-1.05), cases with diabetes were in general less likely to have or to develop Parkinson's disease compared to controls without diabetes (adjusted odds ratio 0.79, 95% confidence interval 0.71-0.87 and adjusted hazard ratio 0.88, 95% confidence interval 0.78-1.00). In a national cohort of more than 1 million persons, patients with diabetes were 21% and 12% were less likely to have prevalent and develop incident Parkinson's disease, respectively, compared to an age- and gender-matched control population without diabetes. We found no indication for diabetic retinopathy as an independent risk factor for incident Parkinson's disease.
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http://dx.doi.org/10.1093/braincomms/fcab262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599077PMC
November 2021

Genomic Alterations in Human Papillomavirus-Positive and -Negative Conjunctival Squamous Cell Carcinomas.

Invest Ophthalmol Vis Sci 2021 11;62(14):11

Department of Ophthalmology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Purpose: The genomic alterations contributing to the pathogenesis of conjunctival squamous cell carcinomas (SCCs) and their precursor lesions are poorly understood and hamper our ability to develop molecular therapies to reduce the recurrence rates and treatment-related morbidities of this disease. We aimed to characterize the somatic DNA alterations in human papillomavirus (HPV)-positive and HPV-negative conjunctival SCC.

Methods: Patients diagnosed with conjunctival SCC in situ or SCC treated in ocular oncology referral centers in Denmark were included. HPV detection (HPV DNA PCR, p16 immunohistochemistry, and mRNA in situ hybridization) and targeted capture-based next-generation sequencing of 523 genes frequently involved in cancer were performed to describe the mutational profile based on HPV status.

Results: Tumor tissue was available in 33 cases (n = 8 conjunctival SCCs in situ, n = 25 conjunctival SCCs), constituting 25 male and 8 female patients. Nine cases were HPV positive. The HPV-positive SCCs in situ and SCCs were characterized by transcriptionally active high-risk HPV (types 16 and 39) within the tumor cells, frequent mutations in PIK3CA (n = 5/9), and wild-type TP53, CDKN2A, and RB1, while the HPV-negative counterparts harbored frequent mutations in TP53 (n = 21/24), CDKN2A (n = 7/24), and RB1 (n = 6/24).

Conclusions: Our findings have delineated two potentially distinct distributions of somatic mutations in conjunctival SCC based on HPV status-pointing to different biological mechanisms of carcinogenesis. The present findings support a causal role of HPV in a subset of conjunctival SCC.
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http://dx.doi.org/10.1167/iovs.62.14.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606794PMC
November 2021

Novel Approaches to Optimize Treatment Strategies in Glaucoma.

J Ophthalmol 2021 16;2021:9876478. Epub 2021 Aug 16.

Department of Ophthalmology, University Medical Centre Ljubljana, Ljubljana, Slovenia.

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http://dx.doi.org/10.1155/2021/9876478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557353PMC
August 2021

Vitrectomy-Assisted Biopsy: An in vitro Study on the Impact of Cut Rate and Probe Size.

Ocul Oncol Pathol 2021 Oct 8;7(5):346-352. Epub 2021 Jul 8.

Department of Ophthalmology, Haukeland University Hospital, Bergen, Norway.

Purpose: The aim of this study was to optimize the technique of performing vitrectomy-assisted biopsy of intraocular tumors by comparing the cytohistological findings in specimens obtained with different vitrectomy probes and cut rates.

Methods: Vitrectomy-assisted biopsies were taken from a fresh porcine liver. For each sampling, the vacuum level was 300 mm Hg. The following parameters were compared; cut rate (60, 600 and 6,000 cuts per minute [cpm]), probe type (standard and two-dimensional cutting [TDC]), and probe diameter (23-gauge and 25-gauge). The specimens were assessed by automated whole-slide imaging analysis and conventional light microscopy.

Results: Seventy-two biopsies were analyzed for the number of hepatocytes, total area of tissue fragments, and total stained area of each microscope slide. For all probe types, these parameters were significantly and positively correlated with the cut rate. TDC probes led to significantly higher scores than those of standard probes, independent of the cut rate. There were no significant differences in results when using 23-gauge or 25-gauge standard probes. Light microscopic examination demonstrated well-preserved cells sufficient for cytohistological analyses in all investigated cases.

Conclusions: The higher the cut rate, the larger is the amount of aspirated cellular material. There were no significant differences between 23-gauge and 25-gauge biopsies. Cut rates up to 6,000 cpm did not adversely affect the cytohistological features of the samples.
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http://dx.doi.org/10.1159/000516960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531738PMC
October 2021

Prevalence and prognostic value of and mutations in ocular adnexal large B-cell lymphoma: a reclassification of ocular adnexal large B-cell lymphoma.

Br J Ophthalmol 2021 Oct 27. Epub 2021 Oct 27.

Department of Pathology, Eye Section, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Aims: To (1) reclassify ocular adnexal large B-cell lymphomas (OA-LBCLs) per 2016 WHO lymphoma classification and (2) determine the prevalence of and mutations and their association with clinical parameters among OA-LBCLs.

Methods: This study is a retrospective analysis of all OA-LBCLs diagnosed in Denmark between 1980 and 2018. Medical records and tissue samples were retrieved. Thirty-four OA-LBCLs were included. Fluorescence in situ hybridisation and Epstein-Barr-encoded RNA in situ hybridisation were used for the reclassification. Mutational status was established by allele-specific PCR and confirmed by Sanger sequencing. Primary endpoints were overall survival, disease-specific survival (DSS) and progression-free survival (PFS).

Results: Two LBCL subtypes were identified: diffuse large B-cell lymphoma (DLBCL) (27 of 32; 84%) and high-grade B-cell lymphoma (HGBL) with and and/or rearrangements (5 of 32; 16%). cMYC/BCL2 double-expressor DLBCLs had a poorer DSS than non-double-expressor DLBCLs (5-year DSS, 25% vs 78%) (HR 0.23; 95% CI 0.06 to 0.85; p=0.014). mutations were present in 10 (29%) of 34 lymphomas and carried a poorer PFS than wild-type cases (5-year PFS, 0% vs 43%) (HR 0.78; 95% CI 0.61 to 0.98; p=0.039). mutations were present in 3 (9%) of 34 cases.

Conclusion: OA-LBCL consists mainly of two subtypes: DLBCL and HGBL with and and/or rearrangements. mutations are important drivers of OA-LBCL. mutations, as well as cMYC/BCL2 double-expressor DLBCL, appear to be associated with a poor prognosis. Implementing mutational analysis in routine diagnostics may improve OA-LBCL prognostication.
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http://dx.doi.org/10.1136/bjophthalmol-2021-319580DOI Listing
October 2021

Benzalkonium Chloride-Preserved Anti-Glaucomatous Eye Drops and Their Effect on Human Conjunctival Goblet Cells in vitro.

Biomed Hub 2021 May-Aug;6(2):69-75. Epub 2021 Aug 13.

Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

Introduction: Most intraocular pressure (IOP)-lowering eye drops are preserved with benzalkonium chloride (BAK). This can increase side effects and decrease adherence. Particularly, damage to the mucin-producing conjunctival goblet cells may be an issue due to instability of the tear film. We aimed to investigate the effect of IOP-lowering eye drops preserved with BAK on cultured human conjunctival goblet cells.

Methods: Eye drops Brimonidine Tartrate Teva (BT) with 0.005% BAK, Dorzolamide Stada (DS) with 0.0075% BAK, Optimol (OP) with 0.01% BAK, and Latanoprost Teva (LT) with 0.02% BAK were included. Human primary cultured goblet cell survival was evaluated using a lactate dehydrogenase assay on human goblet cells after treatment for 30 min and 6 h with the different anti-glaucoma drug formulations.

Results: All eye drops examined, except BT, reduced goblet cell survival. The impact of eye drops on goblet cell viability was correlated with the time of exposure as well as to the concentration of BAK. After 30 min of exposure, cell viability was 93% for BT (0.005% BAK; = 0.93), 71% for DS (0.0075% BAK; = 0.067), 70% for OP (0.01% BAK; = 0.054), and 69% for LT (0.02% BAK; = 0.022), and exposure for 6 h reduced cell survival to 74% for BT ( = 0.217), 52% for DS ( = 0.011), 34% for OP ( = 0.017), and 31% for LT ( = 0.0007).

Conclusion: LT, OP, and DS reduced human goblet cell survival in a time-dependent manner. BT did not affect goblet cell survival. Cell survival was correlated with the BAK concentration in the eye drops making 0.02% BAK-preserved LT most toxic and 0.005% BAK-preserved BT least toxic. Based on the present study, decreasing BAK in eye drops for chronic use seems important to reduce damage to the goblet cells. However, future studies are needed to further explore this finding.
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http://dx.doi.org/10.1159/000517845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460924PMC
August 2021

Topical anaesthesia in strabismus surgery for Graves' orbitopathy: a comparative study of 111 patients.

Acta Ophthalmol 2022 Jun 16;100(4):447-453. Epub 2021 Sep 16.

Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen, Denmark.

Purpose: To evaluate the tolerability and usability of topical anaesthesia in single rectus muscle recession for strabismus caused by Graves' orbitopathy (GO). To compare the perioperative pain score and surgical outcome between GO patients and non-GO patients.

Methods: A retrospective comparative study of consecutive single rectus muscle recession performed under topical anaesthesia was carried out. All patients scheduled for one-stage single rectus muscle recession under topical anaesthesia were included. Numerical visual analogue pain score scale (NVAS) points, rates of motor success (horizontal deviation < 8 prism diopters (PD) and vertical deviation ≤ 6 PD) and sensory success (no diplopia without prisms), complications and postoperative adjustment frequencies were compared between GO and non-GO patients.

Results: A total of 111 patients were included. The mean perioperative pain scores were 2.3 (SD ± 1.3) in GO and 1.6 (SD ± 1.1) in non-GO patients (p = 0.06 adjusted for gender). The postoperative mean alignments in GO and non-GO patients were 2 versus 3 PD horizontally and 1 versus 1 PD vertically respectively. Both motor and sensory success rates were 98% in GO patients and 94% versus 93% in non-GO patients. Adjustments as a second procedure the day after surgery was performed in 10% of the GO patients and 15% of the non-GO patients. The oculocardiac reflex was not triggered in any of the GO patients.

Conclusion: Topical anaesthesia in single muscle recession for GO is safe, well-tolerated and gives comparable surgical outcomes to those achieved in non-GO patients.
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http://dx.doi.org/10.1111/aos.15024DOI Listing
June 2022

In Vivo Labeling and Tracking of Proliferating Corneal Endothelial Cells by 5-Ethynyl-2'-Deoxyuridine in Rabbits.

Transl Vis Sci Technol 2021 09;10(11)

Corneal Graft Biology, Engineering and Imaging Laboratory, Jean Monnet University, Faculty of Medicine, Saint-Etienne, France.

Purpose: To develop a method to label proliferating corneal endothelial cells (ECs) in rabbits in vivo and track their migration over time.

Methods: We compared intraperitoneal (IP) and intracameral (IC) administration of 5-ethynyl-2'-deoxyuridine (EdU) in two experiments: (1) six rabbits received IP or IC EdU. Blood and aqueous humor (AH) samples were incubated with HL-60 cells. Flow cytometry detected the EdU incorporation, representing the bioavailability of EdU. (2) In vivo EdU labeling was investigated in pulse-chase study: 48 rabbits received EdU IP or IC. The corneas were flat-mounted after 1, 2, 5, or 40 days and imaged using fluorescence microscopy. EdU+ and Ki67+ ECs were quantified and their distance from the peripheral endothelial edge was measured.

Results: EdU was bioavailable in the AH up to 4 hours after IC injection. No EdU was detected in the blood or the AH after IP injection. High quality EdU labeling of EC was obtained only after IC injection, achieving 2047 ± 702 labeled ECs. Proliferating ECs were located exclusively in the periphery within 1458 ± 146 µm from the endothelial edge. After 40 days, 1490 ± 397 label-retaining ECs (LRCs) were detected, reaching 2219 ± 141 µm from the edge, indicating that LRCs migrated centripetally.

Conclusions: IC EdU injection enables the labeling and tracking of proliferating ECs. LRCs seem to be involved in endothelial homeostasis, yet it remains to be investigated whether they represent endothelial progenitor cells.

Translational Relevance: EdU labeling in animal models can aid the search for progenitor cells and the development of cell therapy for corneal endothelial dysfunction.
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http://dx.doi.org/10.1167/tvst.10.11.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419885PMC
September 2021
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