WCPOS 2024 Echo of Kinoshita S Kanski Lecture, World Congress of Pediatric Ophthalmology & Strabismus 2024.pdf

Echo of portion lecture of Kinoshita S as a Kanski Lecturer at the 5th World Congress of Pediatric Ophthalmology & Strabismus 2024, held at Kuala Lumpur Convention Center, Malaysia, July 2024, given September 18, 2024, Eye and Vision Institute Conference, The Medical City, Pasig City, Philippines

1. WCPOS V Echo
September 18, 2024Alvina Pauline Dy Santiago, MD

2. Kanski Lecturer:
Prof Shigeru Kinoshita

3. ●Corneal epithelial stem cell
●Amniotic membrane transplantation
●Cultivated oral mucosal epithelial
stem cell transplantation for severe
ocular surface disorders
●Cultivated corneal endothelial cell
injection therapy for corneal
endothelial failure (Corneal
regenerative medicine)
●Topical Rho-associated protein
kinase (ROCK) inhibitor for partial
endothelial dysfunction
●Pathophysiology of
blepharokeratoconjunctivitis

4. Prof Shigeru Kinoshita:
Innovative approaches to managing key
pediatric corneal diseases
●Pathophysiology of blepharokeratoconjunctivitis
●Topical Rho-associated protein kinase (ROCK) inhibitor for partial
endothelial dysfunction
●Cultivated corneal endothelial cell injection therapy for corneal
endothelial failure (Corneal regenerative medicine)

5. Pediatric Blepharoconjunctivitis

7. Definition & Diagnostic Criteria for PBKC 2023
●Expert panel
●Non-RAND Modified Delphi Method
●Establish unified nomenclature, definition, definitive diagnostic Criteria
●September 1, 2021 to August 14, 2022
●Consensus activities via electronic surveys and online virtual meetings
●14/16 Expert international panelists participated
●Pediatric Ophthalmologists, Cornea or External Disease Specialists
Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

8. PBKC: Pediatric blepharokeratoconjunctivitis
Search Terms
●Blepharokeratoconjunctivitis
●Blepharokeratoconjunctivitis,
staphylococcal
●Ocular rosacea
●Ocular acne rosacea
●Phlyctenular keratoconjunctivitis
●Blepharoconjunctivitis
●Meibomitis-related
keratoconjunctivitis
Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750
DEF: frequently underdiagnosed, sight-threatening, chronic,
and recurrent inflammatory eyelid margin disease associated
with ocular surface involvement affecting children and
adolescents
SPECTRUM:
Chronic blepharitis
Meibomitis
Conjunctivitis
Corneal Involvement
SPK
Corneal infiltrates with vascularization and
scarring

9. Pediatric PBKC
<18yrs old
●History: 1 or more symptoms
●Clinical signs from 3 anatomic
regions
○Lid margin
○Conjunctiva
○Cornea
●PBKC Suspect sans corneal
involvement
●*validation w real patient data
analysis
Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

10. Pediatric Blepharoconjunctivitis: LIDS
1.Kinoshita S (2024), WCPOSV Kanski Lecture
2.Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

11. Pediatric Blepharoconjunctivitis: CONJUNCTIVA
1.Kinoshita S (2024), WCPOSV Kanski Lecture
2.Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

12. Pediatric Blepharoconjunctivitis: CORNEA
1.Kinoshita S (2024), WCPOSV Kanski Lecture
2.Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

13. Pediatric Blepharoconjunctivitis: CORNEA
1.Kinoshita S (2024), WCPOSV Kanski Lecture
2.Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750

14. Pediatric blepharokeratoconjunctivitis
What is the etiology of
corneal infiltrates and
meibomitis?
1.Microbes (e.g. Staph)
2.Demodex
3.Altered lipid
composition
4.Severe meibomian
gland dysfunction
5.Others
From Kinoshita S (2024), WCPOSV Kanski Lecture

15. Suzuki, T., Katsuki, N., Tsutsumi, R., Uchida, K., Ohashi, K., Eishi, Y., &
Kinoshita, S. (2022). Reconsidering the pathogenesis of chalazion.
The ocular surface, 24, 31–33.
https://doi.org/10.1016/j.jtos.2021.12.010
P. acnes (C. acnes) antibody in granuloma
●epithelioid cell granulomas
●accompanied by neutrophil infiltration,
●suggesting an immune-type granulomatous reaction to C.
acnes bacterium. A
●many forms of chronic inflammation, induced either by
persistent microbes or by mediators produced by activated
macrophages, continually show large numbers of
neutrophils
●C. acnes, an anaerobic Gram-positive bacillus, usually
inhabits human sebaceous follicles
○acne vulgaris
○sarcoid granulomas
○chalazion, may be triggered by an extracellular
proliferation of C. acnes, as seen in inflammatory
acne vulgaris.
(+) PAB (-) PAB

16. Meibomitis-related Keratoconjunctivitis
Suzuki, T., Mitsuishi, Y., Sano, Y., Yokoi, N., & Kinoshita, S. (2005). Phlyctenular keratitis associated with meibomitis
in young patients. American journal of ophthalmology, 140(1), 77–82. https://doi.org/10.1016/j.ajo.2005.02.039

17. Meibomitis-related Keratoconjunctivitis
Suzuki, T., Mitsuishi, Y., Sano, Y., Yokoi, N., & Kinoshita, S. (2005). Phlyctenular keratitis associated with meibomitis in young patients. American journal of ophthalmology, 140(1),
77–82. https://doi.org/10.1016/j.ajo.2005.02.039
In 60% P. acnes positive in pure meibum cultures

18. From Kinoshita S (2024), WCPOSV Kanski Lecture

19. Rho-kinase (ROCK) inhibitor
For Partial Endothelial Cell
Dysfunction

20. Kinoshita S (2022). Keynote address: Cornea (Demystifiied) Novel Therapeutic Modalities for Corneal Endothelial Dysfunction
https://www.youtube.com/watch?v=BToAjTFM04I

21. ROCK Inhibitors and the Cornea
(Kinoshita S and co-workers)
●Promotes corneal stromal
wound healing
●Promotes endothelial cell
migration, cell adhesion, and
antiapoptotic effects
●Accelerates corneal
endothelial wound healing
●Increase corneal endothelial
cell density (given with
allogenic injection of
cultured endothelial cells)
Kinoshita S, Colby KA, Kruse FE. A Close Look at the Clinical Efficacy of Rho-Associated
Protein Kinase Inhibitor Eye Drops for Fuchs Endothelial Corneal Dystrophy. Cornea. 2021 Oct
1;40(10):1225-1228. doi: 10.1097/ICO.0000000000002642. PMID: 34481406; PMCID:
PMC8423139.
Kinoshita, S., Koizumi, N., Ueno, M., Okumura, N., Imai, K., Tanaka, H., Yamamoto, Y.,
Nakamura, T., Inatomi, T., Bush, J., Toda, M., Hagiya, M., Yokota, I., Teramukai, S., Sotozono,
C., & Hamuro, J. (2018). Injection of Cultured Cells with a ROCK Inhibitor for Bullous
Keratopathy. The New England journal of medicine, 378(11), 995–1003.
https://doi.org/10.1056/NEJMoa1712770
Okumura, N., Koizumi, N., Kay, E. P., Ueno, M., Sakamoto, Y., Nakamura, S., Hamuro, J., &
Kinoshita, S. (2013). The ROCK inhibitor eye drop accelerates corneal endothelium wound
healing. Investigative ophthalmology & visual science, 54(4), 2493–2502.
https://doi.org/10.1167/iovs.12-11320
Yamamoto M, Quantock AJ, Young RD, Okumura N, Ueno M, Sakamoto Y, Kinoshita S, Koizumi
N. A selective inhibitor of the Rho kinase pathway, Y-27632, and its influence on wound
healing in the corneal stroma. Mol Vis. 2012;18:1727-39. Epub 2012 Jun 27. PMID: 22815626;
PMCID: PMC3398489.
increase in the density of corneal endothelial cells after allogeneic transplantation with
cultured endothelial cells supplemented with a kinase inhibitor.

22. ROCK Inhibitors and the Cornea
●Enhanced endothelial cell migration
●Enhanced endothelial cell
proliferation
●Accelerates corneal endothelial
regeneration
Miyagi H, Kim S, Li J, Murphy CJ, Thomasy SM. Topical Rho-
Associated Kinase Inhibitor, Y27632, Accelerates Corneal
Endothelial Regeneration in a Canine Cryoinjury Model. Cornea.
2019 Mar;38(3):352-359. doi: 10.1097/ICO.0000000000001823.
PMID: 30516555; PMCID: PMC6397656.
Meekins LC, Rosado-Adames N, Maddala R, Zhao JJ, Rao PV,
Afshari NA. Corneal Endothelial Cell Migration and Proliferation
Enhanced by Rho Kinase (ROCK) Inhibitors in In Vitro and In Vivo
Models. Invest Ophthalmol Vis Sci. 2016 Dec 1;57(15):6731-6738.
doi: 10.1167/iovs.16-20414. PMID: 27951595; PMCID:
PMC6018452.

23. Kinoshita S (2022). Keynote address: Cornea (Demystifiied) Novel Therapeutic Modalities for Corneal Endothelial Dysfunction
https://www.youtube.com/watch?v=BToAjTFM04I

24. Kinoshita S (2022). Keynote address: Cornea (Demystifiied) Novel Therapeutic Modalities for Corneal Endothelial Dysfunction
https://www.youtube.com/watch?v=BToAjTFM04I

25. ROCK Inhibitor & Fuch’s Endothelial Dystrophy
2 situations
1.Restore acutely
damaged corneal
endothelial
a.Cataract surgery
b.Glaucoma surgery
c.Descemet stripping
2.Preservation of
deteriorating endothelial
cell layer in chronic
cases

26. ROCK Inhibitor & Fuch’s Endothelial Dystrophy
1.Clinical trial to establish LEVEL 1 proof of
concept clinical evidence for patients with
Fuch’s after Descemet’s stripping
2.Standard use for all Descemet stripping
and corneal transplant early post op?
3.Treatment of corneal endothelial damage
in the initial phase after intraocular
surgery such as cataract surgery or
glaucoma surgery
From Kinoshita S (2024), WCPOSV Kanski Lecture

27. Netarsudil 0.02%
●for OAG and OHTN
○USFDA
○European Medicine Agency;s
Commiitee for Medicinal Products for
Human Use
●IOP lowering effect by inhibiting rho-
associated protein kinase
●Once daily dose
●Pharmacologic manipulation of
cytoskeleton of eye’s outflow lead to
decreased outflow resistance
●RHO Kinase function:
○Organize extracellular matrix
○Increase cell stiffness
○Modulate cell adhesion
○Promote contraction of actomyosis
○Influence aqueous humor outflow

28. https://verification.fda.gov.ph/drug_productslist.php?cmd=search&t=drug_products&psearch=netarsudil&psearchtype=

29. Can we use this off-
label for FECD?

30. Corneal Endothelial Cell Injection
for Corneal Endothelial Failure

31. From Kinoshita S (2024), WCPOSV Kanski Lecture

32. From Kinoshita S (2024), WCPOSV Kanski LectureFrom Kinoshita S (2024), WCPOSV Kanski Lecture

33. Corneal Endothelial Cell Injection
1 donor cornea
300 CEC injections
https://youtu.be/BToAjTFM04I?si=gVu5HNzagXYxWiNt. Start At 3:52; End at 4:11

34. Corneal Endothelial Cell Injection
3 years post CEC injection: Superiority of mature cell subpopulation in CEC injection
●Improved BCVA in 10/11 eyes
Ueno, M., Toda, M., Numa, K., Tanaka, H., Imai, K., Bush, J., Teramukai, S., Okumura, N., Koizumi, N., Yamamoto, A., Tanaka, M.,
Sotozono, C., Hamuro, J., & Kinoshita, S. (2022). Superiority of Mature Differentiated Cultured Human Corneal Endothelial Cell
Injection Therapy for Corneal Endothelial Failure. American journal of ophthalmology, 237, 267–277.
https://doi.org/10.1016/j.ajo.2021.11.012
Grp 1: < 76.3% ECCGrp 2: > 90% ECC
CEC Density1349 cells/mm2 (746-2104)3043 cell/mm2 (2182-4417)
CEC Loss23.6%3.2%
CCT recoverydiversePrompt and constant

35. Corneal Endothelial Cell Injection
Local anesthesia
8 mm circle on cornea
Deepithelialize central cornea of loose epithelium
1.6 mm incision
Silicone tube rubbing of corneal endothelium
Trypan blue staining
ROCK inhibitor injection; sutured
AC fluid removal w G30 needle
G26 needle to inject 300 mL of HCEC containing
1x106 HCEC
https://youtu.be/BToAjTFM04I?si=gVu5HNzagXYxWiNt. Start At 5:40; End a 7:28t

36. Corneal Endothelial Cell Injection

37. Numa K, Imai K, Ueno M, Kitazawa K, Tanaka H, Bush JD, Teramukai S, Okumura N, Koizumi N, Hamuro J, Sotozono C, Kinoshita
S. Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure.
Ophthalmology. 2021 Apr;128(4):504-514. doi: 10.1016/j.ophtha.2020.09.002. Epub 2020 Sep 6. PMID: 32898516.

39. From Kinoshita S (2024), WCPOSV Kanski Lecture

40. https://youtu.be/BToAjTFM04I?si=gVu5HNzagXYxWiNt. Start At 5:40; End a 7:28t
From Kinoshita S (2024), WCPOSV Kanski Lecture

41. From Kinoshita S (2024), WCPOSV Kanski Lecture

42. From Kinoshita S (2024), WCPOSV Kanski Lecture

43. WCPOSV 2024
Maan Santos Gonzales, MD
Shigoru Kinoshita, MD, PhD
Alvina Pauline Santiago, MD, MBA
Ken Nischal, MD

44. References
1.Kinoshita S (2022). Keynote address: Cornea (Demystifiied) Novel Therapeutic Modalities for Corneal Endothelial Dysfunction
https://www.youtube.com/watch?v=BToAjTFM04I.
2.Kinoshita S (2024). Kanski Lecture at the World Congress of Pediatric Ophthalmology and Strabismus V in Kuala Lumpur, Malaysia,
July 13, 2024
3.Morales-Mancillas NR, Velazquez-Valenzuela F, Kinoshita S, et al (2024). Definition and Diagnostic Criteria for Pediatric
Blepharokeratoconjunctivitis. JAMA Ophthalmol.2024;142(1):39–47. doi:10.1001/jamaophthalmol.2023.5750
4.Meekins LC, Rosado-Adames N, Maddala R, Zhao JJ, Rao PV, Afshari NA. Corneal Endothelial Cell Migration and Proliferation
Enhanced by Rho Kinase (ROCK) Inhibitors in In Vitro and In Vivo Models. Invest Ophthalmol Vis Sci. 2016 Dec 1;57(15):6731-6738.
doi: 10.1167/iovs.16-20414. PMID: 27951595; PMCID: PMC6018452.
5.Mehran NA, Sinha S, Razeghinejad R. New glaucoma medications: latanoprostene bunod, netarsudil, and fixed combination netarsudil-
latanoprost. Eye (Lond). 2020 Jan;34(1):72-88. doi: 10.1038/s41433-019-0671-0. Epub 2019 Nov 6. PMID: 31695162; PMCID:
PMC7002400.
6.Numa K, Imai K, Ueno M, Kitazawa K, Tanaka H, Bush JD, Teramukai S, Okumura N, Koizumi N, Hamuro J, Sotozono C, Kinoshita S.
Five-Year Follow-up of First 11 Patients Undergoing Injection of Cultured Corneal Endothelial Cells for Corneal Endothelial Failure.
Ophthalmology. 2021 Apr;128(4):504-514. doi: 10.1016/j.ophtha.2020.09.002. Epub 2020 Sep 6. PMID: 32898516.
7.Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol
Vis Sci. 2013;54:2493–2502.
8.Suzuki, T., Mitsuishi, Y., Sano, Y., Yokoi, N., & Kinoshita, S. (2005). Phlyctenular keratitis associated with meibomitis in young patients.
American journal of ophthalmology, 140(1), 77–82. https://doi.org/10.1016/j.ajo.2005.02.039
9.Suzuki, T., Katsuki, N., Tsutsumi, R., Uchida, K., Ohashi, K., Eishi, Y., & Kinoshita, S. (2022). Reconsidering the pathogenesisof
chalazion. The ocular surface, 24, 31–33. https://doi.org/10.1016/j.jtos.2021.12.010

45. References
1.Ueno, M., Toda, M., Numa, K., Tanaka, H., Imai, K., Bush, J., Teramukai, S., Okumura, N., Koizumi, N., Yamamoto, A., Tanaka, M.,
Sotozono, C., Hamuro, J., & Kinoshita, S. (2022). Superiority of Mature Differentiated Cultured Human Corneal Endothelial Cell
Injection Therapy for Corneal Endothelial Failure. American journal of ophthalmology, 237, 267–277.
https://doi.org/10.1016/j.ajo.2021.11.012
1.YamadaJ, UenoM, TodaM, ShinomiyaK, Sotozono, C, Kinoshita, S, HamuroJ. Allogeneic Sensitization and Tolerance Induction
After Corneal Endothelial Cell Transplantation in Mice. Invest Ophthalmol Vis Sci. 2016;57:4572–4580. DOI:10.1167/iovs.15-19020.
https://iovs.arvojournals.org/article.aspx?articleid=2552269.
1.Yamamoto M, Quantock AJ, Young RD, Okumura N, Ueno M, Sakamoto Y, Kinoshita S, Koizumi N. A selective inhibitor of the Rho
kinase pathway, Y-27632, and its influence on wound healing in the corneal stroma. Mol Vis. 2012;18:1727-39. Epub 2012 Jun 27.
PMID: 22815626; PMCID: PMC3398489.

46. https://youtu.be/BToAjTFM04I?si=gVu5HNzagXYxWiNt

47. https://youtu.be/BToAjTFM04I?si=gVu5HNzagXYxWiNt