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Cornea-d-15-00514 145.150

Transepithelial Corneal Cross-Linking With Vitamin E-Enhanced Riboflavin Solution and Abbreviated, Low-Dose UV-A: 24-Month Clinical Outcomes Ciro Caruso, MD,* Carmine Ostacolo, PharmD,† Robert L. Epstein, MD,‡ Gaetano Barbaro, EngD,§ Salvatore Troisi, MD,¶ and Decio Capobianco, MDk cell count. No corneal abrasions occurred, and no bandage contact Purpose: To report the clinical outcomes with 24-month follow-up lenses or prescription analgesics were used during postoperative of transepithelial cross-linking using a combination of a D-alpha- tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence Conclusions: Transepithelial cross-linking using the riboflavin- UV-A treatment.
vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.
Methods: In a nonrandomized clinical trial, 25 corneas of 19patients with topographically proven, progressive, mild to moderate Key Words: corneal cross-linking, transepithelial cross-linking, keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitaminE-TPGS, topically applied for 15 minutes, followed by two 5-minuteUV-A treatments with separate doses both at fluence below 3 mW/cm2 that were based on preoperative central pachymetry.
Corneal collagencross-linking (CXL)was first described in 1998 by Spoerl et al1 with first clinical results reported by Results: During the 6-month pretreatment observation, the average Wollensak et al.2,3 Long-term treatment outcomes in kerato- Kmax increased by +1.99 6 0.29 D (diopter). Postoperatively, conus have been reported4–7 with results now out to 10 years the average Kmax decreased, changing by 20.55 6 0.94 D, by postoperatively.8 Corneal curvature results have been reported 20.88 6 1.02 D and by 21.01 6 1.22 D at 6, 12, and 24 months.
using Scheimpflug photography9 and the Orbscan II (Bausch & Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 Lomb, Bridgewater, NJ).10 The Dresden protocol, a current months, 12 months, and 24 months, respectively. Refractive cylinder cross-linking standard treatment,2 involves the removal of was decreased by 3 months postoperatively and afterward, changing corneal epithelium (epi-off technique) followed by 30 minutes by 21.35 6 0.69 D at 24 months. Best spectacle-corrected visual of riboflavin corneal soaking and 30 minutes of UV-A acuity (BSCVA) improved at 6, 12, and 24 months, including an irradiation at 3 mW/cm2.
improvement of 20.19 6 0.13 logarithm of the minimum angle of Cross-linking with epithelium removed, although effec- resolution units at 24 months. There was no reduction in endothelial tive, is associated with postoperative discomfort, the risk ofsterile corneal infiltrates, the typical use of a bandage contactlens for pain relief, and the risk of corneal ulcer formation.11–13 Received for publication June 7, 2015; revision received September 14, 2015; accepted October 13, 2015. Published online ahead of print November 25, Attempted riboflavin/UVA cross-linking without removing the epithelium, so-called "transepithelial cross-linking" (TE-CXL), From the *Corneal Transplant Center, Pellegrini Hospital, Naples, Italy; has not been effective because riboflavin barely passes any †Department of Pharmacy, University of Naples Federico II, Naples, Italy; concentration into the corneal stroma.
‡Mercy Center for Corrective Eye Surgery, McHenry, IL; §I.R.O.S.
(Institute of Refractive and Ophthalmic Surgery), Naples, Italy; ¶Depart- Cross-linking using riboflavin with added chemical ment of Ophthalmology, Salerno University Hospital, Salerno, Italy; and permeation enhancers to partially breakup the corneal epithe- kOphthalmic Center Med Laser Caserta, Caserta, Italy.
lium to increase riboflavin penetration has met with only limited The work described here was entirely self-funded by I.R.O.S.
success.14,15 TE-CXL with ribo R. L. Epstein has received consultation fees from I.R.O.S. in the past, flavin enhanced with trometamol although not for the preparation of this article. C. Caruso and S. Troisi are (TRIS) and EDTA failed to stabilize keratoconus in a 24-month owners of patent EP 2459 186B1 concerning the vitamin E-TPGS– study.16 But adding an iontophoresis technique to the TRIS/ enhanced riboflavin solution used in this work. The remaining authors EDTA-augmented riboflavin solution during the presoak period have no conflicts of interest to disclose.
and using 10 mW/cm2 Reprints: Robert L. Epstein, MD, Mercy Center for Corrective Eye Surgery, 5400 fluence UV-A irradiation have produced West Elm St, Suite 120, McHenry, IL 60050 (e-mail: .
encouraging early cross-linking results.17 The iontophoresis Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an technique still requires the use of a postoperative contact lens, open access article distributed under the terms of the with its attendant risks, and the use of analgesics.
We report in this TE-CXL clinical study the use of downloading, sharing, and reproducing the work in any medium,provided it is properly cited. The work cannot be used commercially.
a patented riboflavin solution18 that is enhanced with Cornea  Volume 35, Number 2, February 2016 www.corneajrnl.com 145


Cornea  Volume 35, Number 2, February 2016 Clinical observations were recorded and are reported (vitamin E-TPGS). Ostacolo et al19 reported in detail for 6 months before and 1 week before TE-CXL and at 1, 3, 6, in vitro testing in which effective stromal concentrations 12, and 24 months after treatment.
of riboflavin occurred after just 15 minutes of topical Examinations included the following: uncorrected visual application through intact epithelium. In the technique here acuity and best spectacle-corrected distance visual acuity, reported, the presoak period was 15 minutes, and the UV-A measured in mesopic condition with a logarithm of the mini- treatment to the intact cornea was just 10 minutes with mum angle of resolution chart, refraction, Orbscan IIz corneal a fluence level at less than half the UV-A fluence of the topography with measured sim K at the 3 mm optical zone— original Dresden protocol. The precorneal riboflavin film Kmax, Kmin, Kmean, slit-lamp examination of the anterior was rinsed away before UV-A treatment. The results for and posterior segment, Goldmann tonometry, endothelial a group of 25 consecutive eyes of 19 patients are reported corneal cell count (Tomey EM-3000; Tomey Corp, Japan), with 2-year follow-up.
and central corneal thickness measured with ultrasound(Quantel Medical, Clermont-Ferrand, France). Three days MATERIALS AND METHODS before treatment, 1 drop of preservative-free norfloxacin0.3% solution was instilled into the operative eye every 6 This clinical, prospective, nonrandomized study was hours. Twenty minutes before treatment, the anesthetic oxy- conducted according to the ethical standards of the Declara- buprocaine hydrochloride 0.2% (Minims—Bausch & Lomb, tion of Helsinki (revised in 2000). The patients were informed London), a single-use, preservative-free, sterile topical solu- about the nature and the aim of experimentation, and they tion, was instilled at the rate of 2 drops every 5 minutes. One signed an informed consent. Institutional Review Board drop of norfloxacin 0.3% (Naflox 0.3%; Farmigea, Italy) (IRB)/Ethics Committee approval was obtained (authoriza- single-use, preservative-free, sterile topical solution was tion no. 1269).
instilled every 3 minutes for antibiotic prophylaxis, and 2 Nineteen patients (11 male, 8 female), were enrolled drops of pilocarpine 1% (pilocarpine hydrochloride 1%; for treatment, for a total of 25 eyes (13 right eyes, 12 left Allergan, Dublin, Ireland) were instilled.
eyes, 15 eyes of males, 10 eyes of females). The mean Periocular skin was then disinfected with povidone patient age was 26.7 6 7.4 years. Patient demographics iodine 10% solution. For the corneal presoaking, a Landers along with mean clinical parameters are reported in Table 1.
vitrectomy silicone ring (12 mm diameter, 3 mm height All eyes were affected by keratoconus and were Ocular Instruments Inc., Bellevue, WA) was placed on the selected for treatment because of proven Orbscan IIz corneoscleral limbus (Fig. 1) to retain the riboflavin solution, topographic progression during the 6 months before treatment composed of riboflavin-dextran 0.1 g/100 g and vitamin based on an increase in Kmax of over 1.5 D (diopter).
E-TPGS 500 mg/100 mL, (IROS, Naples, Italy). Drops of this Exclusion criteria included any of the following (1) age below solution were delivered into the silicone ring to completely 16 years or above 45 years, (2) evidence of clinical and cover the cornea. Filled with solution, the ring was main- instrumental stability of keratoconus in the last 6 months, (3) tained in place for 15 minutes. Further drops were added as thinnest corneal point less than 350 mm, (4) corrected visual necessary to maintain corneal coverage with the solution.
acuity worse than 0.5, (5) evidence of subepithelial or mid- After the corneal presoak, a slit-lamp examination was then anterior stromal scars or opacities, (6) evidence of marked performed to observe the complete yellow dying of corneal Vogt striae, (7) associated corneal diseases, (8) previous tissue and the greenish Tyndall effect in the anterior chamber ocular surgical procedures, (9) wearing of contact lenses in with a blue filter, indicating adequate passage of the the 4 weeks before examination, (10) pregnancy or breast feeding, and (11) poor compliance.
TABLE 1. Patient Demographics (n = 25)Age Corrected distance acuity (logMAR) (BSCVA) Spherical equivalent Refractive cylinder Maximum keratometry (6 months pre-CXL) Maximum keratometry (1 wk pre-CXL) Mean K (6 months pre-CXL) Mean K (1 wk pre-CXL) Minimum corneal thickness (6 months pre-CXL) Minimal corneal thickness (1 wk pre-CXL) Endothelial cell density (1 wk pre-CXL) logMAR, logarithm of the minimum angle of resolution; BSCVA, best spectacle- corrected visual acuity.
FIGURE 1. Silicone ring during corneal presoak.
146 www.corneajrnl.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea  Volume 35, Number 2, February 2016 Corneal Cross-linking With Vitamin E-Enhanced Riboflavin Solution The power of the emitter used to irradiate the corneas treatments (P , 0.05 calculated with the Student t test, using (Vega CBM X-Linker; CSO, Italy) was lowered from the usual the pretreatment values as reference) in best spectacle- 3 mW/cm2 fluence with partially absorbing UV-filters (Knight corrected visual acuity at 6, 12, and 24 months (P = 0.01, Optical LTD, United Kingdom), to achieve a customized- P , 0.01, and P = 0.02, respectively) and in refractive delivered power, according to the nomogram from our cylinder at 12 and 24 months (P = 0.03, P , 0.01, and P = mathematical model described by Barbaro et al.20 That nomo- 0.02, respectively), compared with pretreatment values. There gram specifies a UV-A fluence that is pachymetry dependent was also a statistically significant decrease of the Kmean at 12 and at a level lower than that specified in the Dresden protocol.
and 24 months compared with pretreatment values. There was The intraoperative UV fluence measurements were performed stabilization of Kmax. During the 6-month pretreatment with a LaserMateQ, (Coherent Inc, Santa Clara, CA). The observation, all 25 eyes had keratoconus progression with treatment diameter was 8 mm at a distance of 5 cm from the increased Kmax. The average pretreatment Kmax increase corneal apex. During the first 5 minutes, the average UV-A was 1.99 6 0.29 D. After TE-CXL treatment, Kmax fluence applied was 1.67 6 0.08 mW/cm2; during the second decreased compared with the 1-week preoperative value in 5 minutes, the average UV-A fluence applied was 1.45 6 0.08 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 mW/cm2. There was no time break between the first UV-A months (P = 0.04, 0.03, and 0.03, respectively). A graph treatment and the second treatment except for the time showing the behavior of Kmax is depicted in Figure 2.
necessary to change the UV-A fluence level.
A stabilization of corneal and refractive parameters was No more riboflavin solution was applied during the observed in all cases. Average best spectacle-corrected visual UV-A exposure. Rather, the corneal surface was washed with acuity was 0.79 at 1 week preoperatively, 0.79 at 1 month balanced salt solution to remove the superficial riboflavin film postoperatively (P = 0.91), and 0.97 (P = 0.02) at 2 years before irradiation. Drops of balanced salt solution were postoperatively. The average preoperative endothelial cell delivered onto the corneal surface during UV exposure to count was 2549 6 263; at 2 years postoperatively it was maintain adequate moisture. Norfloxacin 0.3% eye drops 2548 6 270 (P = 0.97). Average refractive cylinder was were administered at the end of the treatment.
reduced (P , 0.01) from a preoperative value of 3.25 6 1.58 The patients returned home with topical antibiotic and D to 2-year postoperative value of 1.90 6 1.51 D. Spherical lubricant therapy (norfloxacin 0.3% and hyaluronate 0.15% equivalent decreased (P , 0.01) from 24.70 6 3.38 D eye drops every 6 hours), and these drops were used just until preoperatively to 23.50 6 3.10 D at 2 years postoperatively.
the following day. No analgesics were prescribed. There was Kmax averaged 47.6 6 5.2 D at 6 months preoperatively, no use of a bandage contact lens postoperatively.
progressed to 49.6 6 5.2 D at 1 week postoperatively, andwas 48.5 6 4.4 D at 2 years postoperatively (P = 0.03).
Average central corneal thickness, 456 6 56.6 mm at 1 week preoperative, decreased to a minimum of 427.9 6 54.9 Patient discomfort did not require the use of pre- mm at 3 months postoperative and increased to 462.6 6 46.8 scription pain relievers. There were no corneal abrasions.
mm at 24 months postoperatively (P = 0.61). Further We noticed 1 case of transient corneal haze and 2 cases of pachymetry data appear in Table 2.
transient stromal edema; these were managed with topical Intraocular pressure was unchanged (P = 0.808) at 1 corticosteroid therapy, with complete clinical resolution after year postoperatively (15.6 6 1.6 mm Hg) as compared with a few weeks. Mild epithelial edema was sometimes present preoperative levels (15.6 6 2.0 mm Hg).
soon after the treatment but disappeared in all cases withina few days. The clinical outcomes of the TE-CXL treatmentare reported in Table 2.
A statistically significant improvement of corneal, The results of this clinical trial are encouraging, refractive, and visual acuity parameters was evident after TABLE 2. Clinical Outcomes of Transepithelial Corneal Collagen Cross-linking With Riboflavin–Vitamin E-TPGS Difference From Values at 1 Week Preoperative, n = 25, Mean 6 SD Refractive parameters Corrected distance acuity (logMAR) Spherical equivalent Refractive cylinder magnitude Topographical parameters Maximum keratometry Minimum corneal thickness logMAR, logarithm of the minimum angle of resolution.
Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.corneajrnl.com 147


Cornea  Volume 35, Number 2, February 2016 FIGURE 2. Average Kmax value 6 1 SD over time 6 months and 1 week before corneal cross-linking and then at follow-upexaminations at 1 month, 3 months, 6 months, 1 year, and 2 years postoperatively.
progression was obtained in all cases and lasted for 24 months preoperatively. In this way, the UV-A rays reaching the without remarkable side effects.
endothelium were more easily maintained below the endo- The treatment yielded significant improvement in corneal thelial toxicity levels as described by Wollensak.22 topography and visual acuity although the study involved It must be also considered how this approach makes the relatively mild cases of keratoconus. Generally, cross-linking cross-linking technique more reproducible in comparison induces less effect in cases of mild keratoconus than in the with standard techniques, where riboflavin is continually more advanced cases.21 The eyes treated in this study were placed during UV-A irradiation. The periodic application of topographically proven cases of keratoconus, but at a much undefined amounts of riboflavin during treatments, in fact, milder stage (Average preoperative Kmax = 49.64 D) when could be responsible for a different superficial UV-A filtering compared with more typical cross-linking study populations and, finally, for a different efficacy.
reported, such as Caporossi et al4 (average preoperative Kmax = Total treatment time was reduced to 25 minutes (15 mi- 51.72 D), Coskunseven5 (Average preoperative Kmax = 54.02 nutes of presoak and 10 minutes of UV-A treatment) versus D), Raiskup et al8 (Average preoperative Kmax = 53.2 D), and 60 minutes (30 minutes of presoak and 30 minutes of UV-A Vinciguerra et al17 (Average preoperative Kmax = 59.02 D).
treatment) in the Dresden protocol, and the decreased power of We look forward to further testing of this new technique in UV-A irradiation led to rapid recovery of corneal epithelium more advanced keratoconus cases.
with no detectable damage to the corneal endothelium.
In contrast to the Dresden protocol, in this study, the The total applied UV-A energy over the treatment excess of riboflavin solution, derived from the corneal period in this study was approximately 1.5 mW/cm2 for presoaking, was washed off before UV-A irradiation, thus 10 minutes or only 0.9 J/cm2 in our clinical trial. This avoiding superficial UV-A shielding. In this way, the UV-A compares with 5.4 J/cm2 in the Dresden protocol. We believe fluence could be reduced almost to 1.5 mW/cm2, maintaining that, in addition to the increased efficiency of light trans- efficacy. This approach was suggested by our in vitro studies mission to the cornea in our study achieved by eliminating the and is currently submitted for publication. The same studies precornea riboflavin film, it is likely that riboflavin entered revealed that the endothelial shielding effect of intracorneal the cornea more efficiently because of the use of the Landers riboflavin rapidly fades, with time, during UV-A irradiation, vitrectomy silicone ring. That increased riboflavin penetration at a typical rate. Thus, lower UV-A fluence during the second achieved by continuous soaking was studied and reported by 5-minute treatment period was used.
Schumacher et al.23 The UV-A fluence was also modulated on the average In our study, patients were prudently treated with corneal thickness determined by pachymetry measured 1 week antibiotic drops before treatment because the chance of 148 www.corneajrnl.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea  Volume 35, Number 2, February 2016 Corneal Cross-linking With Vitamin E-Enhanced Riboflavin Solution corneal epithelial breaks was unpredictable. Based on the monitored clinical trial is in 2 parts. The first study is to test the experience gained during this study and on the here reported effectiveness of TE-CXL with riboflavin–vitamin E-TPGS absence of epithelial damage, we would now eliminate with presoaking times and UV-A exposure times equal to preoperative topical antibiotic treatment.
those of the Dresden protocol. The second study is to test the Importantly, keratoconus stabilization with cross- effect of shortened UV-A exposure times and presoaking times linking has been achieved in this study without removal or as described in this article.
disturbance of the corneal epithelium. This has led to a morerapid and comfortable visual recovery with lower risk of complications.
1. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue.
The results obtained are further encouraging in light of Exp Eye Res. 1998;66:97–103.
the evidence that inadequate cross-linking effect can be 2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced augmented by further treatment.24 Thus, it becomes increas- collagen cross-linking for the treatment of keratoconus. Am J Ophthal-mol. 2003;135:620–627.
ingly important to produce a cross-linking treatment charac- 3. Wollensak G, Spörl E, Seiler T. Treatment of keratoconus by collagen terized by minimal risk and maximal compliance.
cross linking. Ophthalmologe. 2003;100:44–49.
The correct diagnosis of keratoconus progression 4. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of depends on the reproducibility of topographic measurements.
riboflavin ultraviolet-A corneal collagen cross-linking for keratoconus inItaly: the Siena eye cross study. Am J Ophthalmol. 2010;149:585–593.
Menassa et al25 found that the variance in Kmax measure- 5. Coskunseven E, Jankov MR II, Hafezi F. Contralateral eye study of ments in normal subjects, measured using the Orbscan II, was corneal collagen cross-linking with riboflavin and UVA irradiation in equal to that obtained by the Scheimpflug system of the patients with keratoconus. J Refract Surg. 2009;25:371–376.
Galilei topographer. Nuñez et al26 found that the Orbscan II 6. Vinciguerra P, Albè E, Trazza S, et al. Intraoperative and postoperative had less variance in determining the point of maximal corneal effects of corneal collagen cross-linking on progressive keratoconus.
Arch Ophthalmol. 2009;127:1258–1265.
elevation than the Pentacam. Kim and Joo27 studied kerato- 7. Vinciguerra R, Romano MR, Camesasca FI, et al. Corneal cross- conus patients with the Orbscan every 6 months, assessing as linking as a treatment for keratoconus: four-year morphologic and nonprogressive the changes in average keratometry within clinical outcomes with respect to patient age. Ophthalmology. 2013; +0.15 6 0.15 D per 6-month period. Epstein et al28 found that 8. Raiskup F, Theuring A, Pillunat LE, et al. Corneal collagen crosslinking the 95% confidence level of true change in maximal anterior with riboflavin and ultraviolet-A light in progressive keratoconus: ten- corneal curvature, Kmax, based on single measurements at year results. J Cataract Refract Surg. 2015;41:41–46.
each session was 1.51 D using the Pentacam HR. Based on 9. Koller T, Iseli HP, Hafezi F, et al. Scheimpflug imaging of corneas after these topographer reproducibility findings, a conservative collagen cross-linking. Cornea. 2009;28:505–510.
estimate of the 95% confidence level of keratoconus pro- 10. Tu KL, Aslanides IM. Orbscan II anterior elevation changes following corneal collagen cross-linking treatment for keratoconus. J Refract Surg.
gression using the Orbscan II could be set at 1.51 D, that of the Pentacam HR, because the articles cited here tended to indicate 11. Goldich Y, Marcovich AL, Barkana Y, et al. Safety of corneal collagen that the Orbscan II is as reproducible as Scheimpflug cross-linking with UV-A and riboflavin in progressive keratoconus.
topography. Hence, all 25 eyes in our study reached the 95% 12. Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA-riboflavin cross- confidence level of true keratoconus progression before linking of the cornea. Cornea. 2007;26:385–389.
treatment and none reached 95% confidence of further pro- 13. Dhawan S, Rao K, Natrajan S. Complications of corneal collagen cross- gression at 2 years postoperatively. In fact, 20 of the 25 eyes in linking. J Ophthalmol. 2011;2011:869015.
the study showed a decrease in Kmax at 2 years postopera- 14. Kissner A, Spoerl E, Jung R, et al. Pharmacological modification of the tively as compared with the 1 week preoperative Kmax value.
epithelial permeability by benzalkonium chloride in UVA/Riboflavincorneal collagen cross-linking. Curr Eye Res. 2010;35:715–721.
The statistical power of our experimental model was 15. Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in challenged by a matched, paired Student t test. We took the keratoconus. J Refract Surg. 2010;26:942–948.
data from the left eye of each patient who had 2 eyes cross- 16. Caporossi A, Mazzotta C, Paradiso AL, et al. Transepithelial corneal linked and the data from each patient who had only 1 eye collagen crosslinking for progressive keratoconus: 24-month clinicalresults. J Cataract Refract Surg. 2013;39:1157–1163.
cross-linked. The population was composed of 19 patients. The 17. Vinciguerra P, Randleman JB, Romano V, et al. Transepithelial null hypothesis was that the proposed cross-linking treatment iontophoresis corneal collagen cross-linking for progressive keratoconus: was ineffective, not determining a stop in Kmax increase. The initial clinical outcomes. J Refract Surg. 2014;30:746–753.
post hoc power of our model to correctly reject the null 18. Caruso C, Troisi S: U.S. patent 9192594 pending for publication hypothesis with 95% confidence, 19 independent variables and November 24, 2015; E.P 2459186B1 Bulletin 2013/41 November 10,2013.
average decreases in measured Kmax of 0.8816 at 1 year and 19. Ostacolo C, Caruso C, Tronino D, et al. Enhancement of corneal 1.1395 at 2 years, is 90.25% and 95.3%, respectively.
permeation of riboflavin-5'-phosphate through vitamin E TPGS: a prom- One shortcoming of the present clinical study is the lack ising approach in corneal trans-epithelial cross linking treatment. Int J of a placebo group. Nevertheless, other important cross- 20. Barbaro G, Caruso C, Troisi S, et al. A Mathematical Model of Corneal linking clinical studies in the published literature, such as UV-A Absorption After Soaking With a Riboflavin Solution During those by Caporossi et al16 and Vinciguerra et al,17 have not Transepithelial Cross-Linking. Paper presented at: 1st Joint International included a placebo group.
Congress Refractive online and SICSSO; July 7–9, 2011; Grosseto, Italy.
A prospective randomized, double masked, placebo- controlled clinical trial of cross-linking using riboflavin– Accessed November 15, 2015.
21. Koller T, Pajic B, Vinciguerra P, et al. Flattening of the cornea after vitamin E-TPGS under the US Food and Drug Administration collagen crosslinking for keratoconus. J Cataract Refract Surg. 2011;37: monitoring is in progress. The Food and Drug Administration- Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.corneajrnl.com 149 Cornea  Volume 35, Number 2, February 2016 22. Wollensak G, Spörl E, Reber F, et al. Corneal endothelial cytotox- and the Orbscan II analysis systems. J Cataract Refract Surg. 2008;34: icity of riboflavin/UVA treatment in vitro. Ophthalmic Res. 2003;35: 26. Nuñez MX, Blanco C. Efficacy of Orbscan II and Pentacam topographers 23. Schumacher S, Mrochen M, Wernli J, et al. Optimization model for by a repeatability analysis when assessing elevation maps in candidates UV-riboflavin corneal cross-linking. Invest Ophth Vis Sci. 2012;53: to refractive surgery. Biomedica. 2009;29:362–368.
27. Kim H, Joo CK. Measure of keratoconus progression using orbscan II. J 24. Hafezi F, Tabibian D, Richoz O. Additive effect of repeated corneal Refract Surg. 2008;24:600–605.
collagen cross-linking in keratoconus. J Refract Surg. 2014;30:716–718.
28. Epstein RL, Chiu YL, Epstein GL. Pentacam HR criteria for curvature 25. Menassa N, Kaufmann C, Goggin M, et al. Comparison and reproduc- change in keratoconus and postoperative LASIK ectasia. J Refract Surg.
ibility of corneal thickness and curvature readings obtained by the Galilei 150 www.corneajrnl.com Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

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Doi:10.1016/j.biocel.2004.08.002

The International Journal of Biochemistry & Cell Biology 37 (2005) 1117–1129 Insulin in aging and cancer: antidiabetic drug diabenol as geroprotector and anticarcinogen Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Margarita L. Tyndyk, Ivan V. Anikin, Alexander A. Spasov, Anna V. Semenchenko, Anatoly I. Yashin, Vladimir N. Anisimov a Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, St. Petersburg 197758, Russia

Microsoft word - síndrome de distres respiratorio con formato 321-329 ok

S índrome de distrés respiratorio agudo, una revisión actual. Acute respiratory distress syndrome, a current review. Antonio Wong Lam * Karla Campozano Vásquez * El síndrome de distrés respiratorio agudo, llamado anteriormente pulmón de choque, edema pulmonar no cardiogénico y síndrome de distrés respiratorio del adulto, es una entidad clínica de características devastadoras que afecta principalmente a pacientes en estado