Optical Coherence Tomography guided decisions in

retinoblastoma management

Sameh E. Soliman, MD,1,2 Cynthia VandenHoven,1 Leslie D. MacKeen,1 Elise Héon, MD,

FRCSC,1,3,4 Brenda L. Gallie, MD, FRCSC1,3,5,6-5

Authors affiliations

1Department of Ophthalmology and Vision Sciences, Hospital for Sick Children, Toronto,

Canada.

2Department of Ophthalmology, Faculty of Medicine, University of Alexandria,

Alexandria, Egypt.

3Department of Ophthalmology & Vision Sciences, Faculty of Medicine, University of

Toronto, Toronto, Ontario, Canada.

4Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine,

University of Toronto, Toronto, Ontario, Canada. Department of Pediatrics, Faculty of

Medicine, University of Toronto, Toronto, Ontario, Canada.

5Division of Visual Sciences, Toronto Western Research Institute, Toronto, Ontario,

Canada.

6Departments of Molecular Genetics and Medical Biophysics, Faculty of Medicine,

University of Toronto, Toronto, Ontario, Canada.

Corresponding author:

Sameh E. Soliman, 555 University Avenue, room 7265, Toronto, ON, M5G 1X8.

samehelsayedsoliman@yahoo.com

Authors’ contributions

Concept and design: Soliman, VandenHoven, MacKeen, Héon, Gallie

Data collection: Soliman, VandenHoven, MacKeen.

Figure construction: Soliman, VandenHoven.

Analysis and interpretation: Soliman, VandenHoven, MacKeen, Héon, Gallie.

Critical review: Soliman, VandenHoven, MacKeen, Héon, Gallie

Overall responsibility: Soliman, VandenHoven, MacKeen, Héon, Gallie

Concept and design: Soliman, VandenHoven, MacKeen, Heon, Gallie

Data collection: Soliman, VandenHoven, MacKeen.

Figure construction: Soliman, VandenHoven.

Analysis and interpretation: Soliman, VandenHoven, MacKeen, Heon, Gallie.

Critical review: Soliman, VandenHoven, MacKeen, Heon, Gallie

Overall responsibility: Soliman, VandenHoven, MacKeen, Heon, Gallie

Financial Support: None

Conflict of Interest: No financial conflicting relationship exists for any author.

Running head: OCT guided retinoblastoma management

Word count: 21412 / 3000 words

Numbers of figures and tables: 98 figures and 3 tables; 1 supplementary table

Key Words: retinoblastoma, Optical coherence Tomography, OCT, Cancer,

Guide.

Meeting presentation: American Academy of Ophthalmology Annual Meeting

presentation (Chicago 2016, Monday 17th October 2016)

Abstract: (296185308/350 words)

Purpose: Assess the role of handheld Optical Ccoherence Tomography (OCT) role in

guiding management decisions during guiding diagnosis, treatment and follow-up of

eyes affected by retinoblastoma during active treatment period.

Design: Retrospective non-comparative single institution case series.

Participants: All children newly diagnosed with retinoblastoma children from January

2011 to December 2015 thatwho had an OCT imaging session during their active

treatment at The Hospital for Sick Children (SickKids) in Toronto, Canada. OCT sessions

for fellow eyes of unilateral retinoblastoma without any suspicious lesion and those

performed after 6more than six months after from the last treatment were excluded.

Methods: Data collected included: age at presentation,; sex, family history, RB1

mutation status, 8th edition TNMH Cancer staging and International Intraocular

Retinoblastoma Classification (IIRC), and number of OCT sessions per eye. Details of

each session were reviewedscored for indication-related details (informative or not) and

assessed for being guidanceing (directive or not), diagnosis (staging changed, new

tumors found or excluded), treatment (modified, stopped or modality shifted), or follow-

up modified.

Main outcome measures: Frequency of OCT- guided management decisions, and

stratified by indication and type of guidance (confirmatory versus influential).

Results: Sixty-three eyes of 44 children had 339 OCT sessions per eye (median =5,

range 1-15/eye, range 1-15). Younger Children Age at presentation and the presence

ofhose with positive a heritable RB1 mutation had significantly higher number

ofincreased the number of OCT sessions. Common Indications included evaluation of

post-treatment scar (55%) or fovea (16%), and posterior pole scanning for new tumors

(11%). InformativeOf all sessions were 92% (312/339) were informative; 19/27 non-

informative sessions had and the main cause was large, or elevated lesions; of these, in

70% of non-informative sessions (19/27); 74% of which (14/19 ) were T2a or T2b (for

IIRC{Murphree, 2005 #11984}IIRC GroupGroup CD or D)C eyes at presentation. In 94%

(293/312) of the informative sessions, OCT guideddirected management treatment

decisions in 94% (293/312) of informative sessions (54%, (58%), diagnosis (16 %) and

follow-up (265%). , 15% guided treatment, follow-up and diagnostic decisions

respectively). Influential OCT guidance (OCT datainfluenced and changed management

fromed the pre-OCT clinical decisionplans) was noted in 17% and 15% of directive and

all OCT sessions respectively.

Conclusions: Clinical evaluation remains the gold standard for retinoblastoma

management. OCT improves accuracy of clinical evaluation gives valuable information

on tiny tumors, tumor scars and fovea improving precision in retinoblastoma

management.

AAO submitted abstract

Purpose: Assess Optical coherence Tomography (OCT)

role in management decisions guiding diagnosis,

treatment and follow-up of retinoblastoma.

Methods: Retrospective study of retinoblastoma

children (2011-2015) that had OCT. Details of each

session were reviewed and scored for indication-related

details, guided diagnosis (staging changed, new tumors

found or excluded), treatment modified, stopped or

modality shifted, or follow-up modified.

Results: Forty children (59 eyes) had 300 OCT sessions

(median=5/eye). Common indications were evaluation of

post-treatment scar (67%) or fovea (19%), and new

tumor assessment (10%). Informative sessions were

93% (286/300). OCT guided management decisions in

90% (258/286, p<0.05) of informative sessions (67%,

20%, 13% guided treatment, follow-up and diagnostic

decisions respectively).

Conclusion: OCT gives valuable information on tiny

tumors, tumor scars and fovea improving precision in

retinoblastoma management.

Précis: (3535/35 words; 226/460 characters)

We determined impact of handheld optical coherence tomography in retinoblastoma

management:

Precis:

94% of 339 OCT sessions contributed indication-related details in 63 affected eyes/ 44

patients;Retrospective Review of 339 OCT sessions 86% performed for 59 63 eyes of

40 children with retinoblastoma from 2011 to 2015 during their active treatment phase

showed that in 300 sessions evaluated (median 5/eye), the most common indication was

post-treatment scar evaluation in 2/3 of eyes,OCT provideding indication-related details

in 9394% and significantly guided care;treatment, follow up and diagnosis in 9086% of

sessions and 15% influenced change in management.eyes.

Background sentence:

OCT guides management decisions in macular and retinal diseases. Previous reports

showed OCT signs of retinoblastoma and simulating lesions, tiny tumors, fovea and optic

disc evaluation without studying OCT impact on active management.

Optical Ccoherence Tomography (OCT) hasis well established asto playinging an

integralimportant role in ophthalmic patient assessment, improvingleading to improved diagnostic

accuracy and thus therapeutic decisions making for a variety of ocular and retinal conditionshas

helped in better visualization of the retinal layers, optic disc, vitreoretinal interface and choroidal

anatomy. This improvesd the diagnostic and thus therapeutic decision makings in multiple

disorders as diabetic macular edema, macular hole and choroidal neovascular membranes.1-4

including ocular oncology. 5,6

Features of Retinoblastoma; the most common pediatric ocular malignancy; were better

appreciated Recently,in the recent years Hhandheld OCTwith the introduction of the handheld

OCT that which can be used usedperformed while the supine child is under anesthesia. during

the active management of their condition .7-10 has deepened out understanding of the features of

retinoblastoma, the most common pediatric ocular malignancy. 7-10

There are multiple published reports on the value of OCT in is shown valuable in

retinoblastoma in for detection of small invisible tumors,5,11-139- 12( Add Bremner as 9) foveal

evaluation,14,15 localization and microstructure of tumor seeds,16 and detection of optic nerve

infiltration.10,17 It is documented to help in assessment of tumor anatomy, scar edges and

simulating conditions5,18-20 (e.g. rRetinoma or aAstrocytoma). 5,18-20

Despite these various benefitsHowever, handheld OCT is still not commonly used except in

some highly rankedhighly specialized ocular oncology centers.7,21 In The current Canadian

Guidelines21 for retinoblastoma management we define the a center that has anusing handheld

OCT machine as a tertiary center and it is being updated to quaternary center in the updated

revised guidelines. Despite advances in imaging technologies, cClinical evaluation and decisions

is still the mainstay of retinoblastoma management in most situations. This raises the question of

whether OCT evaluation should be incorporated in the routine management of retinoblastoma or

that whether its use is not thatsignificantly influential on clinical decisions.

In this study, we evaluate the influence of hand held OCT in guiding the management

decisions in patientschildren with retinoblastoma children.

Methods

Study design

This study is a retrospective record review of all new children with retinoblastoma that who

presented to andwere managed in the Hhospital for Ssick Cchildren (SickKids), Toronto, Ontario,

Canada (SickKids) from January 2011 to December 2015. Ethics approval was obtained and the

study follows the guidelines of the Declaration of Helsinki.

Eligibility

The records of all children with rRetinoblastoma that who had receivedexamined with OCT

imaging during their management were reviewed. Fellow eyes of unilateral retinoblastoma

without any suspicious lesion and studied had at a single OCT session at presentation were

excluded. OCT sessions performed after 6 months from after the last treatment were excluded.

Data collection

The data collected included age at presentation, sex, family history, laterality, International

Iintraocular Rretinoblastoma Cclassification (IIRC)22 at presentation, genetics results, indication

for OCT, number of OCT sessions per /eye, and total active duration treatment (time from

diagnosis until last treatment). The extent cancer in each eye was retrospectively defined by the

2017 8th edition AJCC TNMH cancer staging.23

OCT Session and Systems

We defined aAn OCT session was defined as imaging a of single one eye for one or more

indications, using the OCT during an examination under anesthesia for one or more indications.

During the course of the study, two generations of handheld OCT systems were utilized:

Bioptigen® Envisu C2200 andC2200 and Envisu C2300 (Bioptigen, Inc. a Leica Microsystems,

Morrisville, NC USA). We did not compare and contrast both the machines for resolution or

depth. We did not receive sponsorship or financial support to conduct this our research. At any

point of time, we only had one machine was available for both clinic and operating room. All

OCT scans were captured by one of two highly skilled mMedical imaging sSpecialists (authors

CV and LM), following a standardized methodology for improvedgood longitudinal

reproducibility.

DefinitionsTe and technical considerations and indications {24-27

OCT was performed with operator at 12 o’clock position of the supine patient. The Handheld

OCT scanner was pivoted approximately 1 cm above the cornea, the optimal working distance,

aiming the scanning beam through the pupillary center.26 Manually holding the OCT probe was

preferred as it provides the greatest flexibility and ease of angling the probe towards the areas of

interest. AdditionallyBy manually holding the scanner, the operator iswas able to increase the

probe to eye working distance in real time while scanning over the apex of larger lesions. Image

quality and scan brightness was achievedoptimized by a combination of factors: , including

manual adjustment of the OCT spectrometer reference arm settings in accordance to the patient’s

axial length; and optimizing the handheld probe focus for the child’s refraction;.26 and frequent

application of 0.9% NaCl solution to prevents corneal dryness.

The handheld OCT produces a variety of scan configurations of scans. For our

researchWithinFor this study cohort, we consistently routinely obtained volumetric scans that

were composed of non-unaveraged OCT volume scans consisting of( 1000 A-Ascans x 100 B-

scans per volume)x 1 x 1. The accumulation of individual 100 B-scan produceds the associated

C-scan fundus image otherwise called the Sum Voxel Projection or (SVP). The OCT’s

accompanying SVP image provideds critical information about the quality of the scan and so the

OCT operator could respond in real-time the OCT operator can respond with positional

adjustments to improve subsequent scans. Additionally, When ClarificationTo clarify of

pathology localization wasis frequently required; , calipers were sometimescan bewere placed on

the OCT B-scan image to revealing the retinal position on the SVP image so that the precise area

of interest can be correlated to the specific retinal position. Calipers were also usedand to measure

tumor height in some instances . (Fig. Fig 1) . So while the Bscan OCT is of significant value to

interpreting tumour features, the SVP image is also as critical to ensure accurate localization of

lesions and interpretation of Bscan findings. It has been reported that extensiveAlthough

algorithms might be applied to improve image quality via oversampling and averaging of

multiple scans,.27 In our practice, wwe routinely captured single line volume scans as they

achieved both rapid and high quality images with ample clinical detail to provide clinical

information. The SVP image that results when OCTs scans are averaged are unreadable. This

affects the ability to decipher the OCT tumor findings accurately.

Forinfants (≤ 6 months of ageTo assess the posterior pole) (Fig 2) to screen for a new pre-

clinical or “invisible” tumor in infants less than 6 months of age, we by obtaining screening

withused the widest volumetric scan settings available. In our center, weWe performed 9 mm x 9

mm scans with the( Envisu C2200 system) and 12 mm x 12 mm scans with( Envisu C2300

system) of fovea, optic nerve, temporal, superior and inferior quadrants. If a tumor is was

identified, the scan is was repeated with the scanner placement achieving tumor centration

centered within the OCT frame. (Fig .2, 33). (Figures 1-2)

Foveal assessment is indicated In For foveal and or perifoveal tumors, to locate the foveal

center was located by obtaining a horizontal macular volumetric scan. As When needed, this scan

is followed by a vertically oriented foveal volume scan was performed whereby,with the scanning

angle is adjusted 90 degrees (within the software). The handheldthe scanner is held the same

physical configuration while t. The sum voxel fundus projectionSVP image is was consequently

rotated 90 degrees indicating the scan direction change. (Fig.ure Fig 34).

When For parafoveal scansning parafoveally, the handheld probescanner is was angled

pointed towards the area of interest. Increased resolution for small If the lesions is small in size, it

can be ideal towas obtained by reducinge the the area of scan volume area to 8 x 8, or 6 x 6, to

maximizing thee number of A-scans/ per each line. of OCT B-scan, thus increasing the

resolution of the individual OCT scans. To assess the mid-periphery and beyond, a scleral

depressor is was used to rotate the eye toward the area of interest, while angling the handheld

probescanner so that perpendicularity to the retinal plane is achieved. (Fig.ure Fig 54).

Assessment layers

An OCT session will was be assessed as being first as being Informative if it provideds

sufficient data about the main indication for scanning; and being Directive if the information

provided from the OCT imaging helpedobtained guiding guided the management decisions

affecting either diagnosis, treatment or follow-up. Directive guidance that confirmed the pre-OCT

clinical decision can bewas considered Confirmatory, if it confirms the pre-OCT clinical decision

orand Influential if the information providedit changed a pre-OCT clinical decision. Every OCT

session during the active treatment phase of each child will was be collected and assessed for all

layers.

Decision guiding

Guidance is either in diagnosis, treatment or follow-up.

Guidance was provided for diagnosis, treatment or follow-up (Tables 2 and 3).

Diagnosis sessions Diagnostic cwere scored Confirmatory guidance was considered when

OCT OCT confirmeds; a) clinically suspicious tumor mass or in clinically suspicious area(s), b)

clinicalclinical eye IIRC22 grouping Group, or includingc) posterior pole screening in positive

germ line mutationschildren less that 6 months of age known to carry an RB1 mutant allele; and

Influential when OCT excluded tumor in clinically suspicious area(s), changed IIRC22 Group, or

detected an invisible tumor during posterior pole screening.

up to six months of age. Diagnostic influential guidance was considered if OCT; a)

excluded tumor in clinically suspicious area(s), b) changed IIRC22 grouping or c) detected

an invisible tumor during posterior pole screening.

Treatment sessions were scored Confirmatory guidance was considered ifwhen OCT

confirmed a a) clinically suspicious new or recurrent tumor, or b) showed anatomic details (fovea,

scarring, seeds, traction, …etc.) supporting the decided planned treatment plan;. Treatment and

Influential guidance waswhen considered if OCT a) showed revealed an unsuspected recurrent

tumor within a tumor scar, b) or showed anatomic details mandating changing or cessation of the

treatment modality or plan.

Follow-up sessions confirmatory guidance waswere considered Confirmatory if when the

OCT showed no change from the last scan in absence of active treatment;. Follow up influential

guidance was considered if and Influential when OCT showed anatomic details excluding

activity, leading to change of clinically decidedalteration in treatment plan.

Results:

Patient Demographics and numbers of OCTs

This We reviewed included 339 OCT sessions for 63 eyes of 44 children with retinoblastoma;

(26 were male, 59%). Eight children (10 eyes) are were still under active treatment from which;

one child (one eye) was lost to follow up aswhen they moved outside Canada. Demographic data

are summarized in table 1. The median number of OCT sessions per eye is was 5 sessions (range:

1-15 sessions),. significantly higher for fFamilial eyes had a significantly higher median session

number of( 7) than versus 4 sessions to non-familial eyes(4) eyes (p=0.001, Mood’s Median

test). A significant negative correlation existed between the age at presentation and the number of

OCT sessions where Younger age children at presentation required recieved significantly more

OCT sessions (r=-0.26, p=0.04). The most common indication for OCT was tumor scar

evaluation in 55% (186/339, 55%), of sessions followed by foveal assessment and posterior pole

screeningscreening (16% and 11% respectively) (. The indications for OCT imaging for each eye

are summarized in tTable 2). What are the types of the OCT machines for the duration 2011-

2016?

OCT Impact Assessmenton Care

Informative versus Non-informative OCT

Informative OCT was found Informative in 92% of evaluated sessions (312/339) (Table 2).

Large or highly elevated lesions rendered OCT technically challenging and Uninformative iIn

19/27 sessions (8%), no valuable information was acquired. The main cause of non-informative

OCT was large or elevated lesion in 70% of sessions (19/27) (Table 3, Fig 1)2,5); approximately

74% of which (14/19 ) were cT2a23 or cT2b23 (was IIRC22 Group D or C) at first

tumorpresentation. In two2 eyes/children, there was loss of thOCT became e Uniformative

informative status of the OCT after multiple previously Informative OCTs OCTs, due to

progression of the central tumor (in one) aeye and tractional retinal detachment in another

eye(one).

Directive versus Non-Directive OCT

Directive OCT was Directive found in 86% (293/339) of all OCT sessions and in 94%

(293/312) of Informative sessions (Table 2), guiding . OCT directed treatment (168/312, 54%),,

diagnosis (46/312, 15%), or follow up in 54% (168/312), 15% (46/312) and 25% (79/312, 25%)

of informative sessions respectively. In 19Nineteen OCT sessions were Non-

DirectiveUninformative, mainly because the OCT, the information given was not important in

directing management decisions. The main cause was performing non-not indicated performed to

assess a clinical decision OCT (17/19) or OCT performed for academic interest (2/19). (Table 3).

Confirmatory versus Influential OCT

Of Directive OCT sessions, Confirmatory OCT was found in 83% (243/293 (83%) were)

Confirmatory: of directive sessions and guidedfor treatment 141 (58%), diagnosis 39 (16%) and

or follow-up 63 (up of 58%, 16% and 26%) of confirmatory sessions respectively (Table 2)..

Influential Of Directive OCT sessions, OCT was found in 17% (50/293 (17%) were Influential:

of directive sessions and guided for treatment 27/293 (11%), diagnosis 7/293 (3%) and or follow-

up 16/293 (7%) (Table 2). of 54%, 14% and 32% of influential sessions. Different OCT

influences are shown in table 3The most Influential OCT sessions were for scar and foveal

evaluation (Table 3).

OCT provided limited information in eyes with that were staged cT2 (TNMH 8th edition23)

(IIRC22 Group C, D) or with large tumors, due to absorption of optical signal by dense lesions and

lesion elevation beyond the scan capacity.26 Eyes staged cT123 (IIRC22 Groups A and B) were

easily scanned up to the mid periphery25 (Fig 5). OCT assessed well the location of tumor with

respect to retina: intra-retinal, pre-retinal, vitreal or subretinal (Fig 6). This supported accurate

TNMH23,24 or IIRC22 staging, for example, suspected tumor separate from the primary tumor was

shown by OCT to be subretinal tumor extension, not an independent new tumor (Fig 6C). This

influenced the diagnosis from multifocal tumor to seeding of a unifocal tumor. The verification of

tumor seeds by OCT16 also affected the choice of treatment modality (i.e., intra-vitreal

chemotherapy)28,29.

Discussion

The introduction of OCT in retinal imaging has been shown its effective ness in guidingto guide

management (diagnostic and therapeutic) decisions in multiple conditions, including as macular

holes,2, macular edema1 (diabetic and vascular) and age related macular degeneration.3,4 Multiple

reports were published showinghave shown the OCT differences between ocular tumors and how

useful OCT it can be useful to differentiate ocular tumors and simulating lesions.5,6,9-12,14-16,18-20,25

At presentation, we showed that OCTs provide limited information of eyes where the with is

T225 (TNMH 8th edition23) equivalent toIIRC22 group C or higher or higher and of individual large

tumors are usually non-informative regarding large tumor. s, Thetumors. The optical signal is

absorbed through dense lesions and the lesion elevation is beyond the imaging capacity.as the

scan cannot include them in its focus together with associated changes as calcification and

detachment.26 Eyes with T125 tumors (IIRC22 groups A and B) are easily scanned even in the mid

periphery245 (Fig. 1,2,4). OCT helps assessing the level of the tumor whether intra-retinal, pre-

retinal, vitreal or subretinal (Fig. 6). This allows more accurate TNMH23,25 or IIRC22 grouping in

certain eyes where a suspected tumor mass away from the primary tumor is shown to by OCT to

be a subretinal mass versus and not a new separate tumor (Fig 6C). This changes the diagnosis

from a multifocal tumor (IIRC22 group B or C) to a seeding unifocal mass with IIRC22group D.

The verification of vitreous tumor seeds by OCT16 helps better grouping(what do you mean by

this??)helped accurate IIRC22 grouping and affects the choice of treatment modality (i.e.intra-

vitreal chemotherapy)28,29.

Detection of small and sometimes invisible tumors5,11 (Fig. Fig 2-3), has changedchanges the

visual outcome especially in familial retinoblastoma,. This leads to achieving eEarlier tumor

detection and control with less treatment burden (focal therapy only) and less retinal damage.24 In

familial casesFor children at risk of familial retinoblastoma under 3 months of age, detection of

the first invisible tumor by OCT can facilitated early, minimalized therapy.24 {Fe-Bornstein, 2002

#12863}29modify the follow up plan to include EUA instead of clinic visits.21

In unilateral retinoblastoma, OCT helpeds differentiateation of suspicious lesions from

retinoblastoma (Fig. Fig 7) in the fellow normal eye. Previously, this depended on clinical

examination opinion or B-scan ultrasonography, which does not show the inner architecture of

the retina and lesion. Sometimes,LackingWithout invivoin-vivo evidence of the nature of these

suspicious lesions, presumably many such lesions were may have been treated treated with focal

therapy, potentially and falsely changing the diagnosis of thislabeling the child into as bilateral ,

heritable retinoblastoma, imposing which has a totally different follow-up, schedule with multiple

unnecessary examinations under anesthesia and life-long surveillance for second cancers.21,30

Foveal pit detection (Fig. Fig 4) provides an important clueinformation about visual potential

in with perifoveal tumors.14 Its Foveal localization respective to the tumor location can affect

choice of treatment modality (chemoreduction chemotherapy versus primary focal therapy with

Laser), its which laser to use subtype (532 nm versus 810 nm laser) and technique (ie, sequential

targeted laser therapy from away inwardsfrom the tumor side opposite the fovea, shown in

Figure 8). An intact flat fovea after treatment guides suggests benefit of the early start of

amblyopia therapy even in eyes with severe disease.31,32

It has been shown that OCT appearance can may help raise suspicionus of optic nerve

invasion in with peripapillary tumors,.10,17,33 In OCT, suspected optic nerve invasion can present

similarly to that of optic nerve edema. The but may fail to distinguish tumor from

papilledemaOCT appearance of optic nerve swelling is not necessarily pathognomic for optic

nerve invasion but should be considered and ruled out as being highly suspicious.

Scar evaluation was the most common indication for OCT in our seriesstudy. This helpsOCT

distinguishes gliosis and scar from precise diagnosis of tumor recurrence , (isodense areas with

medium reflectivity, Fig 9), especially useful with versus gliosis. It determines the exact extent of

recurrence especially in white choroidal scars, where visualization of recurrence is challenging to

appreciate,;33 which that canand thereby affect alter the choice of treatment modality. We have

observed that active tumor recurrence at the edge of a scar presents as isodense areas with

medium reflectivity (Fig. 9). Additionally, the lesion will present with localized thickening within

several consecutive B-scans. Medium gray, isodense, with localized retinal thickening in relation

to surrounding structures are more suspicious than areas that may be highly reflective, flat and/or

sharply demarcated.11

The current study is limited by being a single center, retrospective study, with. absence of

correlation to a quantifiable outcome. I, since it was not practical to correlate OCT sessions with

outcomes such as eye salvage, vision salvage, life salvage, which are affected by many other

factors like (tumor location, number and type, stage at presentation, complications of treatments,

treatment duration, etc.). rather than a single OCT session decision. The pPresence of a single

OCT machine limited the number of sessions in some eyes due to occasional unavailability due

related to maintenance or concomitant use by others.

Timeothersother surgeons. Time constraints may have affected the number of OCTs per eye

due to limited OR time. Training and academic interest may have increased the number of the

OCT sessions performed for some eyes, and we took this into account in scoring the impact of the

OCT session.

In conclusion, multiple studies have reported OCT signs of retinoblastoma at presentation,

seeds, scar, fovea and optic nerve evaluation. To our Knowledgeknowledge, this is the first study

with the largest number ofto evaluate thed OCT sessions impact on to determine whether the

OCT was valuable in guiding the management decisions of active retinoblastoma. In 86% of all

studied OCT sessions, OCT imaging directed was useful in the management decisions. In 17% of

these OCT sessions, the OCT provided evidence that influencedstrongystrongly influenced

changing the clinical decisions, showing that OCT enhanceingd precision of management.

Acknowledgement

There are no conflicts of interests or disclosures. BLG is the unpaid medical director of Impact

Genetics.

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Figure Legends

Figure 1. Central tumors. (A) A perifoveal tumor mass (cT1b23, or IIRC22 Group B) (iswas

isodense within the retinal layers; the exact foveal location is was evident (yellow *) ; maximal

tumor height of 0.75 mm (Informative, Directive and Influential in guiding laser treatment) was

over-estimated on B-scan ultrasonography. (B) A peripapillary tumor (cT1b23 , or IIRC22 Group

B) not involving the fovea measured 1.36 mm in height on B-scan ultrasonography; OCT

provided no additional data (Non-informative). (C) A juxtafoveal tumor (cT1b23 b{Soliman, In

Press #18014}, or IIRC22 Group B) measured 1.65 mm in height on B-scan ultrasonography;

OCT showed intact overlying retinal layers and minimal surrounding subretinal fluid (arrow

head) (Informative, Directive and Confirmatory for diagnosis) . (D) OCT on aA large er central

tumor (cT1b23 , or IIRC22 Group B) measuring 3.08 mm in height by on B-scan ultrasonography

was Confirmatoryey; OCT was Non-informative regarding both tumor internal architecture and

overlying retinal layers. In (B--D) tumors, calipers could not be accurately utilized to measure

tumor thickness, as the internal outer tumor boundary was ill defined.

Figure 2.: OCT screening of posterior quadrants (superior, temporal, inferior, and nasal). (A,

B) An invisible lesion was seen found (white **) in the inferior quadrant scan; (C) reimaging

centralized on the suspicious area (green 12mm x 12mm box) showeding an isodense small tumor

within the inner nuclear layer (Informative, Influential for diagnosis and treatment).

Figure 3.: First diagnosis of small tumors. (A - D) After detection on posterior pole screening,

small intra-retinal elevated isodense round tumors centralized on the inner nuclear layer

(cT1a23 {Soliman, In Press #18014} or, IIRC22 Group A) were confirmed when reimaged

centralized in a 12mm x 12mm box (Informative, Influential for diagnosis and treatment).

Figure 4. : Perifoveal tumors. The exact location of the foveal center (yellow **) was located in

horizontal (green line) and vertical (dotted green dotted line) scans with the foveal pit at the

intersection. The foveal center was (A) on top of tumor, (B) partially involved or (C) adjacent to

the tumor mass (Informative, Influential for diagnosis and treatment).

Figure 5: Pre-equatorial lesions. The eyes were deviated in the required direction with

complimentary tilting of the OCT scanner; peripheral indentation with scleral depressor was

helpful. (A) OCT of a peripheral nasal elevated isodense lesion. (B) OCT to evaluate a tumor tag

(yellow *) vs vitreous seed revealed an unsuspected nearby edge recurrence (arrow) (Informative,

Directive, Influential for diagnosis and treatment); . (C) tTwo months after both active tumors

were treated, clinical exam and OCT showed that the tumor tag (white *) extending into vitreous

had increased in size, while the edge recurrence (arrow) had completely disappeared was a flat

scar (Informative, Directive, Confirmatory); . (fFurther laser and cryotherapy resolved ablated the

tumor tag.)

Figure 6: Suspected tumor seeds. (A) Multiple white small masses in the macular area of an eye

harboring a large nasal tumor were shown by OCT to be preretinal vitreous seeds (Informative/

Directive/ Influential for diagnosis and treatment). (B) Multiple yellowish spots in an eye with

treated retinoblastoma, were shown on OCT to be retinal calcified with shadowing (arrows)

tumors in the retina; an isodense inner nuclear layer lesion (white **) was considered an active

new tumor, thereby treated with laser (Informative/ Directive/ Influential for diagnosis and

treatment).. Multiple vitrouus seeds cast shadowing on the OCT (arrowheads). (C) A A large

white lesion (arrowwhead) inferior to large central tumor with inferior shallow retinal detachment

in unilateral retinoblastoma; was considered likely to be a separate primary tumordue to its

rounded appearance, so, it was considered as a separate primary tumor and the eye was staged

cT2a23 ( or IIRC22 Group C); OCT showed a this to be subretinal seeding within the shallow

retinal detachment, upgrading changing the initial staging to cT2b23 or (IIRC22 Group D) eye

changing treatment  (Informative/ Directive/ Influential for diagnosis and treatment).

Figure 7. Exclusion of retinoblastoma in second eyes of unilateral retinoblastoma. (A) Coloboma

(arrowhead), (B) peripapillary thickening, and (C) a kinked vessel (*) could have been

misdiagnosed or mistreated, but were verified by OCT to be not retinoblastoma (Informative/

Directive/ Confirmatory (Influential) for diagnosis and treatment).

Figure 8. Sequential targeted Laser therapy (STLT) in juxtafoveal retinoblastoma. The child

presented with a cT2b23 ( or IIRC22 Group D) eye with two large tumors; the central tumor was

juxtafoveal; . (A) aAfter six cycles of systemic chemotherapy, the fovea was visible on OCT;

STLT was initiated using 532 nm laser starting from the edge farthest from the fovea sequentially

moving inwards (direction of the arrows) avoiding the tumor nearest to the fovea (*);. (B)

aAppearance 6 months after starting STLT;. (C) fovea was further away from the tumor edge

Appearance 12 months after starting STLT; the fovea is further away from the tumor edge that

can be treated. (D) 18 months after starting STLT OCT showed a flattened lesion with preserved

foveal pit; 18 months after last treatment the tumor remaineds the same .  (Informative/ Directive/

Confirmatory (Influential) for diagnosis, treatment, follow-up). Fovea marked by yellow *.

Figure 9 (A-C).: Evaluation of tumor scars. (A) OCT of aA clinically suspected recurrence in

scar (white arrow*head) showed on OCT an isodense elevation of indicating active tumor; , the

adjacent scar showed an unsuspected similar edge recurrence; both which waswere treated with

laser. The adjacent unsuspected scar showed a similar edge recurrence and was also treated. (B)

OCT detected tumor activity (arrow) hidden within areas of calcification (star).  (C) OCT of 2

two clinically suspicious white areas showed that the upper white area (white *) was a flat scar

(gliosis) and the lower white area (arrowwhite *) was an elevated lesiona tumor. (Informative/

Directive/ Influential (Confirmatory) for diagnosis and, follow-up).

Figure 3: Foveal assessment

Figure 4: Peripheral lesions

Figure 5: Optic nerve head assessment

Figure 6: Exclusion of RB.

Figure 7: Level of tumor

Figure 8: Sequential targeted laser therapy

Figure 9: Scar evaluation

Table legends

Table 1. Demographic characteristics of the studied GroupClinical, Genetic and Tumor

characteristics..

Character

Patient

s Eyes‍

Laterality

Bilateral 36 53

Unilateral 8 10

Total 44 63‍

Genetics

Germline

Familia

l 11 20

Sporadi

c 25 34

Total 36 54

Mosaic 2 3

Non‍Germline 6 6‍

Tumour

status

Character Patients

Laterality

RB 44 58

Stable 36

Salvage

d 37

Enucleated 9

Active 8* 10

No

RB 0 5‍

*‍one‍child‍is‍lost‍follow‍up,‍RB:‍Retinoblastoma

Table 2: layers of Assessment for the OCT sessions based on its indication

Treatment complication 0 0 0 0 0 0 1 4 1 3 0 0 1 2 0 0

Suscpicious lesion 0 0 0 0 0 0 0 0 1 3 11

4 0 0 0 0‍

Total (n)2

7 1001

91

001

411

002

71

003

91

00 71

006

31

001

61

00 43

Indication

Non-Informative (27, 8%)

Table 2: Stratification of different OCT assessments in diagnosis, treatment and follow up with indication for OCT imaging.. blah blah…..

Table 3.: Causes of different OCT assessment layers.

OCT

Assessment Causes N %

Non informative

Large‍tumor/elevated‍lesion¶

1

9 70

Peripheral‍lesion 4 15

Retinal‍detachment 2 7

Media‍Opacity 1 4

Awake‍child 1 4

Total

2

7

10

0

Non Directive

Doubtful‍indication

1

7 89

Academic‍interest 2 11

Total

1

9

10

0

Directive

Influential

Diagnosis

Exclude‍RB* 1 2

Upstage‍Clinical‍grouping‍§ 2 4

Invisible‍tumors‍£ 1 2

Modify‍treatment‍plan‍# 2 4

Recurrence‍versus‍Gliosis‍¥ 1 2

Table 3. Causes of different OCT assessment layers.

OCT Assessment

Non informative