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Precision Laser Therapy for Retinoblastoma in the Era of Optical Coherence

Tomography

Authors:

Sameh Soliman1-2 , Stephanie Kletke1 , Kelsey Roelofs3 , Cynthia VandenHoven1 ,

Leslie Mckeen1 , Brenda Gallie1 .

Authors’ affiliations:

1 Department of Ophthalmology and Visual Sciences, Hospital for Sick children,

Toronto, Ontario, Canada.

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

Alexandria, Egypt.

3 Department of Ophthalmology, Alberta children hospital, University of Calgary,

Alberta, Canada

Corresponding author:

Dr. Brenda Gallie at the Department of Ophthalmology and Vision Sciences, the

Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada,

or at brenda@gallie.ca

Type of article: Review

Word limit: (/7000)

Tables and Figures: 4 figures and 2 tables.

Abstract

Introduction–The past several decades have seen vast advancements in the

treatment paradigm for retinoblastoma, and the use of Laser therapy is certainly no

exceptiona cornerstone for control of intraocular retinoblastoma, after chemotherapy

has brought the disease under initial control. .Since first described over 6 decades

ago, laser technologies and approaches several improvements in protocols have

occurred have evolved. to that have greatly improved our ability to achieve local

tumor control. Despite its important role, It was observed that the published literature

is deficient lfew publications describe techniques, types of lasers, and modes of

delivery for retinoblastoma and even its role in disease control.

Areas covered–The physical and optical properties of lasers are briefly discussed,

and the various mechanisms of action, delivery systems, and potential complications,

are described. Hand-held optical coherence tomography (OCT) guidesd treatment

decisions and management detection of sub-clinicalmicroscopic retinoblastoma

tumors, achieving precision primary therapy and elimination of recurrences are

discussed. the literature search undertaken.????

Expert commentary–In all the excitement of new therapies to cure intraocular

retinoblastoma, laser treatment always compliments but is rarely mentioned. Hand-

held OCT now puts adds precision to put laser in the forefront in achieving cure of

retinoblastoma.

Summary

This review discusses laser therapy for intraocular retinoblastoma and highlights the

role of optical coherence tomography in improving laser therapy to precision levels.

Keywords

Retinoblastoma; laser therapy; hand-held optical coherence tomography; precision

medicine; primary tumor detection; early recurrence intervention.

[1.] Introduction

Retinoblastoma is the most common intraocular malignancy, that is initiated by

mutations in both copies of the retinoblastoma gene (RB1 gene). [1]. Worldwide,

approximately 8000 children are newly diagnosed annually. Survival approaches

100% if retinoblastoma is diagnosed and treated while still intraocular, while but

when retinoblastoma is extraocular, children with extraocular retinoblastoma have

poor survival. [1, 2]. Treatment strategies vary according to presentation but The

fundamental primary goal of treating cancer is life salvage, and for retinoblastoma

with vision salvage is a secondary goal. Salvage of an eye without visual potential

may be a dangerous goal since that can lead to unrecognized recurrence of the

cancer, can leads to extraocular extension and loss of life.[3]

With Despite the recent advances and new treatment modalities in retinoblastoma

management, the main primarystay of therapy for intraocular retinoblastoma remains

tumor size reduction by chemotherapy (systemic, intra-arterial or periocular)

followed by focal therapy with laser, cryotherapy, plaque radiotherapy and/or

intravitreal chemotherapy, according to tumor location and size. Chemotherapy

without focal consolidation is rarely sufficient to control retinoblastoma. [4-6]

However, the role of laser therapy in achieving tumor control is commonly

unmentioned in presentation of outcomes of treatment modalities such as intra-

arterial and intravitreal chemotherapy.[5, 6]

Laser therapy for retinoblastoma is a topic rarely addressed in publications. Laser is

rarely utilizedappropriate as a primary therapy except inonly for small tumors.

Techniques of laser therapy are rarely described making it difficult to study or learn

outside an apprenticeship situation. Choice of the type of laser wave length is highly

variable according to experience and availability without a consensus. Furthermore,

the role of laser in achieving primary or recurrent tumor control is unmentioned or

even neglected in reporting or comparing outcomes of recent treatments as intra-

arterial chemotherapy (IAC) or iIntravitreal chemotherapy (IViC) giving the reader

the false impression of insignificant role of Laser. [7, 8]. techniques of laser therapy

are rarely described making it difficult to study or learn outside an apprenticeship

situation.

Optical coherence tomography (OCT) has revolutionized our perspective of variable

retinal disorders including retinoblastoma by allowing detailed anatomical evaluation

of the retinal layers and tumor architecture. OCT visualizes subclinical new tumors

and tumor recurrences, differentiates tumor from gliosis during scar evaluation, and

improves perception of important anatomic landmarks for vision such as the fovea

and optic nerve. [5, 9].

1.[2.] Physics of laser

Although Einstein initially postulated the concept behind the stimulated emission

process upon which lasers are based in 1917, but it was not until 1960 that T.H.

Maiman performed the first experimental demonstration of a ruby (Cr3+AL2O3) solid

state laser. [10]. .In fact, The acronym LASER represents the underlying

fundamental quantum-mechanical principals involved: Light Amplification by

Stimulated Emission of Radiation. [11] . All lasers require a pump, an active medium

and an optical resonance cavity. Energy is introduced into the system by the pump,

which excites electrons to move from a lower to higher energy orbit. As these

electrons to return to their ground state, they emit photons, all of which will be of the

same wavelength resulting in light that is monochromatic (one color), coherent (in-

phase) and collimated (light waves aligned). Mirrors at either end of the resonance

cavity reflect photons traveling parallel to the cavityie’s axis, which then stimulate

more electrons, resulting in amplification of photon emission. Eventually photons

exit the laser cavity through the partially reflective mirror into the laser delivery

system.[11]

Lasers are typically categorized by their active medium, as this is whatwhich

determines the laser beam wavelength. For all lasers, tThe wavelength multiplied by

the frequency of oscillation for all lasers equals the speed of light. Therefore, as the

lasers wavelength increases its frequency decreases proportionally and vice versa.

Additionally, Planck’s law (E=h) states that the energy (E) of a photon is a product

of Planck’s constant (h=6.626 x 10-34 m2kg/s) multiplied by the frequency (). As

such, lasers with low wavelengths (and high frequency) impart high energy, and

those with high wavelengths (and low frequency) are less powerful. Broad

categories of lasers include solid state, gas, excimer, dye and semiconductor.

The power of a laser is expressed in watts (W), which is the amount of energy in

joules (J) per unit time (J/sec). Power density takes into account both the power (W)

and the area over which it is distributed (W/cm2). It is important to note that if spot

size is halved, the power density is quadrupled, and that if the amount of energy (J)

remains constant, decreasing the duration will increase the power (W) delivered.

Longer pulse duration increases the risk that heat waves will extend beyond the

optical laser spot, thus damaging surrounding normal tissue.[12] All lasers machines

have the option to control the shot pace or inter-shot interval, according to the

experience of treating ophthalmologist. In general, trainees are better to start by with

single shots or a longer inter-shot interval.

2.[3.] Types of lasers for retinoblastoma

Xenon arc photocoagulation, first described by Meyer-Schwickerath in 1956, was

one of the earliest photocoagulation methods adopted for treatment of

retinoblastoma.[13, 14] Xenon emission is white light, consists ofa mixture of

wavelengths between 400 and 1600 -nm and results in full-thickness burns without

selectively targeting ocular tissues. It has since beenis now replaced by laser

photocoagulation for retinoblastoma.

The commonest lasers used for focal therapy in retinoblastoma include are the green

(532 nm) frequency doubled neodymium Nd:YAG:YAG (yttrium-aluminum-garnet)

by indirect ophthalmoscope, 810 nm semiconductor infrared indirect or trans-scleral

diode laser, and the 1064 nm far infrared continuous wave Nd:YAG laser and the

810nm semiconductor infrared indirect or trans-scleral diode laser. While all three

lasers can be delivered with use of an indirect ophthalmoscope, the 810nm

diodeinfrared lasers can also be applied in a trans-scleral manner, which can be

particularly useful for anteriorly located tumors. and for treating tumors in the

presence of media opacities. Trans-scleral delivery also decreases the risk of cataract

formation by limiting laser transmittance through the pupil.[13] Of the three, the

GreenThe 532 nm laser and 810 nm lasers can treat tumor by photocoagulation. Both

The 810 nm and 1064 nm lasers can also treat by raising tumor temperature

(hyperthermia, commonly called trans-pupillary thermotherapy or TTT) in a sub-

threshold manner..[12]. Table 1 demonstrates the main differences between the

different types of laser in retinoblastoma.

3.[4.] Laser delivery

Retinal laser treatments can be delivered by either binocular indirect ophthalmoscopy

(BIO) using non-contact, hand-held lenses (20 D, pan-retinal 2.2 D or 28 D) or by

microscope-mounted laser with contact lenses (Goldmann Universal Three-Mirror,

Ocular Mainster Wide Field) and a coupling agent (Table 2).

4.1. Laser indirect ophthalmoscopy (LIO).

LIOIt was first described to treat retinoblastoma in 1992.[15] LBIO combined with

manipulation of eye position with a scleral depressor is the ideal laser delivery

technique for children under general anesthesia. The higher the power of the

condensing lens utilized, the lower the image magnification and the greater the field

of view. The laser spot size on the retina varies is minimized (with most power)

because the laser beamat the focuses at some focal point, a specific distance from the

indirect ophthalmoscope, and diverges on either side ofcloser and farther from the

focal point. It thereforeEffect depends on the power, relative positions of the headset

and BIO lenses, amount of light scattering by ocular media, as well asand the

patient’s refractive error. For instance, a 20 D lens causes a 900 µm image plane spot

to be reduced to 300 µm in an emmetropic eye.[16] The Retinal spot size can be

calculated by (ppower of the condensing aspheric lens multiplied byx iImage plane

spot size) divided by/ 60.[16] However, caution must be exercised as LBIO is less

stable than other delivery systems due torequires careful optimization and

coordination of the inherent instability of the patient’s eye, and the clinician’s head,

particularly withand simultaneous foot pedal depression, .[14] The positional

requirements and relatively long treatment durations associated with LBIO laser

deliverywhich contribute to higher prevalence of self-reported neck, hand, wrist and

lower back pain amongst ophthalmologists.[17]

4.2. Microscope-mounted delivery system.

This systemIt connects the Laser may also be delivered with through a slit-lamp or

operating microscope: . While the working distance for LBIO is variable, the

distance from the microscope to the patient’s eye is fixed. Therefore, retinal laser

spot size is only dictated by the patient’s refractive error, contact lens and pre-

selected laser spot diameter on the microscope.[16] Tilting the contact lens within 15

degrees does not cause significant distortion of the laser spot, as irradiance differs by

maximum 6.8%.[18] The universal Goldmann three-mirror (Power -67 D) has a flat

anterior surface that cancels the optical power of the anterior cornea, therefore

decreasing peripheral aberrations.[19, 20] It contains mirrors at 59, 67 and 73

degrees to aid in visualization and treatment of the periphery.[19] However,

photocoagulation efficiency is reduced in the far periphery, as the laser follows an

off-axis, oblique trajectory. LBIO is preferred for peripheral retinal laser treatments

as the field of view is greater than with a microscope-mounted laser.

Also nother commonly used contact lens is the Mainster wide-field (Power +61 D) ,

contact lens, which containings an aspheric lens in contact with the cornea and a

convex lens at some a fixed distance.[19, 20] Compared to the Goldmann three-

mirror which has the highest on-axis resolution, The Mainster lens has improved

field of view at the expense of poorer resolution, while the Goldmann three-mirror

which has the highest on-axis resolution.[18] Inverted image lenses may produce

smaller anterior than posterior segment laser beam diameters, thus leading to higher

irradiance in the anterior segment. Injury to the cornea and lens have been reported

during retinal photocoagulation with inverted image lenses, particularly in the

presence of high power settings and ocular media opacities.[18]

4.3 Trans-scleral laser therapy. (STEPHANIE)

DiodeInfra-redInfrared laser photocoagulation may also be delivered via a trans-

sclerally approach using an optical fiber.optic probe.[21, 22] This technique was first

described for the treatment of retinoblastoma in 1998.[23] Direct visualization of a

red laser aiminglaser aiming- beam through the wall of the globe confirms the

treatment area, with the main outcome being whitening of the tumor and surrounding

retina. In vitro and in vivo studies of trans-scleral thermotherapy for choroidal

melanoma suggest tumor cell destruction occurs at a threshold of 60° degrees

CCelsius, without permanent damage to scleral collagen or increased risk of retinal

tears.[24, 25] Given the precise nature of delivery and effective scleral transmission,

trans-scleral diode is useful for treatment of anteriorly located retinoblastoma tumors

andand for treating tumors in the presence of media opacities. Trans-scleral

deliverydiode also decreases the risk of cataract formation by limiting laser

transmittance through the pupillens.[23] The use of trans-scleral laser delivery is

rarely utilized nowadays.

[5.] MECHANISMS OF Laser therapyappraochesapproaches

for retinoblastoma:

54.1. Photocoagulation:

Photocoagulation is the process by which laser light energy is absorbed by a target

tissue and converted into thermal energy. A 10-20° C degree Celsius temperature

rise induces protein denaturation and subsequent coagulation and necrosis, depending

on the duration and extent of thermal change.[13] Heat generation is influenced by

the laser parameters and optical properties of the absorbing tissue.[19] Absorption

characteristics are dictated by tissue-specific chromophores, such as melanin in the

retinal pigment epithelium (RPE) and choroidal melanocytes, hemoglobin in blood

vessels, xanthophyll in the inner and outer plexiform layers, lipofuscin and

photoreceptor pigments.[26]

Laser lights in the visible electromagnetic spectrum, such as the(iei.e. 532 -nm

frequency-doubled Nd:YAG), are is largely absorbed by hemoglobin and melanin,

approximately half in the RPE and half in the choroid.[19] Heat is then conducted to

the neurosensory retina, causing inner retinal coagulation and focal increase in

necrotic cellsnecrosis, noted ophthalmoscopically as. This leads to loss of retinal

transparency and the a white laser response notedburn ophthalmoscopically. The 532

-nm laser is near the absorption peaks of oxyhemoglobin and deoxyhemoglobin so is

taken up by also destroys the retinal blood supply vessels, which is countered by as

the wavelength is near to the absorption peaks of oxyhemoglobin and

deoxyhemoglobin. However, this requires more energy due to the cooling effect of

blood flow, which has greater velocity than stationary tissues.[19] Confluent laser

burns encircling retinoblastoma tumors may occlude capillaries and large retinal

blood vessels, cutting off the tumor blood supply, and other feeder vessels may

require supplementary treatment.[15] so This explains why it is preferred not to start

photocoagulation is initiated only before after systemic or intra-arterial

chemotherapy completionare completed, in order to preserve the delivery of

chemotherapy to the tumorumor-delivery uninterrupted.

Tumors less than 3 mm elevation may be successfully controlled successfully by

laser without chemotherapy. Larger tumors require first chemotherapy to initiate

tumor regression, followed by laser In larger tumors, encircling photocoagulation to

cut off blood supply and o n subsequent treatments, 4–6 weeks apart, laser

photocoagulation is applied directly to the tumor (Figure 2). Tumors that are too

large for laser therapy require other modalities of treatmentespecially without

chemotherapy, may sometimes lead to failure of tumor control or earlier vitreous

seeding secondary to obliteration of tumor blood supply, with resultant tumor

necrosis and loss of tumor compactness (Figure 1). In our experience, combined

tumor encircling and painting by lLaser is preferred over encircling laser alone.

(Figure 2)

“Thermal blooming” is the process by which the photocoagulation zone may be

extended beyond the laser spot size particularly with with longer duration burns.[19]

This may not be clinically apparent during treatment and is one factorbut

contributesing to increased a larger size of the laser scar post-operatively. When the

tumor becomes white with laser photocoagulation, fa whitish response to the laser is

noted, further penetration of the light energy to deeper structures is prevented by

light scattering.[26] Thus, repeated laser treatments on the same area will only

increase the lateral extent of the laser application, known as the “shielding effect”.

[27] Laser photocoagulation ultimately leads to gliosis replacing the tumor withleads

to scarring, gliosis and variable RPE retinal pigment eplithelialepithelial hyperplasia.

54.2. Trans-pupillary thermotherapy:

Trans-pupillary thermotherapy (TTT) has also been applied to retinal tumors to

achieve localized tissue apoptosis. It involves continuous long duration (60 seconds)

laser application in the near-infrared spectrum (800-1064 nm), (usually 810 -nm

diode), for longer durations (60 seconds) and with larger spot size and lower power

than photocoagulation.[19] This TTT results in deeper tissue penetration (4 mm)

since melanin absorption decreases with increasing laser wavelength. The penetration

depth of Continuous wave 1064 nm laser thus exceedspenetrates deeper that that

forthe 810 nm diode, and 532 nm lasers, which is important when consideringin

treatment of thicker tumors.[28] Resultant Temperatures of TTT (45 to 60 °o C) rises

are lower than for classic photocoagulation (45 to 60 degrees Celsius).[29] The

endpoint of TTT is faint whitening or graying of the tumor and prominent visible

laser changes may not be visible at the time of treatment.[19, 29] In 1982, Lagendijk

used trans-pupillary thermotherapy (TTT) in two cases of recurrent retinoblastoma

successfully.[30] Subsequently, a relatively large study by Lumbroso et al reported

their outcomes in 239 children using TTT delivered with a diode laser through an

operating microscope and found that when this was combined with chemotherapy

excellent local tumor control and eye preservation was achieved.[31] Abramson et al.

concluded that tumors <1.5 disc diameters in base diameter can be successfully

treated with TTT alone, with nearly two thirds (64%) of tumors only requiring one

session.[29]This is dependent on fundus pigmentation and laser parameters.

Standard TTT may be insufficient to treat large, thick tumors or lesions associated

with significant chorioretinal atrophy. Furthermore, while TTT requires inherent

lesion pigmentation to achieve an adequate response, retinoblastoma is

characteristically non-pigmented. [27-29]Pretreatment with intravenous indocyanine

green (ICG), a chromophore with an absorption peak (805 nm) complementing the

diode 810 nm laser emission of 810 nm, results in photosensitization and a dose-

dependent decrease in the TTT fluencefluency threshold and irradiance required for

treatment.[32] Enhancement of the laser effect by with systemic ICG may lead to

regression of tumors withthat have shown a suboptimal response to systemic

chemotherapy and standard TTT.[33-35] The optimal timing between ICG injection

and TTT has not been full elucidateddetermined.

Several clinicians investigated this potentially synergistic role between

thermotherapy and chemotherapy. This treatment algorithm was termed

chemothermotherapy and was based on the hypothesis that the delivery of heat

facilitates the cellular uptake of certain chemotherapeutic agents.[36] In fact, in a

series of 103 tumors treated with chemothermotherapy, Lumbroso et al[37] reported

that tumor regression was seen in 96.1%. In this study, TTT was delivered shortly

after an intravenous injection of carboplatin. [29]

(FA and ICG enhanced TTT, STEPHANIE)

Complications of TTT reported following treatment of retinoblastoma include

chorioretinal scarring with focal scleral bowing.[23]

54.3 SEQUENTIAL LASER Therapy combining different lasers:

Certain tumors especially large central juxtafoveal and perifoveal

tumorsRetinoblastoma might can be treated with a necessitate combination of both

photocoagulation and thermotherapy in successive one or sequential treatments. The

tumor border and periphery are treated with 532 nm lLaser. A longer wavelength

laser is used to treat the elevated center either in the same or sequential session.[9]

Unfortunately, there is no randomized clinical trial that comparedcomparing lasers

and technologies mechanisms to set establish evidence to use any.[38]

[6.] Complications of laser therapy:

The most serious complications caused byof laser therapy are often usually caused by

use of excessive energy. Therefore, and as such, starting your treatments start at a

lower power and to titrateing to the desired effect to decreases the likelihood of

complications. In cases where tooToo small a spot size, too high a power or too short

a duration is usedcan induce, an iatrogenic rupture of Bruchs’ membrane, which may

occur. This might act asbe a precursor for choroidal neovascular membrane

formation. Additionally, Intense photocoagulation may result in full thickness retinal

holes which may progress to rhegmatogenous retinal detachment, or may . In

retinoblastoma, this can result in induce vitreous seeding of retinoblastoma.[39] OCT

can help inis useful to visualize and analyze ing and following these complications.

Although rare, Biopsy-proven orbital recurrence of retinoblastoma has been reported

following successful repeated treatment of a macular recurrence of retinoblastoma

with aggressive argon and diode laser.[40] In this case, MRI demonstrated a large

intraconal mass contiguous with the sclera, and B-scan ultrasound confirmed scleral

thinning at the recurrence site. The orbital recurrence was felt to result from tumor

seeding of the orbit at a site of focal scleral thinning within an atrophic chorioretinal

scar, following multiple intense laser treatments.[40]

Additional Common less serious complications can include focal iris atrophy,

lenticular opacification, retinal traction, retinal vascular obstruction and localized

serous retinal detachment.[39, 41] Additionally, Scars from TTT (810 nm) have been

shownare recognized to increase in size with time after treatment for

retinoblastomaretinoblastoma [42] and as such, one must be cautiousso may be in

using TTTthis laser may befor tumors l suboptimal for tumors located near the fovea

and optic nerve. Other cComplications of TTT reported following treatment of

retinoblastoma include cChorioretinal scarring with focal scleral bowing is reported

following TTT.[43]

Laser is ineffective in should be avoided over areas with any retinal detachment

whether high or shallow. OCT is useful to delineatecan help diagnose subtle

detachments. Laser over the optic nerve can compromise nerve fibers vitality and

should be avoided. The exact tumor relation to the optic nerve can be mapped by

OCT and to is thus considered during treatment planningguide accurate laser

treatment near critical structures.

[7.] Laser guided by optical coherence tomography (OCT) IN

RETINOBLASTOMA:

First reports of OCT was introduced to retinoblastoma in the early 2000s. The first

few reports focused on describing howthe appearance of retinoblastoma appears and

how toand differentiation e it from other simulating tumorslesions .[44, 45].

Introduction ofThe hand- held OCT expanded the use tohelped examining supine

children under anesthetic allowing imaging of moreto image retinoblastoma tumors

from diagnosis through treatments, to eventual stability.at different phases of their

active treatment from diagnosis to stability.[46, 47] This allowedOCT visualization

facilitates accurate of a multitude of situations that can affect and guide laser therapy,

revealing for example, as subclinical invisible tumors,[48, 49] subclinical tumor

recurrences either within a previous scar or edge recurrences,[9] topographic

localization of the foveal center,[9, 50] and differentiatingng benign whitish white

lesions (such as gliosis, and perivascular sheathing from of active retinoblastoma

and possible optic nerve involvement).[51] OCT can demonstrate intraretinal tumor

location (within the retina whether superficial, deep or diffuse infiltrating)

retinoblastoma,.[9] OCT can visualize vitreous or subretinal tumor seeds, either

vitreous or subretinal.[9, 52] It can alsoand determine the solid or cavitary internal

architecture of retinoblastoma whether solid or cavitary[53] that might affect the

therapeuticy approach (Figure 2X). . Despite very difficultWith skill and persistence,

the hand-held OCT can be used to in examine the mid periphery. but highly

dependent on the expertise of the photography specialist.[9]

OCT has become crucially influenced in our management decisions in

retinoblastoma management.[9] In a recent research, The role of OCT in each

examination under anesthetic (EUA) session for a child with retinoblastoma was

retrospectively classified determined to be into directive (direct diagnosis, treatment

or follow up) in 94% (293/312) of OCT and sessions, or academicacademic sessions.

Directive OCTs was found in 94% (293/312) OCT sessions. Directive OCTs were

further classified into as confirmatory (if they confirm the pre-OCT clinical decision)

or influential (17%) (if they influence change ing the pre-OCT clinical decision), . It

was found that 17% of directive OCTs were influential highlighting the importance

of OCT in the optimal retinoblastoma management.

armamentarium of evaluation during an EUA.

THE FUTURE: OPTICAL COHERENCE TOMOGRAPHY GUIDED LASER:

Currently, OCT is an essential tool in diagnosis, planning and monitoring of laser

therapy in certain scenarios in retinoblastoma.

678.1. Invisible tumors:

Invisible tumors can beare anticipated in children with carrying a pathogenic variant

of the positive RB1 tumor suppressor gene variant either detected either prenatal or

postnatal, because they have a positive parental family history of retinoblastoma.[54-

56] These children are classified now by the 2017 Tumor Node Metastasis

HeritablityHeritability cancer staging for retinoblastoma to be “H1” even if they do

not yet have detectable cancer.[5, 57] or a child with other clinical tumors (in H1

children). The ideal procedure to Sscreening for invisible tumors is by OCT mapping

of the posterior pole of each eye especially in the first 6–9 months of age can reveal.

tiny spheres of altered density in the inner nuclear layer of the retina. Once detected,

the the subclinical tumor should becan be centralized in the OCT scan and

combination of c. Calipers and anatomic landmarks especially (branching vessels,

etc) and its branching can be used to help locating to locate the invisible tumor in the

retinal retina for ablation by 532 nm laserimage. Photocoagulation with low laser

power (100 mW) and short pulse duration (0.5 seconds) is delivered, to gradually

increasinge power until whitening is noted. Post laser OCT can verify that the laser

burn(s) were in the correct location, including the tiny tumor treatment where the

tumor swells with increase reflectiveness and back shadowing. (Figure 3).[9]

678.2. Juxtafoveal tumors:

Tumors around near the fovea are a treatment challenge to treat with focal therapy

and preserve the foveolaal center. Classical laser treatment will eventually destroy

the fovea as the resultant scar is usually greater than the tumor size. OCT

localizesOCT with two OCT macular cube scans (vertical and horizontal) determines

the foveal location to avoidto avoid laser to this critical area.[9] Photocoagulation is

more precise than TTT for this sensitive precise work, to preserve vision and avoid

scar migration.[42, 58] Recently, a laser crescent photocoagulation method was

described for perifoveal tumors.[Submitted] The anti-foveal tumor crescent is

photocoagulated using 532 nm laser to obliterate the tumor blood supply that causes

central tumor flattenflattening to be treated in sequential sessions. Additionally, the

peripheral anti-foveal scarring causes a tangential pulling force. This technique was

observed to have better anatomical and visual outcome when the fovea is OCT-

detectable at initial laser session. Furthermore, OCT can detect subtle surrounding

exudative retinal detachment that might stops us from initiating laser treatment

initiation.

678.3.: Recurrent and residual tumors:

OCT can detect subclinical tumor edge recurrences. OCT can differentiate between

gliosis tumor calcification and homogenous potential active tumor associated with

scars.[9] Comparison between of successive OCT scans of the same area between

EUAs can detect subtle tumor recurrencedifferences . (Figure 4), facilitating early,

less intensive This potentiate less treatments (burden regarding laser power, number

of sessions) and improved final outcomes. Recurrences on flat retina are usually

treated with photocoagulation with 532 nm laser. However, recurrences over

calcified tumor require longer wavelength photocoagulation. With OCT, laser can be

delivered with precision to specific areas of recurrence instead of the whole scar,

reducing risk of excessive scarring and retinal dragging. When OCT images suggest

stability, observation can be undertaken without danger of tumor growth requiring

increased treatment burden. and even TTT.

Whiteish treatment scars previously posed a clinical challenge to determine

distinguish whether it is a tumorresidual or recurrennt tumor and gliosis. residual,

recurrence or a fibrosis. This was usually managed either byWith OCT, more laser

treatment can be delivered with precision to specific areas of recurrence instead of

the whole scar, reducing risk of excessive scarring and retinal draggingwith the

possibility of more scarring and traction. When OCT images suggest stability, o or

observation can be undertaken without the potential danger of tumor growth

requiring more increased treatment burden. OCT helped visualizing the layers of this

scars differentiating between these conditions guiding the diagnosis and subsequent

treatment choice. OCT directed repeating laser treatment to specific areas with

recurrence instead of the whole scar thus reducing potential extensive scarring and

retinal dragging.

678.4. Pre-equatorial tumors:

Pre-equatorial tumors can be treated by either photocoagulation or cryotherapy.

Laser therapy is usually preferred in superior tumors to avoid uveal effusion and

exudative detachment associated potential with cryotherapy associated uveal effusion

and exudative detachment.[59, 60] Flat Shallow pre-equatorial tumors are

usuallymay be treated with 532 nm laser photocoagulation for one or two sessions.

More Elevated pre-equatorial tumors might require multiple laser treatments as the

laser beam is not able tocannot be appliedy perpendicular to the tumor cannot be

treated equally as the inward curve of the tumor cannot be thoroughly painted with a

trans-pupillary laserapproach. In subsequent sessions with more outward flattening of

the tumor, the inward curvetumorit can be better visualized and treated.

Despite challengingWith expertise, peripheral OCT can assess tumor elevation,

differentiate scarring from residual tumors and identify peripheral potential tumor

seeding. (Figure 5). In certain tumors, Llaser can be utilized as an initial belt like

treatment to surrounding the tumor with a barrier to retinal detachment as a

preparatory step prior to cryotherapy, or plaque radiotherapy or pars plana

vitrectomy.[61] Peripheral Laser can be also used to ablate for potential ischemic or

potentially ischemic retina peripheral isolated by to an extensive tumor scar to

prevent protect againstdevelopment of neovascularization and probable subsequent

vitreous hemorrhage. As a general rule, a smaller spot size is required in peripheral

lesions to prevent iris injury.

FUTURE PRESPECTIVE: (can be written in the 5 year view)

OCT and wide field imaging in one unit??

Conclusions

Laser therapy in retinoblastoma is integral in retinoblastoma tumor control after

initial reduction in size by chemotherapy size reduction. In spite of this factHowever,

lLaser was never properlynot been studied in any clinical triala randomized

controlled fashion to set evidence. Improved tumor visualization and assessment

Introduction ofby OCT improved tumor visualization and assessment

improvingopens the door to precision our laser strategies treatments of smaller

tumors and recurrence, potentially improving cancer outcomes, reducing invasive

procedures, and and minimizingreducing complications.

Expert Commentary

I would include something related to the future of OCT guided laser.

BG will do next.

Five year view

Imaging technology are continuing to rapidly improve. Soon wide-angle fundus

imaging will be combined with There is huge advance in Imaging technology that

will allow incorporation of fundus imaging and OCT in hand-held units appropriate

for children under anaesthetic. Perhaps in five years, laser therapy will also be able to

be delivered in on tool, guided directly by both fundus image and OCT cross-section

to allow quick and accurate laser delivery. the incorporation of Laser therapy within

this machine is expected to follow to facilitate better aiming and improve the

reproducibility of Laser techniques.

References

1. Dimaras, H., et al., Retinoblastoma. Nat Rev Dis Primers, 2015. 1: p. 15021.2. Kivela, T., The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an

issue of birth and death. Br J Ophthalmol, 2009. 93(9): p. 1129-31.3. Canadian Retinoblastoma, S., National Retinoblastoma Strategy Canadian Guidelines for Care:

Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol, 2009. 44 Suppl 2: p. S1-88.

4. Gallie, B.L. and S. Soliman, Retinoblastoma, in Taylor and Hoyt's Paediatric Ophthalmology and Strabismus, B. Lambert and C. Lyons, Editors. 2017, Elsevier, Ltd.: Oxford, OX5 1GB, United Kingdom. p. 424-442.

5. Soliman, S.E., et al., Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia Pac J Ophthalmol (Phila), 2017. 6(2): p. 197-207.

6. Shields, C.L., et al., The effect of chemoreduction on retinoblastoma-induced retinal detachment. J Pediatr Ophthalmol Strabismus, 1997. 34(3): p. 165-9.

7. Yousef, Y.A., et al., Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol, 2016. 134(6): p. 584-591.

8. Scelfo, C., et al., An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol, 2017. 10(6): p. 961-967.

9. Soliman, S.E., et al., Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology, 2017.

10. Maiman, T.H., Stimulated Optical Radiation in Ruby. Nature, 1960. 187(4736): p. 493-494.11. Eichhorn, M., Laser physics : from principles to practical work in the lab. 1st edition. ed.

Graduate texts in physics. 2014, New York: Springer. pages cm.12. Niederer, P. and F. Fankhauser, Theoretical and practical aspects relating to the photothermal

therapy of tumors of the retina and choroid: A review. Technol Health Care, 2016. 24(5): p. 607-26.

13. Krauss, J.M. and C.A. Puliafito, Lasers in ophthalmology. Lasers Surg Med, 1995. 17(2): p. 102-59.14. Abramson, D.H., The focal treatment of retinoblastoma with emphasis on xenon arc

photocoagulation. Acta Ophthalmol Suppl (Copenh), 1989. 194: p. 3-63.15. Augsburger, J.J. and C.B. Faulkner, Indirect ophthalmoscope argon laser treatment of

retinoblastoma. . SO Ophthalmic-Surg., 1992(Sep. 23(9)): p. P 591-3.16. Friberg, T.R., Principles of photocoagulation using binocular indirect ophthalmoscope laser

delivery systems. Int Ophthalmol Clin, 1990. 30(2): p. 89-94.17. Kitzmann, A.S., et al., A survey study of musculoskeletal disorders among eye care physicians

compared with family medicine physicians. Ophthalmology, 2012. 119(2): p. 213-20.18. Mainster, M.A., et al., Ophthalmoscopic contact lenses for transpupillary thermotherapy. Semin

Ophthalmol, 2001. 16(2): p. 60-5.19. Blumenkranz, D.P.a.M.S., Chapter 39. Retinal Laser Therapy: Biophysical Basis and Applications,

in Retina, S.J. Ryan, Editor. 2013, Saunders, Elsevier Inc.: China. p. 746-760.20. Mainster, M.A., et al., Retinal laser lenses: magnification, spot size, and field of view. Br J

Ophthalmol, 1990. 74(3): p. 177-9.

21. Peyman, G.A., K.S. Naguib, and D. Gaasterland, Trans-scleral application of a semiconductor diode laser. Lasers Surg Med, 1990. 10(6): p. 569-75.

22. McHugh, D.A., et al., Diode laser contact transscleral retinal photocoagulation: a clinical study. Br J Ophthalmol, 1995. 79(12): p. 1083-7.

23. Abramson, D.H., C.A. Servodidio, and M. Nissen, Treatment of retinoblastoma with the transscleral diode laser. Am J Ophthalmol, 1998. 126(5): p. 733-5.

24. Rem, A.I., et al., Temperature dependence of thermal damage to the sclera: exploring the heat tolerance of the sclera for transscleral thermotherapy. Exp Eye Res, 2001. 72(2): p. 153-62.

25. Rem, A.I., et al., Transscleral thermotherapy: short- and long-term effects of transscleral conductive heating in rabbit eyes. Arch Ophthalmol, 2003. 121(4): p. 510-6.

26. Mainster, M.A., Wavelength selection in macular photocoagulation. Tissue optics, thermal effects, and laser systems. Ophthalmology, 1986. 93(7): p. 952-8.

27. Stefansson, E., The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand, 2001. 79(5): p. 435-40.

28. Rol, P., et al., Transpupillar laser phototherapy for retinal and choroidal tumors: a rational approach. Graefes Arch Clin Exp Ophthalmol, 2000. 238(3): p. 249-72.

29. Abramson, D.H. and A.C. Schefler, Transpupillary thermotherapy as initial treatment for small intraocular retinoblastoma: technique and predictors of success. Ophthalmology, 2004. 111(5): p. 984-91.

30. Lagendijk, J.J., A microwave heating technique for the hyperthermic treatment of tumours in the eye, especially retinoblastoma. Phys Med Biol, 1982. 27(11): p. 1313-24.

31. Lumbroso, L., et al., [Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. J Fr Ophtalmol, 2003. 26(2): p. 154-9.

32. Peyman, G.A., et al., Transpupillary thermotherapy threshold parameters: effect of indocyanine green pretreatment. Retina, 2003. 23(3): p. 378-86.

33. Al-Haddad, C.E., et al., Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma. Ocul Oncol Pathol, 2015. 1(2): p. 77-82.

34. Hasanreisoglu, M., et al., Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors. J Pediatr Ophthalmol Strabismus, 2015. 52(6): p. 348-54.

35. Francis, J.H., et al., Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol, 2013. 97(2): p. 164-8.

36. Inomata, M., et al., In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Int J Hyperthermia, 2002. 18(1): p. 50-61.

37. Lumbroso, L., et al., Chemothermotherapy in the management of retinoblastoma. Ophthalmology, 2002. 109(6): p. 1130-6.

38. Fabian, I.D., et al., Focal laser treatment in addition to chemotherapy for retinoblastoma. Cochrane Database Syst Rev, 2017. 6: p. CD012366.

39. Hamel, P., et al., Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS, 2000. 4(6): p. 334-7.

40. Jacobsen, B.H., et al., Orbital Recurrence following Aggressive Laser Treatment for Recurrent Retinoblastoma. Ocul Oncol Pathol, 2015. 2(2): p. 76-9.

41. Shields, C.L., et al., Thermotherapy for retinoblastoma. Arch Ophthalmol, 1999. 117(7): p. 885-93.

42. Lee, T.C., et al., Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology, 2004. 111(5): p. 992-6.

43. de Graaf, P., et al., Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Ophthalmic Genet, 2006. 27(1): p. 33-5.

44. Sony, P. and S.P. Garg, Optical coherence tomography in children with retinoblastoma. J Pediatr Ophthalmol Strabismus, 2005. 42(3): p. 134; author reply 134-5.

45. Shields, C.L., M.A. Materin, and J.A. Shields, Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol, 2005. 16(3): p. 141-54.

46. Scott, A.W., et al., Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol, 2009. 147(2): p. 364-373 e2.

47. Maldonado, R.S., et al., Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci, 2010. 51(5): p. 2678-85.

48. Rootman, D.B., et al., Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol, 2013. 97(1): p. 59-65.

49. Berry, J.L., D. Cobrinik, and J.W. Kim, Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. Ocul Oncol Pathol, 2016. 2(3): p. 148-52.

50. Hasanreisoglu, M., et al., Spectral Domain Optical Coherence Tomography Reveals Hidden Fovea Beneath Extensive Vitreous Seeding From Retinoblastoma. Retina, 2015. 35(7): p. 1486-7.

51. Yousef, Y.A., et al., Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS, 2012. 16(5): p. 481-3.

52. Berry, J.L., K. Anulao, and J.W. Kim, Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. Ophthalmology, 2017. 124(8): p. 1208.

53. Fuller, T.S., R.A. Alvi, and C.L. Shields, Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA Ophthalmol, 2016. 134(5): p. e155355.

54. Soliman, S.E., et al., Prenatal versus Postnatal Screening for Familial Retinoblastoma. Ophthalmology, 2016. 123(12): p. 2610-2617.

55. Soliman, S.E., et al., Psychosocial determinants for treatment decisions in familial retinoblastoma. Ophthalmic Genet, 2017: p. 1-3.

56. Soliman, S.E., M. ElManhaly, and H. Dimaras, Knowledge of genetics in familial retinoblastoma. Ophthalmic Genet, 2016: p. 1-7.

57. Mallipatna, A., et al., Retinoblastoma, in AJCC Cancer Staging Manual, M.B. Amin, S.B. Edge, and F.L. Greene, Editors. 2017, Springer: New York, NY. p. 819-831.

58. Fabian, I.D., et al., Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes. Am J Ophthalmol, 2017. 179: p. 137-144.

59. Anagnoste, S.R., et al., Rhegmatogenous retinal detachment in retinoblastoma patients undergoing chemoreduction and cryotherapy. Am J Ophthalmol, 2000. 129(6): p. 817-9.

60. Shields, J.A., C.L. Shields, and P. De Potter, Cryotherapy for retinoblastoma. Int Ophthalmol Clin, 1993. 33(3): p. 101-5.

61. Zhao, J., et al., Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology, 2017.

Table 1: Comparison between lasers in retinoblastoma.

Type of

laser

Green

532nm

Diode

810nm

Continu

ous

wave

1064nm

Frequency-

doubled Nd-

YAG

Solid State

Semi-

conduct

or

Nd-

YAG

Solid

State

Common

delivery

method

Indirect Indirect

or

transcle

ral

Indirect

Mechani

sm of

action

Retinal

photocoagulatio

n results in

tumor apoptosis

Acts in a subthreshold manner

to raising choroidal

temperature. Causing minimal

thermal damage to the RPE

and overlying retina

Depth of

penetrati

on

Superficial:

limited by the

resultant

coagulation [39]

and by nature of

Deep: primary anatomical site

of action is in the choroid.

Diode and Nd:YAG lasers are

estimated to penetrate 4.2 and

5.1mm respectively.

shorter

wavelength.

Estimated to

penetrate ~2

mm in non-

pigmented

tumors such as

retinoblastoma.

[12]

Penetration depth decreases in

necrotic tumors.[12]

Paramete

rs

Power: 0.3 – 0.8

W

Duration: 0.3-

0.4 seconds

Power:

0.3-1.5

W

Duratio

n: 0.5 –

1.5

seconds

Power:

1.4 – 3.0

W

Duration

: 1

second

Clinical

endpoint

Increase power

by 0.1W

increments until

tumor/retinal

whitening

visible[39]

Slight graying of retina without

causing vascular spasm [29,

41]

Table 2. Types of contact and non-contact fundus lenses [15, 18, 19]

L

e

n

s

T

y

p

e

I

m

a

g

e

M

a

g

n

if

ic

at

i

o

n

L

a

s

e

r

S

p

o

t

M

a

g

n

if

ic

at

i

o

n

Sta

tic

Fie

ld

of

Vi

ew

(°)

D

y

n

a

m

i

c

F

i

e

l

d

o

f

V

i

e

w

C

on

ta

ct

or

N

on

-

co

nt

ac

t

Im

ag

e

Ch

ara

cte

ris

tic

s

(

°

)

G

o

l

d

m

a

n

n

3

-

M

i

r

r

o

r

U

n

0.

9

3

X

1.

0

8

X

36 7

4

(

w

i

t

h

1

5

°

t

i

l

t

)

C

on

ta

ct

Vi

rtu

al,

ere

ct

im

ag

e

loc

ate

d

ne

ar

po

ste

rio

r

len

s

ca

i

v

e

r

s

a

l

ps

ule

O

c

u

l

a

r

M

a

i

n

s

t

e

r

0.

6

7

X

1.

5

0

X

11

8

1

2

7

C

on

ta

ct

Re

al,

in

ve

rte

d

im

ag

e

in

air

W

i

d

e

F

i

e

l

d

2

0

D

B

I

O

3.

1

3

X

0.

3

2

X

466

0

N

on

-

co

nt

ac

t

Re

al,

in

ve

rte

d,

lat

era

lly

re

ve

rse

d

P

a

n

-

r

e

t

i

n

a

l

2

.

2

B

I

O

2.

6

8

X

0.

3

7

X

567

3

N

on

-

co

nt

ac

t

Re

al,

in

ve

rte

d,

lat

era

lly

re

ve

rse

d

2

8

D

2.

2

7

X

0.

4

4

X

53 6

9

N

on

-

co

Re

al,

in

ve

B

I

O

nt

ac

t

rte

d,

lat

era

lly

re

ve

rse

d

D= Diopter; BIO= Binocular indirect ophthalmoscopy

1. Dimaras, H., et al., Retinoblastoma. Nat Rev Dis Primers, 2015. 1: p. 15021.2. Kivela, T., The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an

issue of birth and death. Br J Ophthalmol, 2009. 93(9): p. 1129-31.3. Canadian Retinoblastoma, S., National Retinoblastoma Strategy Canadian Guidelines for Care:

Strategie therapeutique du retinoblastome guide clinique canadien. Can J Ophthalmol, 2009. 44 Suppl 2: p. S1-88.

4. Gallie, B.L. and S. Soliman, Retinoblastoma, in Taylor and Hoyt's Paediatric Ophthalmology and Strabismus, B. Lambert and C. Lyons, Editors. 2017, Elsevier, Ltd.: Oxford, OX5 1GB, United Kingdom. p. 424-442.

5. Soliman, S.E., et al., Genetics and Molecular Diagnostics in Retinoblastoma--An Update. Asia Pac J Ophthalmol (Phila), 2017. 6(2): p. 197-207.

6. Shields, C.L., et al., The effect of chemoreduction on retinoblastoma-induced retinal detachment. J Pediatr Ophthalmol Strabismus, 1997. 34(3): p. 165-9.

7. Yousef, Y.A., et al., Intra-arterial Chemotherapy for Retinoblastoma: A Systematic Review. JAMA Ophthalmol, 2016. 134(6): p. 584-591.

8. Scelfo, C., et al., An international survey of classification and treatment choices for group D retinoblastoma. Int J Ophthalmol, 2017. 10(6): p. 961-967.

9. Soliman, S.E., et al., Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management. Ophthalmology, 2017.

10. Maiman, T.H., Stimulated Optical Radiation in Ruby. Nature, 1960. 187(4736): p. 493-494.

11. Eichhorn, M., Laser physics : from principles to practical work in the lab. 1st edition. ed. Graduate texts in physics. 2014, New York: Springer. pages cm.

12. Niederer, P. and F. Fankhauser, Theoretical and practical aspects relating to the photothermal therapy of tumors of the retina and choroid: A review. Technol Health Care, 2016. 24(5): p. 607-26.

13. Krauss, J.M. and C.A. Puliafito, Lasers in ophthalmology. Lasers Surg Med, 1995. 17(2): p. 102-59.14. Abramson, D.H., The focal treatment of retinoblastoma with emphasis on xenon arc

photocoagulation. Acta Ophthalmol Suppl (Copenh), 1989. 194: p. 3-63.15. Augsburger, J.J. and C.B. Faulkner, Indirect ophthalmoscope argon laser treatment of

retinoblastoma. . SO Ophthalmic-Surg., 1992(Sep. 23(9)): p. P 591-3.16. Friberg, T.R., Principles of photocoagulation using binocular indirect ophthalmoscope laser

delivery systems. Int Ophthalmol Clin, 1990. 30(2): p. 89-94.17. Kitzmann, A.S., et al., A survey study of musculoskeletal disorders among eye care physicians

compared with family medicine physicians. Ophthalmology, 2012. 119(2): p. 213-20.18. Mainster, M.A., et al., Ophthalmoscopic contact lenses for transpupillary thermotherapy. Semin

Ophthalmol, 2001. 16(2): p. 60-5.19. Blumenkranz, D.P.a.M.S., Chapter 39. Retinal Laser Therapy: Biophysical Basis and Applications,

in Retina, S.J. Ryan, Editor. 2013, Saunders, Elsevier Inc.: China. p. 746-760.20. Mainster, M.A., et al., Retinal laser lenses: magnification, spot size, and field of view. Br J

Ophthalmol, 1990. 74(3): p. 177-9.21. Peyman, G.A., K.S. Naguib, and D. Gaasterland, Trans-scleral application of a semiconductor

diode laser. Lasers Surg Med, 1990. 10(6): p. 569-75.22. McHugh, D.A., et al., Diode laser contact transscleral retinal photocoagulation: a clinical study.

Br J Ophthalmol, 1995. 79(12): p. 1083-7.23. Abramson, D.H., C.A. Servodidio, and M. Nissen, Treatment of retinoblastoma with the

transscleral diode laser. Am J Ophthalmol, 1998. 126(5): p. 733-5.24. Rem, A.I., et al., Temperature dependence of thermal damage to the sclera: exploring the heat

tolerance of the sclera for transscleral thermotherapy. Exp Eye Res, 2001. 72(2): p. 153-62.25. Rem, A.I., et al., Transscleral thermotherapy: short- and long-term effects of transscleral

conductive heating in rabbit eyes. Arch Ophthalmol, 2003. 121(4): p. 510-6.26. Mainster, M.A., Wavelength selection in macular photocoagulation. Tissue optics, thermal

effects, and laser systems. Ophthalmology, 1986. 93(7): p. 952-8.27. Stefansson, E., The therapeutic effects of retinal laser treatment and vitrectomy. A theory based

on oxygen and vascular physiology. Acta Ophthalmol Scand, 2001. 79(5): p. 435-40.28. Rol, P., et al., Transpupillar laser phototherapy for retinal and choroidal tumors: a rational

approach. Graefes Arch Clin Exp Ophthalmol, 2000. 238(3): p. 249-72.29. Abramson, D.H. and A.C. Schefler, Transpupillary thermotherapy as initial treatment for small

intraocular retinoblastoma: technique and predictors of success. Ophthalmology, 2004. 111(5): p. 984-91.

30. Lagendijk, J.J., A microwave heating technique for the hyperthermic treatment of tumours in the eye, especially retinoblastoma. Phys Med Biol, 1982. 27(11): p. 1313-24.

31. Lumbroso, L., et al., [Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. J Fr Ophtalmol, 2003. 26(2): p. 154-9.

32. Peyman, G.A., et al., Transpupillary thermotherapy threshold parameters: effect of indocyanine green pretreatment. Retina, 2003. 23(3): p. 378-86.

33. Al-Haddad, C.E., et al., Indocyanine Green-Enhanced Thermotherapy for Retinoblastoma. Ocul Oncol Pathol, 2015. 1(2): p. 77-82.

34. Hasanreisoglu, M., et al., Indocyanine Green-Enhanced Transpupillary Thermotherapy for Retinoblastoma: Analysis of 42 Tumors. J Pediatr Ophthalmol Strabismus, 2015. 52(6): p. 348-54.

35. Francis, J.H., et al., Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol, 2013. 97(2): p. 164-8.

36. Inomata, M., et al., In vitro thermo- and thermochemo-sensitivity of retinoblastoma cells from surgical specimens. Int J Hyperthermia, 2002. 18(1): p. 50-61.

37. Lumbroso, L., et al., Chemothermotherapy in the management of retinoblastoma. Ophthalmology, 2002. 109(6): p. 1130-6.

38. Fabian, I.D., et al., Focal laser treatment in addition to chemotherapy for retinoblastoma. Cochrane Database Syst Rev, 2017. 6: p. CD012366.

39. Hamel, P., et al., Focal therapy in the management of retinoblastoma: when to start and when to stop. J AAPOS, 2000. 4(6): p. 334-7.

40. Jacobsen, B.H., et al., Orbital Recurrence following Aggressive Laser Treatment for Recurrent Retinoblastoma. Ocul Oncol Pathol, 2015. 2(2): p. 76-9.

41. Shields, C.L., et al., Thermotherapy for retinoblastoma. Arch Ophthalmol, 1999. 117(7): p. 885-93.

42. Lee, T.C., et al., Chorioretinal scar growth after 810-nanometer laser treatment for retinoblastoma. Ophthalmology, 2004. 111(5): p. 992-6.

43. de Graaf, P., et al., Atrophic chorioretinal scar and focal scleral bowing following thermochemotherapy with a diode laser for retinoblastoma. Ophthalmic Genet, 2006. 27(1): p. 33-5.

44. Sony, P. and S.P. Garg, Optical coherence tomography in children with retinoblastoma. J Pediatr Ophthalmol Strabismus, 2005. 42(3): p. 134; author reply 134-5.

45. Shields, C.L., M.A. Materin, and J.A. Shields, Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol, 2005. 16(3): p. 141-54.

46. Scott, A.W., et al., Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol, 2009. 147(2): p. 364-373 e2.

47. Maldonado, R.S., et al., Optimizing hand-held spectral domain optical coherence tomography imaging for neonates, infants, and children. Invest Ophthalmol Vis Sci, 2010. 51(5): p. 2678-85.

48. Rootman, D.B., et al., Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol, 2013. 97(1): p. 59-65.

49. Berry, J.L., D. Cobrinik, and J.W. Kim, Detection and Intraretinal Localization of an 'Invisible' Retinoblastoma Using Optical Coherence Tomography. Ocul Oncol Pathol, 2016. 2(3): p. 148-52.

50. Hasanreisoglu, M., et al., Spectral Domain Optical Coherence Tomography Reveals Hidden Fovea Beneath Extensive Vitreous Seeding From Retinoblastoma. Retina, 2015. 35(7): p. 1486-7.

51. Yousef, Y.A., et al., Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. J AAPOS, 2012. 16(5): p. 481-3.

52. Berry, J.L., K. Anulao, and J.W. Kim, Optical Coherence Tomography Imaging of a Large Spherical Seed in Retinoblastoma. Ophthalmology, 2017. 124(8): p. 1208.

53. Fuller, T.S., R.A. Alvi, and C.L. Shields, Optical Coherence Tomography of Cavitary Retinoblastoma. JAMA Ophthalmol, 2016. 134(5): p. e155355.

54. Soliman, S.E., et al., Prenatal versus Postnatal Screening for Familial Retinoblastoma. Ophthalmology, 2016. 123(12): p. 2610-2617.

55. Soliman, S.E., et al., Psychosocial determinants for treatment decisions in familial retinoblastoma. Ophthalmic Genet, 2017: p. 1-3.

56. Soliman, S.E., M. ElManhaly, and H. Dimaras, Knowledge of genetics in familial retinoblastoma. Ophthalmic Genet, 2016: p. 1-7.

57. Mallipatna, A., et al., Retinoblastoma, in AJCC Cancer Staging Manual, M.B. Amin, S.B. Edge, and F.L. Greene, Editors. 2017, Springer: New York, NY. p. 819-831.

58. Fabian, I.D., et al., Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes. Am J Ophthalmol, 2017. 179: p. 137-144.

59. Anagnoste, S.R., et al., Rhegmatogenous retinal detachment in retinoblastoma patients undergoing chemoreduction and cryotherapy. Am J Ophthalmol, 2000. 129(6): p. 817-9.

60. Shields, J.A., C.L. Shields, and P. De Potter, Cryotherapy for retinoblastoma. Int Ophthalmol Clin, 1993. 33(3): p. 101-5.

61. Zhao, J., et al., Pars Plana Vitrectomy and Endoresection of Refractory Intraocular Retinoblastoma. Ophthalmology, 2017.