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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 [email protected]
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
Laser therapy is a cheap, available, non-invasive, easy to learn and relatively safe
technique to destroy residual tumor after chemoreduction (either systemic chemotherapy
or IAC). It is a necessity for posterior pole and superior tumors (especially if partially
calcified) where cryotherapy is not recommended or even contraindicated.
Despite all the recent improvements in retinoblastoma treatment, laser therapy remains an
underreported cornerstone in tumor control after chemotherapy. Laser therapy is one of
the most frequently available modalities especially in low and income countries that
cannot afford expensive modalities as IAC or plaque radiotherapy. The published
literature is highly deficient in details regarding methods and techniques of laser therapy
which make it highly variable between different centers based on the experts’ experience.
Variability in technique and consequently the variability in endpoint of therapy (flat scar
versus stable fish flesh like lesion) make dissemination of proper knowledge and
implementation of this therapy. An effective way of teaching would be recording videos
in microscope mount laser delivery technique or pre- and post-laser photos using the
wide fundus camera in indirect laser delivery option. Another method would be
preoperative planning of the laser with experts via telemedicine which has proven
effectiveness in decision making.
Currently, minimal research is conducted on laser techniques and laser is regarded as a
non-essential tool. As a consequence, centers in low income countries are failing to
utilize their available laser machines effectively in trial to set more fancy expensive tools
that are effective but require laser to control. Workshops, conferences and proper
collaborative or twinning programs between centers of excellence and new centers in
developing countries should be implemented to effectively utilize all resources to
improve life, vision and eye salvage in retinoblastoma.
OCT has improved our understanding of many aspects in retinoblastoma diagnosis,
treatment and follow-up. It is essential now as an adjunct tool in Laser for invisible
tumors and edge recurrences. Despite its high cost, a center of high excellence must have
at least one OCT machine to improve and achieve precision therapy in retinoblastoma.
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.
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