Laser Therapy for Retinoblastoma in the Era of Optical Coherence Tomography

Authors:Comment by Sameh Soliman: Authors’ names and affiliation: Including address, academic qualifications and job titles of all authors, as well as telephone number and email address of the author for correspondence on a separate cover sheet as the peer reviewers will be blinded to the authors’ identity. Please note that only the address of the first author of the article will appear on Medline/PubMed, not necessarily the corresponding author.

Sameh Soliman1-2, Stephanie Kletke1, Kelsey Roelofs3, Cynthia VandenHoven1, Leslie Mckeen1, Brenda Gallie1.

Authors’ affiliations:

1Department of Ophthalmology and Visual Sciences, Hospital for Sick children, Toronto, Ontario, Canada.

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

3Department 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: Comment by Sameh Soliman: The word limit for Reviews is 7,000 words (not including figures, tables or references).

Tables and Figures: Comment by Sameh Soliman: Figures and Tables: Up to 5 figures and 5 tables are permitted.

Keywords: Comment by Sameh Soliman: Keywords: A brief list of keywords, in alphabetical order, is required to assist indexers in cross-referencing. The keywords will encompass the therapeutic area, mechanism(s) of action, key compounds and so on.

AbstractComment by Sameh Soliman: Structured abstract (maximum 200 words): The aim of the abstract is to draw in the interested reader and provide an accurate reflection of the content of the paper. We therefore request the following structure is followed for full-length review articles:Introduction: Authors are required to describe the significance of the topic under discussion.Areas covered: Authors are required to describe the research discussed and the literature search undertaken.Expert commentary: The author’s expert view on the current status of the field under discussion.References must not be included in the abstract.

Introduction: The past several decades have seen vast advancements in the treatments paradigm for retinoblastoma., and the use of Focal laser therapy is certainly no exceptionconsistently a cornerstone for disease control, but techniques have not been extensively described. T While the first description of focal laser therapy for retinoblastoma dates towas over 6 decades ago, with technologies and approaches several improvements in protocols have occurred over the past two decades evolving with the intention to that have greatly improved our ability to achieve local tumor control. It was observed that the published literature is deficient regarding laser therapy techniques, types, mode of delivery and even its role in disease control.

Areas covered: In this review the physical and optical properties of lasers are briefly discussed, and the various mechanisms of action, delivery systems and potential complications, optical coherence tomography (OCT) guided treatment decisions and management of sub-clinical tumors are discussed. the literature search undertaken.????

Expert commentary:

Key issuesComment by Sameh Soliman: Key issuesAn executive summary of the authors’ main points (bulleted) is very useful for time-constrained readers requiring a rapidly accessible overview.

Introduction Comment by Sameh Soliman: Body of the article:Introduction: Incorporating basic background information on the area under review.Body: Body of the review paper covering the subject under review, using numbered subsections.Conclusion: The conclusion for all articles should contain a brief summary of the data presented in the article. Please note that this section is meant to be distinct from, and appear before the ‘Expert opinion’ section.

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 while still intraocular, while 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, with vision salvage a secondary goal. Salvage of an eye without visual potential may be a dangerous goal that can lead to unrecognized recurrence of the cancer, extraocular extension and loss of life.

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.[3, 4] 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.

Laser therapy for retinoblastoma is a topic rarely addressed in publications. Laser is rarely utilized as a primary therapy except in 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 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 Intravitreal chemotherapy (IViC) giving the reader the false impression of insignificant role of Laser.[5, 6] 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.[4, 7]

We now review the role of different lasers in management of retinoblastoma and describe OCT guided laser therapy to achieve precision in tumor control and visual outcome.

BodyPHYSICS 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.[8] In fact, The acronym LASER represents the underlying fundamental quantum-mechanical principals involved: Light Amplification by Stimulated Emission of Radiation.[9] 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.[9]Comment by Gallie Brenda: What is the correct format for refs?? Check carefully if the ref number comes before or after the .

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.[10] 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.

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.[11, 12] 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. Comment by Gallie Brenda: What else was there? None I know of…..

The commonest lasers used for focal therapy in retinoblastoma include are the green (532 nm) frequency doubled neodymium Nd: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 green 532 nm laser and 810 nm lasers can treat tumor by photocoagulation. Both 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.[10] Table 1 demonstrates the main differences between the different types of laser in retinoblastoma.

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).

3.1: Laser indirect ophthalmoscopy (LIO).

LIOIt was first described to treat retinoblastoma in 1992.[13] 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 because the laser beam focuses at some 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.[14] The retinal spot size can be calculated by (ppower of the condensing aspheric lens multiplied byx iImage plane spot size) divided by/ 60.[14] However, caution must be exercised as LBIO is less stable than other delivery systems due to inherent instability of the patient’s eye and the clinician’s head, particularly with simultaneous foot pedal depression.[14] The positional requirements and relatively long treatment durations associated with LBIO laser delivery contribute to higher prevalence of self-reported neck, hand, wrist and lower back pain amongst ophthalmologists.[15]Comment by Gallie Brenda: ???

3.2: Microscope-mounted delivery system.

This systemIt connects delivers the laser 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.[14] Tilting the contact lens within 15 degrees does not cause significant distortion of the laser spot, as irradiance differs by maximum 6.8%.[16] 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.[17, 18] It contains mirrors at 59, 67 and 73 degrees to aid in visualization of the periphery.[17] 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. Comment by Gallie Brenda: explain this?

Another commonly used contact lens is the Mainster wide-field (Power +61 D), which contains an aspheric lens in contact with the cornea and a convex lens at some fixed distance.[17, 18] 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.[16] 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.[16]

3.3: Trans-scleral laser therapy. (STEPHANIE)Comment by Gallie Brenda: Are there any current paper on this for retinoblastoma?We used to occasionally do this but not in many years.

Infra-red laser photocoagulation may also be delivered via a trans-scleral approach using a fiberoptic probe.[19, 20] This technique was first described for the treatment of retinoblastoma in 1998.[21] Direct visualization of a red laser 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 Celsius, without permanent damage to scleral collagen or increased risk of retinal tears.[22, 23] Given the precise nature of delivery and effective scleral transmission, trans-scleral diode is useful for treatment of anteriorly located retinoblastoma tumors and in the presence of media opacities. Trans-scleral diode also decreases the risk of cataract formation by limiting laser transmittance through the pupil.[21]

MECHANISMS OF LASER THERAPYAPPRAOCHES FOR RETINOBLASTOMA: 4.1. PHOTOCOAGULATION:

Photocoagulation is the process by which laser light energy is absorbed by a target tissue and converted into thermal energy. A 10-20 degree Celsius temperature rise induces protein denaturation and subsequent coagulation and necrosis, depending on the duration and extent of thermal change.[11] Heat generation is influenced by the laser parameters and optical properties of the absorbing tissue.[17] 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.[24]

Lasers in the visible electromagnetic spectrum, such as the 532 -nm frequency-doubled Nd:YAG, are largely absorbed by hemoglobin and melanin, approximately half in the RPE and half in the choroid.[17] Heat is then conducted to the neurosensory retina, causing inner retinal coagulation and focal increase in necrotic cellsnecrosis. This leads to loss of retinal transparency and the white laser response noted ophthalmoscopically. The 532 -nm laser also destroys the retinal blood supply 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.[17] Confluent laser burns encircling retinoblastoma tumors occlude large retinal blood vessels and other feeder vessels may require supplementary treatment.[13] Since the initial laser treatments cut off the tumor blood supply, This explains why it is preferred not to start photocoagulation is initiated only before after systemic or intra-arterial chemotherapy completionare completed to preserve the chemotherapy tumor-delivery uninterrupted.

Eyes with tumors less than 3 mm elevation may be successfully controlled by laser without chemotherapy. Larger tumors require first chemotherapy, followed by first laser In larger tumors, encircling photocoagulation to cut off blood supply and initiate tumor regression. On subsequent treatments, four to six weeks apart, laser photocoagulation will be applied directly to the tumor (Figure 2). Tumors that are too large for laser therapy only may not be controlled, and 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 Laser is preferred over encircling laser alone. (Figure 2) Comment by Sameh Soliman: Combined approachComment by Sameh Gaballah: FIGURE 1 include tumors with encircling photocoagulation. Leslie.Comment by Sameh Soliman: Combined approach

“Thermal blooming” is the process by which the photocoagulation zone may be extended beyond the laser spot size particularly with with longer duration burns.[17] 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.[24] Thus, repeated laser treatments on the same area will only increase the lateral extent of the laser application, known as the “shielding effect”. Laser photocoagulation ultimately replaces the tumor with leads to scarring, gliosis and variable RPE retinal pigment eplithelial hyperplasia.Comment by Gallie Brenda: Reference????

4.2. 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 treatment 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.[17] 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 exceeds that forthe 810 nm diode and 532 nm lasers, which is important when considering treatment of thicker tumors.[25] Resultant temperatures (45 to 60 oC) rises are lower than for classic photocoagulation (45 to 60 degrees Celsius).[26] 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, dependent on fundus pigmentation and laser parameters.[17, 26] This is dependent on fundus pigmentation and laser parameters. Comment by Gallie Brenda: check the ref style: if superscript will be after the punctuation, if number in brackets will ve before the punctuation

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. ADDIN EN.CITE ADDIN EN.CITE.DATA [27-29]Pretreatment with intravenous indocyanine green (ICG), a chromophore with absorption peak 805 nm, complementing the diode laser emission of 810 nm, results in photosensitization and a dose-dependent decrease in the TTT fluence threshold and irradiance required for treatment.[27] Enhancement of the effect with systemic ICG may lead to regression of tumors that have shown a suboptimal response to systemic chemotherapy and standard TTT.[28-30] The optimal timing between ICG and TTT has not been full elucidated.

(FA and ICG enhanced TTT, STEPHANIE)

Complications of TTT reported following treatment of retinoblastoma include chorioretinal scarring with focal scleral bowing.[23] Comment by Gallie Brenda: more papers on the dragging of retina and shifting of scara?

4.3 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.[7] Unfortunately, there is no randomized clinical trial that compared laser mechanisms to set evidence to use any.[31] Comment by Sameh Soliman: ADD our sequential and the Pakistani paper here

COMPLICATIONS OF LASER THERAPY:

The most serious complications caused by laser therapy are often caused by use of excessive energy, and as such, starting your treatment at a lower power and titrating to the desired effect decreases the likelihood of complications. In cases where too small a spot size, too high a power or too short a duration is used, an iatrogenic rupture of Bruchs’ membrane may occur. This might act as precursor for choroidal neovascular membrane formation. Additionally, intense photocoagulation may result in full thickness retinal holes which may progress to rhegmatogenous retinal detachment. In retinoblastoma, this can result in vitreous seeding.[32] OCT can help in visualizing and following these complications.

Although rare, biopsy-proven orbital recurrence of retinoblastoma has been reported following successful treatment of a macular recurrence with aggressive argon and diode laser.[33] 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.[33]Comment by Sameh Soliman: Brenda, do you want to include a figure regarding SMW?

Additional complications can include focal iris atrophy, lenticular opacification, retinal traction, retinal vascular obstruction and localized serous retinal detachment.[32, 34] Additionally, scars from TTT (810 nm) have been shown to increase in size after treatment for retinoblastomaretinoblastoma [35] and as such, one must be cautious in using this laser for tumors located near the fovea and optic nerve. Other complications of TTT reported following treatment of retinoblastoma include chorioretinal scarring with focal scleral bowing.[36]

Laser should be avoided over areas with retinal detachment whether high or shallow. OCT can help diagnose subtle detachments. Laser over the optic nerve can compromise nerve fiber vitality and should be avoided. The exact tumor relation to the optic nerve can be mapped by OCT and is thus considered during treatment planning.

PUBLISHED EVIDENCE ON LASER IN RETINOBLASTOMA:

Meyer-Schwickerath reported the results first introduced the idea of xenon photocoagulation into the management paradigm for retinoblastoma in 1955 and subsequently reported their results in 1964. [37] Although laser therapy for retinoblastoma has been used for several decades[37, 38] it wasn’t until the 1980’s and 1990’s that the role for focal laser therapy in the management of retinoblastoma became widely popularized.[39] In 1982 Lagendijk used trans-pupillary thermotherapy (TTT) in two cases of recurrent retinoblastoma successfully.[40] 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.[41] Other groups similarly concluded that while chemoreduction alone may not be adequate at achieving complete tumor control, chemoreduction in combination with adjuvant treatment (including laser photocoagulation, thermotherapy, cryotherapy and radiation) resulted in good retinal tumor control, even in eyes with advanced disease.[42]

As the use of laser therapy in the management of retinoblastoma gained traction, 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.[43] In fact, in a series of 103 tumors treated with chemothermotherapy, Lumbroso et al[44] reported that tumor regression was seen in 96.1%. ADDIN EN.CITE Lumbroso20024690[46]4690469017Lumbroso, L.Doz, F.Urbieta, M.Levy, C.Bours, D.Asselain, B.Vedrenne, J.Zucker, J. M.Desjardins, L.Department of Ophthalmology, Institut Curie, Paris, France.Chemothermotherapy in the management of retinoblastomaOphthalmologyOphthalmology1130-61096Antineoplastic Agents/*therapeutic useCarboplatin/*therapeutic useChild, PreschoolCombined Modality TherapyFemaleFollow-Up StudiesHumanHyperthermia, Induced/*methodsInfantInfant, NewbornMaleRemission InductionRetinal Neoplasms/pathology/*therapyRetinoblastoma/pathology/*therapySalvage TherapyTreatment Outcome2002Jun12045055http://www.aaojournal.org/cgi/content/full/109/6/1130http://www.aaojournal.org/cgi/content/abstract/109/6/1130http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12045055[46] In this study, TTT was delivered shortly after an intravenous injection of carboplatin.

Predictors for success of focal laser photocoagulation and thermotherapy have also been identified. 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.[26] Alternative laser techniques have also been described, including the use of the 532-nm laser which has been shown to effectively treat small (<2mm in height, <4 disc diameter) tumors. [32] Depending on the tumor location, the clinician may prefer one laser type over the other. For instance, while TTT using the 810-nm diode laser is effective, the scar that is created can increase in size after treatment [35] and therefore when applying laser near vital macular structures some prefer laser photocoagulation (532-nm laser). Similarly, trans-scleral diode laser may be the preferred modality for small anteriorly located retinoblastomas.[21] Although a variety of potential complications as discussed above have been noted, the majority of these can be avoided by using the minimal effective laser power.[32] It is important to note however that despite the use of laser focal therapy being a mainstay in the treatment of retinoblastoma, there have been no randomized controlled trials evaluating the effect of systemic chemotherapy with versus without laser therapy for post-equatorial retinoblastoma.[31]

NEW PAPERS ON LASER AND VISUAL OUTCOME: (KELSEY)Comment by Sameh Soliman: Fabian, Am J Ophthalmol. 2017 Jul;179:137-144.

OPTICAL COHERENCE TOMOGRAPHY (OCT) IN RETINOBLASTOMA:

OCT was introduced to retinoblastoma in the early 2000s. The first few reports focused on describing how retinoblastoma appears and how to differentiate it from other simulating tumors.[45, 46] Introduction of hand held OCT helped examining supine children under anesthetic allowing imaging of more retinoblastoma tumors at different phases of their active treatment from diagnosis to stability.[47, 48] This allowed visualization of a multitude of situations that can affect and guide laser therapy as subclinical invisible tumors,[49, 50] subclinical tumor recurrences either within a previous scar or edge recurrences,[7] topographic localization of foveal center,[7, 51] differentiating whitish lesions such as gliosis and perivascular sheathing from active retinoblastoma and possible optic nerve involvement.[52] OCT can demonstrate tumor location within the retina whether superficial, deep or diffuse infiltrating retinoblastoma.[7] OCT can visualize tumor seeds either vitreous or subretinal.[7, 53] It can also determine the internal architecture of retinoblastoma whether solid or cavitary[54] that might affect the therapy approach (Figure 2X). Despite very difficult, OCT can be used to examine the mid periphery but highly dependent on the expertise of the photography specialist.[7] Comment by Sameh Gaballah: Include an image of every point mentioned in the paragraph.

OCT has crucially influenced our management decisions in retinoblastoma management. In a recent research, the role of OCT in each examination under anesthetic (EUA) session for a child with retinoblastoma was retrospectively classified into directive (direct diagnosis, treatment or follow up) and academic sessions. Directive OCTs was found in 94% (293/312) OCT sessions. Directive OCTs were further classified into confirmatory (if they confirm the pre-OCT clinical decision) or influential (if they influence changing the pre-OCT clinical decision). It was found that 17% of directive OCTs were influential highlighting the importance of OCT in the 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.

68.1. INVISIBLE TUMORS:

Invisible tumors can be anticipated in children with positive RB1 variant either detected prenatal or postnatal, positive parental family history of retinoblastoma or a child with other clinical tumors (in H1 children). The ideal procedure to screen for invisible tumors is OCT mapping of the posterior pole especially in the first 6 months of age. Once detected, the subclinical tumor should be centralized in the OCT scan. Calipers and anatomic landmarks especially vessels and its branching can be used to help locating the invisible tumor in the retinal image. Photocoagulation with low laser power (100 mW) and short pulse duration (0.5 seconds) is delivered, to gradually increase power until whitening is noted. Post laser OCT can verify treatment where the tumor swells with increase reflectiveness and back shadowing. (Figure 3) Comment by Sameh Soliman: VV images (leslie)

68.2. JUXTAFOVEAL TUMORS:

Tumors around the fovea are a treatment challenge to preserve the foveal center. Classical laser treatment will eventually destroy the fovea as the resultant scar is usually greater than the tumor size. OCT localizesOCT localizes the foveal center by obtaining two OCT macular cube scans (vertical and horizontal) to precisely determine the foveal location, to avoidto avoid laser application to this critical area. Photocoagulation is superior to TTT in posterior pole tumors to preserve vision and avoid scar migration. Recently an OCT guided sequential laser crescent photocoagulation method was described for juxtafoveal tumors avoiding the fovea. The antifoveal tumor crescent is photocoagulated using 532 nm laser to obliterate the blood supply to the tumor. This will flatten the tumor center that will be treated in sequential sessions. Additionally, the peripheral scarring causes a tangential anti-foveal force pulling tumor away from the fovea. (Figure 3) This technique was described to have better anatomical and visual outcome in juxtafoveal tumors where the fovea is OCT detectable at initial laser session. Furthermore, OCT can detect subtle surrounding exudative retinal detachment that might stop us from initiating laser treatment. Comment by Gallie Brenda: Ref???Fabian paper

68.3: RECURRENT AND RESIDUAL TUMORS:

OCT can detect subclinical tumor edge recurrences. OCT can differentiate between tumor calcification and homogenous potential active tumor. Comparison between successive OCT scans of the same area can detect subtle tumor recurrence. (Figure 4) This potentiate less treatment burden regarding laser power, number of sessions and final outcome. Recurrences on flat retina are usually treated with photocoagulation with 532 nm laser. However, recurrences over calcified tumor require longer wavelength photocoagulation and even TTT.

Whitish treatment scars previously posed a clinical challenge to determine whether it is a tumor residual, recurrence or a fibrosis. This was usually managed either by more laser treatment with the possibility of more scarring and traction or observation with the potential danger of tumor growth requiring more 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.

68.4. PRE-EQUATORIAL TUMORS:

Pre-equatorial tumors can be treated by either photocoagulation or cryotherapy. Laser therapy is usually preferred in superior tumors to avoid potential cryotherapy associated uveal effusion and exudative detachment. Flat pre-equatorial tumors are usually treated with 532 nm laser photocoagulation for one or two sessions. More elevated tumors might require multiple laser treatments as the tumor cannot be treated equally as the inward curve of the tumor cannot be thoroughly painted with trans-pupillary laser. In subsequent sessions with more outward flattening of the tumor, the inward curve can be better visualized and treated.

Despite challenging, peripheral OCT can assess tumor elevation, differentiate scarring from residual tumors and identify peripheral potential tumor seeding (Figure 5). In certain tumors, laser can be utilized as an initial belt like treatment surrounding the tumor as a preparatory step prior to cryotherapy or plaque radiotherapy. Peripheral laser can be also used for potential ischemic retina peripheral to an extensive tumor scar to prevent development of neovascularization and probable subsequent vitreous hemorrhage. As a general rule, a smaller spot size is required in peripheral lesions to prevent iris injury. Comment by Sameh Soliman: Discuss with Brenda. ?? AD

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 tumor control after initial chemotherapy size reduction. In spite of this fact, Laser was never properly studied in a randomized controlled fashion to set evidence. Introduction of OCT improved tumor visualization and assessment improving our laser strategies and minimizing complications.

Expert CommentaryComment by Sameh Soliman: Expert Commentary: 500-1000 words (included in overall word count).To distinguish the articles published in the Expert Review series, authors must provide an additional section entitled ‘Expert Commentary’. This section affords authors the opportunity to provide their interpretation of the data presented in the article and discuss the developments that are likely to be important in the future, and the avenues of research likely to become exciting as further studies yield more detailed results. The intention is to go beyond a conclusion and should not simply summarise the paper. Authors should answer the following:What are the key weaknesses in clinical management so far?What potential does further research hold? What is the ultimate goal in this field?What research or knowledge is needed to achieve this goal and what is the biggest challenge in this goal being achieved?Is there any particular area of the research you are finding of interest at present?Please note that ‘opinions’ are encouraged in the Expert commentary section, and, as such, referees are asked to keep this in mind when peer reviewing the manuscript.

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

Five year viewComment by Sameh Soliman: Five-year viewAuthors are challenged to include a speculative viewpoint on how the field will have evolved five years from the point at which the review was written.

There is huge advance in imaging technology that will allow incorporation of fundus imaging and OCT. the incorporation of Laser therapy within this machine is expected to follow to facilitate better aiming and improve the reproducibility of Laser techniques.

ReferencesComment by Sameh Soliman: References: A maximum of 100 references is suggested. Ensure that all key work relevant to the topic under discussion is cited in the text and listed in the bibliography. Reference to unpublished data should be kept to a minimum and authors must obtain a signed letter of permission from cited persons to use unpublished results or personal communications in the manuscript.Annotated bibliography: Important references should be highlighted with a one/two star system and brief annotations should be given (see the journal’s Instructions for Authors page for examples and for a more detailed description of our referencing style).

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Table 1: Comparison between lasers in retinoblastoma.

Type of laser

Green

532nm

Diode

810nm

Continuous wave 1064nm

Frequency-doubled Nd-YAG

Solid State

Semi-conductor

Nd-YAG

Solid State

Common delivery method

Indirect

Indirect or transcleral

Indirect

Mechanism of action

Retinal photocoagulation 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 penetration

Superficial: limited by the resultant coagulation [32] and by nature of shorter wavelength. Estimated to penetrate ~2 mm in non-pigmented tumors such as retinoblastoma.[10]

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. Penetration depth decreases in necrotic tumors.[10]

Parameters

Power: 0.3 – 0.8 W

Duration: 0.3-0.4 seconds

Power: 0.3-1.5 W

Duration: 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[32]

Slight graying of retina without causing vascular spasm [26, 34]

Table 2. Types of contact and non-contact fundus lenses [13, 16, 17]

Lens Type

Image Magnification

Laser Spot Magnification

Static Field of View (°)

Dynamic Field of View (°)

Contact or Non-contact

Image Characteristics

Goldmann 3-Mirror Universal

0.93X

1.08X

36

74

(with 15° tilt)

Contact

Virtual, erect image located near posterior lens capsule

Ocular Mainster Wide Field

0.67X

1.50X

118

127

Contact

Real, inverted image in air

20 D BIO

3.13X

0.32X

46

60

Non-contact

Real, inverted, laterally reversed

Pan-retinal 2.2 BIO

2.68X

0.37X

56

73

Non-contact

Real, inverted, laterally reversed

28 D BIO

2.27X

0.44X

53

69

Non-contact

Real, inverted, laterally reversed

D= Diopter; BIO= Binocular indirect ophthalmoscopy