Search

Background: This study aimed to identify best practices for treating 13q deletion syndrome (13q-) patients with retinoblastoma in the era of super-selective ophthalmic artery chemosurgery (OAC) and intravitreal injection therapy (IVIT)., Methods: Retrospective study of 21 eyes from 14 patients with retinoblastoma and 13q- who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between May 2006 and May 2020, with a mean follow up of 3.7 years. Ocular survival, patient survival, and treatment toxicities were assessed., Results: Nine of the 12 eyes that underwent OAC/IVIT at MSKCC have been progression free for at least 1 year since their last treatments. Fifteen out of 26 OAC cycles resulted in grade 3-4 hematologic toxicity. There was one death from sepsis in the setting of intravenous chemotherapy (IVC) for metastatic disease that occurred after OAC/IVIT therapy. The 2-year Kaplan-Meier ocular survival estimate for the whole cohort was 75% and for the eyes that received OAC or IVIT at MSKCC 83%. For OAC hematologic toxicities, one platelet transfusion and two filgrastim doses were administered, and one patient was hospitalized for neutropenic fevers., Conclusions: The majority of 13q- eyes treated with OAC/IVIT-based regimens can be cured, and there were no deaths related to complications from OAC or IVIT. 13q- Patients did have increased risk of systemic treatment complications, even from super-selective chemotherapies. Despite these toxicities, only one patient developed febrile neutropenia, one patient required a blood product transfusion, and two patients received filgrastim for both OAC and IVC complications. PRÉCIS: Children with 13q deletion syndrome with retinoblastoma managed with intra-arterial and intravitreal chemotherapy have excellent patient and ocular survival with acceptable toxicity., (© 2020 Wiley Periodicals LLC.)

A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core ( p < 0.05). Importantly, topotecan penetration correlated with its cytotoxic activity. Therefore, the studied tridimensional cell model recapitulated several characteristics of vitreous seeds observed in patients with retinoblastoma and were successfully used to assess live-cell imaging of chemotherapy penetration for drug distribution studies.

Purpose: To evaluate the management and outcomes of naïve bilateral retinoblastoma treated at a single-center over a 5-year period during the era of ophthalmic artery chemosurgery (OAC) and intravitreous chemotherapy., Methods: Retrospective cohort study of 46 patients (92 eyes) with naïve bilateral retinoblastoma treated at Memorial Sloan Kettering Cancer Center between January 2012 and February 2017. Indirect ophthalmoscopy, fundus photography, ultrasonography, and ultrasonic biomicroscopy were used to evaluate clinical response. Patient, ocular, ocular progression-free, ocular recurrent event-free, and second ocular survivals were assessed by Kaplan-Meier estimates. Retinal toxicity was evaluated by electroretinography. Snellen visual acuity and complete blood count metrics were recorded., Results: Sixty-four eyes (70%) in 41 patients (89%) received ophthalmic artery chemosurgery as part of their treatment. Twenty-six patients (56%) received tandem OAC (bilateral simultaneous infusions). Seven eyes were primarily enucleated. No eye receiving initial OAC was enucleated. There was a single secondary enucleation in an eye initially treated with focal therapy with anterior chamber recurrence. The 3-year Kaplan-Meier estimates for overall ocular, secondary ocular (survival after treatment for recurrence), progression-free, and recurrent event-free survival were 91.3% [95% confidence interval (CI) 83.4-95.5], 98.7% (95% CI 91.3-99.8), 91.5% (95% CI 83.0-95.8), and 78.9% (95% CI 68.2-86.3), respectively. Overall and secondary ocular survivals were 100% for International Classification of Retinoblastoma (ICRB) groups A-C. Overall ocular survival was 91.5% (95% CI 70-97.8) for ICRB group D and 71.4% (95% CI 47.1-79.4) for group E. Secondary ocular survival was 95.4% (95% CI 71.8-99.3) for ICRB group D and 100% for group E. There were no treatment-related deaths, three patients developed trilateral retinoblastoma (one died), and one patient (who did not receive OAC) developed metastatic disease and is in remission at 32-month follow-up., Conclusion: The majority (89%) of bilateral retinoblastoma patients in the current era and at this center were treated with OAC. This has resulted in saving a historic number of eyes. A quarter of eyes developed recurrent disease (defined as recurrent disease requiring any treatment including focal), the majority of which occurred in the first year after treatment, and all but one was saved. There has been no compromise in patient survival., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There has been no effective method for treating newly visible ("new") subretinal seeding in retinoblastoma except enucleation. The objective of this report is to determine whether intravitreal chemotherapy combined with 810 nm indirect laser can successfully treat retinoblastoma eyes with "new" subretinal seeding which appeared after intra-arterial chemotherapy (ophthalmic arterial chemosurgery: OAC)., Material and Methods: Single center retrospective study from a tertiary cancer hospital of a case series of 14 eyes treated with combined intravitreal chemotherapy and laser from 2012 to 2017. Ocular salvage, patient survival, recurrence-free ocular survival, metastases, and extraocular extension were assessed., Results: A total of 14 eyes in 13 unilateral or bilateral retinoblastoma patients with "new" subretinal seeding after initial eye salvage therapy were treated with combined intravitreal injection of melphalan (30 ug) or melphalan (30 ug) and topotecan (20 ug) and with 810 nm indirect continuous wave laser. All eyes were salvaged. Only two eyes (14%) recurred again for subretinal seeds after 6 and 8 months, respectively, and required additional cycles of intravitreal injections and laser. Combined intravitreal injection of melphalan or melphalan plus topotecan with 810 nm indirect continuous wave laser was not associated with any metastatic events, patient deaths, extraocular extension, or need for enucleation., Conclusion: There has been no effective treatment for "new" subretinal seeding after OAC except enucleation or second course OAC. Combined intravitreal chemotherapy with 810 nm indirect laser may be an effective and safe alternative to enucleation.

Purpose: To report associations between disease- and treatment-related variables and rates of recurrence-free survival and ocular survival in eyes treated with ophthalmic artery chemosurgery (OAC) for retinoblastoma., Design: Pre-post study., Subjects: All eyes treated with OAC for retinoblastoma at Memorial Sloan Kettering Cancer Center between May 2006 and February 2017., Methods: This retrospective review included 452 retinoblastoma eyes treated with OAC. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), progression-free survival (PFS) and ocular survival (OcS), and Cox regression was used to estimate hazard ratios. Eyes treated in the pre-intravitreous chemotherapy era were analyzed separately from eyes treated in the intravitreal era., Main Outcome Measures: Recurrence-free survival, ocular survival, associations with risk of recurrence., Results: Disease and treatment characteristics were recorded over a median 23.6 month follow-up. One-year OcS, PFS and RFS were 96% (95% CI 93-99%), 88% (95% CI 88-94%) and 74% (95% CI 67-81%) in the pre-intravitreal era and 96% (95% CI 94-99%), 93% (95% CI 89-96%) and 78% (95% CI 72-83%) in the intravitreal era, respectively. Presence of vitreous seeds was associated with increased risk of recurrence in the pre-intravitreal era but not in the intravitreal era. Longer time interval between OAC sessions was associated with increased risk of recurrence and majority OAC access via the ophthalmic artery was associated with decreased risk of recurrence in both eras., Conclusions: Approximately a quarter of eyes initially treated with ophthalmic artery chemosurgery develop recurrent disease, with the majority of recurrences within the first year following completion of OAC. Despite this, these eyes have a very good chance of salvage. In eyes with vitreous seeds at presentation, intravitreal injections are useful in minimizing future vitreous recurrence. Eyes that receive the majority of drug infusions via non-ophthalmic artery routes or greater interval between OAC are more likely to recur and might warrant closer monitoring., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC)., Patients and Methods: Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases., Results: 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 μV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases., Conclusion: OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.

Background/aims: Survivors of retinoblastoma carry a lifetime risk of secondary malignancies. It is well established that external beam radiation increases this risk; however, the risk with ophthalmic artery chemosurgery (OAC) remains unknown. We report on 10 years of experience with OAC and the rate of second primary malignancy (SPM) development., Methods: This is a single-centre retrospective review approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board of all patients who received OAC over a 10-year period, from May 2006 to November 2016. The second tumour incidence and survival in patients with germline disease (bilateral and unilateral with family history or confirmed germline mutation) was estimated using the Kaplan-Meier method. Patients who received external beam radiotherapy were excluded from analyses., Results: Two hundred and thirty-three patients with heritable retinoblastoma who received OAC were analysed. Nineteen patients were excluded for having received external beam radiation. The Kaplan-Meier estimate of the likelihood for SPM development was 2.7% at 5 years (95% CI 0 to 25). All of the SPMs were pineoblastomas and all patients had bilateral disease in this cohort., Conclusions: In our 10-year experience, we have found that SPM development in patients with germline retinoblastoma treated with OAC alone is comparable to previously published rates. In the first 10 years, OAC did not increase the known incidence of SPMs. This cohort will continue to be followed to establish the rate of development with extended follow-up., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Importance: The risk of extraocular extension from injecting chemotherapy into eyes with retinoblastoma is minimally understood; however, understanding this risk is important because of the increasing use of intravitreous chemotherapy., Objective: To evaluate the risk of extraocular extension in eyes with retinoblastoma that have received intravitreous chemotherapy injections., Design, Setting, and Participants: This retrospective cohort study was performed in 655 patients at 10 retinoblastoma centers in North and South American, European, Israeli, and Chinese centers. Physicians at the retinoblastoma centers administered more than 120 intravitreous chemotherapy injections in eyes with retinoblastoma from February 1, 1999, through February 28, 2017., Main Outcomes and Measures: Risk of extraocular extension with secondary observational variables, including injection and precautionary techniques., Results: A total of 3553 intravitreous chemotherapy injections (3201 melphalan hydrochloride, 335 topotecan hydrochloride, and 17 methotrexate sodium) were administered to 704 eyes in 655 patients with retinoblastoma (mean [SD] age of patients at the time of the initial injections, 31.6 [11.6] months; 348 male [53.1%]). There were no extraocular tumor events related to prior intravitreous injections. This finding resulted in a calculated proportion of zero extraocular events per eye. According to the rule of 3, the risk is no greater than 0.08% injections. All 10 centers included in this study used at least 2 presumed precautionary injection methods (lowering of intraocular pressure, cryotherapy, ocular surface irrigation, ultrasonic biomicroscopy surveillance of the injection site, and subconjunctival chemotherapy deposition)., Conclusions and Relevance: With use of at least 2 presumed precautionary safety methods, no extraocular extension of tumor events occurred. According to the rule of 3, this finding suggests that the risk is no greater than 0.08% injections.

Purpose: To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors., Participants: A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT)., Design: Single-center, retrospective cohort study., Methods: Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point., Main Outcome Measures: Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation., Results: The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001)., Conclusion: The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate fluoroscopic time and radiation dose parameters, and factors affecting these parameters, during selective ophthalmic artery chemosurgery (SOAC) for retinoblastoma., Materials and Methods: Retrospective review from the prospective database of all patients with retinoblastoma treated with SOAC over a 5-year period (September 2009-January 2015) at a single institution after receiving institutional review board approval. Patient demographics, arterial approach, access device, side of treatment, number of SOAC cycles/patient, number of drugs/SOAC, and radiation parameters (outcome variables), including the fluoroscopic time, dose-area product (DAP), and total radiation dose, were obtained from the database. Generalized linear regression was used for univariate and multivariate analysis of the outcome variables., Results: In 218 patients (M:F=94:124), 272 eyes were treated by 833 SOAC infusions during 792 procedures. Mean age, weight, SOAC cycle/patient, and drugs/cycle were 19±19.5 months, 11.4±6.4 kg, 2.72±1.6, and 2.48±0.8, respectively. Mean fluoroscopic time, DAP, and doses were 10.2±8.4 min, 218.7±240.8 cGy.cm 2 , and 42.3±41.4 mGy, respectively. Radiation parameters (fluoroscopic time, DAP, and dose) were significantly lower (p<0.001) for the ophthalmic artery (OA) approach (7.5±5.4; 147.7±138.4; 28.5±29.4) than with middle meningeal artery (13.4±5.6; 242±138; 51.4±27) and balloon-assisted infusion in the internal carotid artery (ICA; 17.8±11.5; 449.8±361; 81.8±63.3). Radiation parameters for microcatheter access (8.6±7.1; 193.4±181.3; 42.3±37) were significantly lower (p<0.001) than with the ICA (17.8±11.5; 449.8±361; 81.8±63.3). Radiation parameters for bilateral IA chemotherapy (IAC; 16.8±11.6; 320.7±268.7; 60.8±45.6) were significantly higher (p<0.001) than for unilateral IAC (8.9±6.6; 212.7±247; 42±41)., Conclusions: In SOAC for retinoblastoma, the OA approach, microcatheter access, and unilateral treatment were associated with significantly lower radiation parameters. We established benchmark radiation parameters for retinoblastoma SOAC in our patient cohort., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Aim: To report retinal function outcomes after ophthalmic artery chemosurgery (OAC) for advanced retinoblastoma (RB) in eyes with minimal pretreatment retinal function., Methods: For 72 advanced RB eyes with baseline electroretinograms (ERGs) indistinguishable from noise ('extinguished') or flicker ERG amplitudes <25 µV ('poor'), ERGs were obtained before OAC and at 3 months, 1 year and 2 years after OAC. Presence of baseline retinal detachments (RDs) and their subsequent resolution or persistence was also noted., Results: At 3 months, 1 year and 2 years post-OAC, 'extinguished' eyes showed 9/15, 4/11 and 2/6 detectable ERGs, respectively, and 'poor' eyes showed 19/55, 14/30 and 8/18 ERGs exceeding 25 μV, respectively. Correlations between baseline and post-OAC ERGs were poor; however, good correlation (R 2 ) existed between ERGs post-OAC at 3 months and 1 year (0.749), at 3 months and 2 years (0.773) and at 1 year and 2 years (0.771). Overall, 49/70 eyes presented with RD; 29 RDs resolved 3 months post-OAC, with an average ERG change of +20.6 μV. Eyes with persistent RD had an average ERG change of -2.2 μV. No eyes underwent ≥25 μV change without RD resolution., Conclusions: Minimal baseline ERGs do not preclude significant recovery of retinal function after OAC. Good correlation exists between ERG outcomes at 3 months and those at subsequent follow-ups, suggesting that ERG amplitudes at 3-month post-OAC can prognosticate longer term retinal function, and that improvement is durable. For eyes presenting with RD, RD resolution is necessary but not sufficient for significant (≥25 μV) increases in ERG amplitudes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Purpose: To report globe salvage rates, patient survival and adverse events of ophthalmic artery chemosurgery (OAC) for International Classification of Retinoblastoma (ICRB) group D retinoblastoma (naive and after prior failures)., Methods: Single institution retrospective review of all Group D eyes treated with OAC from 5/2006-12/2012. Patients were treated according to our previously-published techniques. Primary outcome was globe retention without need for external beam radiotherapy (EBRT). Demographics, prior treatments, OAC agents used, and adverse events were also recorded., Results: 112 group D eyes (103 patients) that underwent OAC were included (average follow-up was 34 months, range: 2-110 months). 47 eyes were treatment-naïve, 58 eyes received prior treatments elsewhere, and 7 young infants (7 eyes) underwent our published "bridge therapy" (single agent intravenous carboplatin) until old enough to undergo OAC. Median number of OAC sessions/eye was 3 (range 1-9). 110/112 eyes received intra-arterial melphalan, but only 31 eyes received melphalan alone. 43 eyes received carboplatin, and 78 eyes received topotecan (never as a single agent). 80/112 eyes received >1 drug over their treatment course, and 39 eyes received all three agents. 24 eyes (16 pretreated, 7 treatment-naïve, 1 bridge) failed treatment and required enucleation during the study period. Enucleation and EBRT were avoided in 88/112 eyes (78.6%; including 40/47 [85.1%] treatment-naïve eyes, 42/58 [72.4%] previously-treated eyes, and 6/7 eyes [85.7%] among bridge patients). By Kaplan-Meier survival analysis, globe salvage rate was 74% at 110 months among all patients, and 85% at 110 months in the treatment-naïve subgroup. Transient grade 3/4 neutropenia was more common in patients receiving OAC bilaterally. No child died of metastatic disease., Conclusions: OAC is effective for curing group D retinoblastoma, achieving rates of globe salvage many times higher than systemic chemotherapy (10-47%), even in eyes that previously failed other treatments. OAC can be performed multiple times, using multiple agents, on one or both eyes of patients.

Purpose: To review reported retinal side effects from current cancer therapy drugs., Methods: Retinal toxicities from ophthalmologic or oncologic case reports, case series, and clinical trials were identified by a systematic literature search using Lexicomp and PubMed., Results: Four biologics, 8 small molecule inhibitors, and 17 traditional chemotherapy agents had reported retinal side effects. For biologics, interferon alpha 2b was associated with retinopathy, denileukin diftitiox with pigmentary retinopathy, ipilimumab with a Vogt-Koyanagi-Harada-like syndrome, and trastuzumab with retinal ischemia. For small molecule inhibitors, v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors were associated with uveitis, mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitors with pigment epithelium detachments, and tyrosine kinase inhibitors with macular edema. Steroid antagonists were associated with crystalline retinopathy and macular edema. Nitrosoureas, platinum analogs, and cytosine arabinoside were associated with retinal vascular occlusions. Antimicrotubular agents were associated with cystoid macular edema but without fluorescein leakage. Retinoic acid derivatives were associated with impaired night vision, and mitotane was associated with a pigmentary retinopathy and papilledema., Conclusion: Certain agents used in the treatment of systemic cancer are associated with ocular complications. Awareness of these complications will allow early detections and maybe reversal of some of the ocular problems.

Purpose: Review our experience in the use of indocyanine green (ICG) enhanced transpupillary thermotherapy (TTT) in combination with ophthalmic artery chemosurgery for retinoblastomas unresponsive to standard TTT., Methods: Single centre, retrospective study of 16 eyes in 13 retinoblastoma patients treated with TTT and ICG via indirect ophthalmoscope: 23 treatments of 16 eyes, with a mean follow-up of 12.1 months (range 3-35 months). Outcome measures included tumour response and electroretinogram., Results: Treatment resulted in significant tumour regression in all eyes: 13 eyes with well-differentiated characteristics, 2 with implanting vitreous seeds and 1 eye refractory to traditional TTT. ERG function was retained in all eyes., Conclusions: ICG-enhanced TTT with ophthalmic artery chemosurgery can effectively treat retinoblastoma refractory to conventional focal treatments without deleterious ocular side effects.

For many cancers, the lack of potency and the toxicity of current drugs limits the dose achievable in patients and the efficacy of treatment. Among them, retinoblastoma is a rare cancer of the eye for which better chemotherapeutic options are needed. Combination therapy is a compelling approach to enhance the efficacy of current treatment, however clinical trials to test rationally designed combinations of approved drugs are slow and expensive, and limited by our lack of in-depth knowledge of drug specificity. Since many patients already turn to nutraceuticals in hopes of improving their condition, we hypothesized that certain approved drugs could potentially synergize with widely consumed supplements. Following this hypothesis, we devised an alternative screening strategy aimed at taking advantage of a bait compound such as a nutraceutical with potential therapeutic benefits but low potency, by screening chemical libraries for approved drugs that synergize with this companion effector. As a proof of concept, we sought to identify approved drugs with synergetic therapeutic effects toward retinoblastoma cells in combination with the antioxidant resveratrol, popular as a supplement. We systematically tested FDA-approved drugs and known bioactives seeking to identify such pairs, which led to uncovering only a few additive combinations; but to our surprise, we identified a class of anticancer drugs widely used in the clinic whose therapeutic effect is antagonized with resveratrol. Our observations could explain in part why some patients do not respond well to treatment. Our results validate this alternative approach, and we expect that our companion effector strategy could significantly impact both drug discovery and the nutraceutical industry.

Aim: To report the experience of the authors with efficacy and toxicity of periocular chemotherapy over a 12-year period., Methods: 102 periocular injections of 2 cc (10 mg of carboplatin/1 cc) were given every 4-6 weeks in 33 eyes of 29 patients. Patient's data were reviewed retrospectively., Results: Thirty-three eyes were followed for 7-148 months following initiation of periocular injections, and 13 (39%) have avoided enucleation. There were two cases of second malignancy resulting in one death and one survivor, two survivors of metastatic disease, and two survivors of orbital recurrence. Twenty eyes were enucleated for disease progression at a mean time of 15 months postinitiation of periocular carboplatin (POC). The Kaplan-Meier estimate of eye survival at 36 months is 36%. Eleven of the 13 salvaged eyes received concurrent treatment with chemotherapy (n=4, 30%), external beam radiation and chemotherapy in (n=6, 46%), or brachytherapy (n=1, 8%). Two of the salvaged eyes (16%) were treated with POC alone. Orbital swelling occurred in 14/33 (42%) eyes. There were no symptomatic motility disorders. One severe toxicity reaction resulted in acute loss of vision, down to light perception, which failed to recover and one eye had progression of optic nerve pallor., Conclusions: This paper demonstrates that POC has limited short-term and long-term systemic toxicity and most of the ocular complications were acute, not delayed. Only two select cases showed long-term complete responses to POC alone and the data do not support the use as monotherapy, although where it was used in combination with other modalities, 39% of the eyes were saved.

Background/aims: We have previously introduced electroretinography (ERG) as a proxy for visual function to monitor for retinal toxicity due to intra-arterial chemotherapy for retinoblastoma in young children. In this paper, we report ERG results for patients with retinoblastoma receiving initial treatment with systemic chemotherapy., Methods: Inclusion criteria were patients presenting with retinoblastoma at <3 months of age or <6.0 kg in weight, with large tumours not amenable to local laser treatment, cryotherapy or plaque brachytherapy. Patients received intravenous carboplatin 18.7 mg/kg every 3-5 weeks, contingent on recovery of blood counts, until they had grown sufficiently to receive intra-arterial chemotherapy. ERG was performed during examination under anaesthesia at monthly intervals, using contact lens electrodes and a hand-held ganzfeld stimulator. 30-Hertz flicker responses are reported., Results: Four patients were treated for bilateral retinoblastoma. All eyes responded well to systemic chemotherapy. 30-Hertz flicker ERGs improved during treatment in all eyes, significantly in six of eight eyes, and at least in one eye of each patient., Conclusion: Effective systemic chemotherapy for retinoblastoma in children who are too small for intra-arterial chemotherapy is compatible with significant increases in ERG amplitudes, even in eyes presenting with extinguished ERGs. ERG signals may increase independent of resolution of retinal detachment.

Background/aims: To review the effectiveness of intra-arterial chemotherapy for advanced intra-ocular retinoblastoma with vitreous and/or subretinal seeds in naive (untreated) and previously treated eyes., Methods: Retrospective study, approved by the institutional review board, of 76 eyes of 67 patients with retinoblastoma with subretinal and/or vitreous seeding treated with intra-arterial chemotherapy at Memorial Sloan-Kettering Cancer Center between May 2006 and August 2010., Results: Despite advanced intraocular disease with seeding, the majority (56/76) of eyes were saved; 20/76 eyes were enucleated. Among treatment-naive eyes, the 2-year probability of ocular salvage was 83% (95% CI 27% to 97%) for eyes with subretinal seeding only, 64% (95% CI 24% to 87%) for eyes with vitreous seeding only, and 80% (95% CI 40% to 95%) for eyes with both. Among eyes that received previous treatment and had progressed, the 2-year probability of ocular salvage was 50% (95% CI 15% to 78%) for eyes with only subretinal seeding, 76% (95% CI 48% to 91%) for eyes with vitreous seeding only, and 54% (95% CI 20% to 79%) for eyes with both. Nine of 29 naive eyes (31%) were cured with intra-arterial (super-selective ophthalmic artery infusion of chemotherapy) chemotherapy alone., Conclusion: Unlike radiation or systemic chemotherapy, intra-arterial chemotherapy can usually prevent the need for enucleation in naive eyes with advanced intraocular retinoblastoma with seeding-especially if the seeding is subretinal. Treatment appears to be less effective in previously treated eyes when subretinal seeding is present (50% at 2 years), but may be more effective in eyes that failed to respond to previous systemic chemotherapy and have only vitreous seeding.

Background: Intra-arterial (i.a.) chemotherapy has more risks of procedural complications in neonates and young infants. For these reasons, we have developed a strategy of bridge intravenous single agent chemotherapy to postpone i.a. chemotherapy in these children, Procedure: Neonates and young infants with retinoblastoma who required chemotherapy were treated with systemic carboplatin chemotherapy (18.7 mg/kg i.v. every 3-4 weeks) until they reached the age of 3 months and a weight of 6 Kg. If necessary, i.a. chemotherapy was subsequently performed at 4 weeks intervals. Efficacy was judged by tumor regression on ophthalmological examination. Retinal toxicity was judged by electroretinography., Results: Eleven children (19 eyes) were treated. All patients are alive and no patient has developed metastatic disease or second malignancies (mean follow-up 27 months, range 9-46 months). Intravenous carboplatin (median 2 cycles, range 1-5) combined with cryotherapy and laser was given to all children. This was effective for five eyes, which did not require i.a. chemotherapy. I.a. chemotherapy was administered to 14 eyes (median 3.5 cycles per eye, range 1 to 6). No radiation therapy was required. The Kaplan Meier estimate of ocular radiation-free survival was 94.7% at one year (95% confidence interval 68.1-99.2%). One eye was enucleated due to tumor progression. ERG showed no deterioration of retinal function., Conclusion: Bridge i.v.-i.a. chemotherapy was feasible and safe, and is a promising strategy to treat retinoblastoma in neonates and young infants.

Background: Ophthalmic artery chemosurgery (OAC) for retinoblastoma was introduced by us 5 years ago for advanced intraocular retinoblastoma. Because the success was higher than with existing alternatives and systemic side effects limited we have now treated less advanced intraocular retinoblastoma (Reese-Ellsworth (RE) I-III and International Classification Retinoblastoma (ICRB) B and C)., Methodology/principal Findings: Retrospective review of 5 year experience in eyes with Reese Ellsworth (Table 1) I (7 eyes), II (6 eyes) or III (6 eyes) and/or International Classification (Table 2) B (19 eyes) and C (11 eyes) treated with OAC (melphalan with or without topotecan) introduced directly into the ophthalmic artery. Patient survival was 100%. Ocular event-free survival was 100% for Reese-Ellsworth Groups I, II and III (and 96% for ICRB B and C) at a median of 16 months follow-up. One ICRB Group C (Reese-Ellsworth Vb) eye could not be treated on the second attempt for technical reasons and was therefore enucleated. No patient required a port and only one patient required transfusion of blood products. The electroretinogram (ERG) was unchanged or improved in 14/19 eyes., Conclusions/significance: Ophthalmic artery chemosurgery for retinoblastoma that was Reese-Ellsworth I, II and III (or International Classification B or C) was associated with high success (100% of treatable eyes were retained) and limited toxicity with results that equal or exceed conventional therapy with less toxicity.

Purpose: Preclinical studies demonstrate that cardiac glycosides such as ouabain and digoxin have antitumor effects on retinoblastoma cells in vitro and in a xenograft murine model of retinoblastoma., Methods: Based on these findings, we report a case of intra-arterial followed by systemic oral digoxin therapy in a patient with unilateral retinoblastoma that had failed prior intra-arterial chemotherapy., Results: Oral administration of digoxin produced no effect, while intra-arterial digoxin therapy produced a modest but measurable response that was likely limited by the inability to achieve sustained drug concentration in the eye., Conclusions: This case highlights both the potential promise and limitations of cardiac glycoside therapy in retinoblastoma.

Objective: To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation., Design: Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications., Results: Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications., Conclusion: Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma., (©2011 AACR.)

Topotecan is a promising drug with activity against retinoblastoma, however, attaining therapeutic concentrations in the vitreous humor is still a challenge for the treatment of vitreous seeds in retinoblastoma. Our aim was to characterize topotecan pharmacokinetics in vitreous and aqueous humor, and to assess the systemic exposure after intra-vitreal injection in rabbits as an alternative route for maximizing local drug exposure. Anesthetized rabbits were administered intra-vitreal injections of 5 microg of topotecan. Vitreous, aqueous, and blood samples were collected at pre-defined time points. A validated high-performance liquid chromatography assay was used to quantitate topotecan (lactone and carboxylate) concentrations. Topotecan pharmacokinetic parameters were determined in vitreous, aqueous and plasma using a compartmental analysis. Topotecan lactone concentrations in the vitreous of the injected eye were about 8 ng/mL 48 h after drug administration. The median maximum vitreous, aqueous and plasma total topotecan concentrations (C(max)) were 5.3, 0.68 and 0.21 microg/mL, respectively. The C(max) vitreous/aqueous of treated eyes and the C(max) vitreous/plasma were approximately 8 and 254, respectively. Total topotecan exposure (AUC) in the vitreous of the injected eye was 50 times greater than the total systemic exposure. These findings suggest that intra-vitreal administration of only 5 microg of topotecan reaches significant local levels over an extended period of time while minimizing systemic exposure in the rabbit. Intra-vitreal topotecan administration offers a promising alternative route for enhanced drug exposure in the vitreous humor with potential application for treatment of vitreal seeds in retinoblastoma while avoiding systemic toxicities., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.

Purpose: To assess potential retinal viability by electroretinography following selective ophthalmic artery chemotherapy infusion for retinoblastoma., Methods: Uncontrolled prospective case series. Patients with advanced retinoblastoma were offered elective ophthalmic artery chemotherapy infusion treatment under an IRB-approved protocol as an alternative to enucleation. The ophthalmic artery was cannulated under fluoroscopic control, and chemotherapeutic agents (melphalan and occasionally carboplatin) were directly infused at doses resulting in very high local tissue concentrations, but low systemic drug levels. Eyes were examined under anesthesia at 1-month intervals, and re-treated as indicated, up to a maximum of six infusions. Electroretinograms were obtained during examination under anesthesia, using ERG-jet contact lens electrodes and a hand-held mini-ganzfeld stimulator. The ERG protocol was similar to ISCEV standards except for briefer adaptation times as necessary to reduce the total anesthesia duration., Results: We report initial results in the first ten patients attempted. Nine eyes were successfully cannulated and perfused. ERG data for these nine patients are reported. [Clinical results have been published elsewhere.] Follow up ranged from 3 to 14 months. Extensive, often total, retinal detachments were present in many of the treated eyes. While regression of tumor mass and vitreous seeds was observed in nearly all the patients, retinal detachment occasionally persisted. ERG responses were extinguished in these eyes. Eyes with largely attached retinas, notwithstanding the presence of large tumors at baseline, remained free of detachment after treatment. Normal or near-normal ERGs in these eyes were repeatedly obtained. Recovery of ERG amplitudes was observed in three patients following treatment., Conclusions: Retinal function can persist and even recover following selective ophthalmic artery chemotherapy infusion for retinoblastoma. Further work is indicated to determine optimal dosing regimens, maximal tolerated dosage, and subsequent visual function in these patients.

Purpose: Intra-arterial delivery of chemotherapeutic agents offers a new and exciting opportunity for the treatment of advanced intraocular retinoblastoma. It allows local delivery of relatively high doses of chemotherapy agents while bypassing general blood circulation. For this reason, this study was undertaken to revisit some of the FDA-approved drugs for the treatment of retinoblastoma., Methods: High-throughput screening (HTS) of 2640 approved drugs and bioactive compounds resulted in the identification of cytotoxic agents with potent activity toward both the Y79 and RB355 human retinoblastoma cell lines. Subsequent profiling of the drug candidates was performed in a panel of ocular cancer cell lines. Induction of apoptosis in Y79 cells was assessed by immunofluorescence detection of activated caspase-3. Therapeutic effect was evaluated in a xenograft model of retinoblastoma., Results: Several FDA-approved drugs were identified that showed potent cytotoxic activity toward retinoblastoma cell lines in vitro. Among them were several cardiac glycosides, a class of cardenolides historically associated with the prevention and treatment of congestive heart failure. Caspase-3 activation studies provided an insight into the mechanism of action of cardenolides in retinoblastoma cells. When tested in a xenograft model of retinoblastoma, the cardenolide ouabain induced complete tumor regression in the treated mice., Conclusions: Cardenolides were identified as a new class of antitumor agents for the treatment of retinoblastoma. Members of this class of cardiotonic drugs could be repositioned for retinoblastoma if administered locally via direct intra-arterial infusion.

Purpose: To identify the maximum tolerated dose and dose-limiting toxicity of periocular topotecan in patients with relapsed or resistant intraocular retinoblastoma who are facing imminent enucleation., Methods: For this phase I study, a starting dose of 0.5 mg of periocular topotecan administered through a 25-gauge needle was given with intrapatient escalation at a rate of 0.5 mg/cycle according to toxicity, up to a maximum dose of 2 mg. Two courses separated by 2 weeks were scheduled. Plasma levels of topotecan were measured by high-performance liquid chromatography in patients with available intravenous catheters., Results: Seven eyes of five patients were treated with a total of 14 courses of periocular topotecan. Only mild orbital edema occurred, and grade 1 vomiting developed in the first patient that was controlled with ondansetron for the following courses. Dose-limiting toxicity was not reached and the maximum tolerated dose was set at the target dose of 2 mg (n=5 eyes). Lactone topotecan systemic exposure was lower than 55 ng/mL x h and it correlated linearly with dose in this small cohort. Even though the study was not designed to assess response, one eye was preserved after a partial response, but the remaining six were enucleated, either after a short period of disease stabilization followed by further therapy with other agents in five patients or by rapidly progressive disease in one., Conclusions: The dose limiting toxicity was not reached. Up to 2 mg of periocular topotecan could be given safely, but further studies are necessary to determine its effect on retinoblastoma (ClinicalTrials.gov number, NCT00460876).

Chemoreduction is currently the most popular treatment strategy for intraocular retinoblastoma worldwide. Despite the dramatic clinical responses obtained with multiagent systemic chemotherapy regimens, enthusiasm for this treatment approach has been tempered by the potential toxicities of these drugs in the pediatric population. As a response to these concerns, novel approaches for the local delivery of chemotherapeutic agents to ocular structures have been investigated by both clinicians and scientists. Ocular oncologists have developed the periocular injection of carboplatin as a method for controlling intraocular tumor growth of retinoblastoma while minimizing systemic drug exposure. In parallel, the pharmaceutical industry has introduced drug-delivery systems to the posterior segment of the globe for a variety of ocular diseases. One example of the collaborative work by ophthalmologists and biopharmaceutical scientists is the use of fibrin sealants as a targeted drug-administration device, formulated to deliver sustained concentrations of chemotherapy at the site of application. This review integrates the recent ophthalmology and pharmaceutics literature on the potential role of fibrin sealants for periocular chemotherapy administration in the treatment of retinoblastoma.

Purpose: To determine the extent and the mechanism by which topotecan, a candidate agent for the treatment of retinoblastoma, gains access to the vitreous when administered by periocular injection or intravenous infusion., Methods: In vivo experiments were conducted in which albino rabbits received 1 mg topotecan by periocular injection (POI group; n = 30) or as a 30-minute intravenous infusion (IV group; n = 16). Plasma and vitreal topotecan concentrations were analyzed during the 10 hours after administration. A population pharmacokinetic model was fit to the data. Additionally, periocular injections were performed postmortem to study the effect of removing the blood vasculature barrier., Results: Potentially active lactone topotecan levels were detected in the vitreous in the POI and IV groups. Both administration schedules induced high total topotecan plasma exposures because of absorption from the periocular depot, though plasma lactone area under the curve (AUC) was significantly higher in the IV group. Similar vitreal concentrations were found in treated and control eyes in the POI group. The transfer from the periocular compartment to the vitreous was negligible. The absence of drug levels in the control eye of the postmortem-injected rabbits confirmed the systemic delivery of topotecan. Local toxicity was not observed., Conclusions: As a consequence of a favored passage across the blood-retinal barrier, considerable topotecan vitreous levels were detected in a rabbit model after systemic or periocular administration. Transscleral entry in vivo was constrained by rapid clearance from the administration site.

Survival rates for retinoblastoma patients have increased dramatically over the last century, with documented 5-year survival figures reaching 87-99% in developed countries. During the last decade, there has been a dramatic paradigm shift in the treatment approach for intraocular retinoblastoma, emphasising chemoreduction protocols and minimising the use of external beam radiation. The recognition of the increased risk for second non-ocular cancers with external beam radiation contributed to the growing emergence of chemotherapy. Although chemoreduction protocols vary slightly between institutions, many centres are currently treating intraocular retinoblastoma with carboplatin, vincristine and etoposide as a three-drug regimen given in two to six cycles. Clinical studies have demonstrated that systemic chemotherapy must be combined with other modalities, such as laser treatment and cryotherapy, for adequate tumour control and many eyes with advanced intraocular disease require salvage therapy with radiation or enucleation. Therefore, modern centres treating retinoblastoma continue to manage patients with a variety of modalities, individualising the therapy according to the patient's presentation and clinical course.

Purpose: To determine the frequency and timing of new intraocular tumor formation in children with hereditary retinoblastoma initially treated with systemic carboplatin., Design: Retrospective, noncomparative case series., Participants: This study included 34 children (57 eyes) with hereditary bilateral retinoblastoma initially treated with systemic carboplatin at the Robert M. Ellsworth Ophthalmic Oncology Center at NewYork-Presbyterian Hospital from 1994 through 2000., Main Outcome Measures: New tumor formation after initial treatment with systemic carboplatin., Results: There were a total of 165 tumors in 57 eyes. There were 63 new tumors in 27 eyes (47%) after administration of systemic carboplatin, for a mean of 1.1 new tumors per eye. The mean patient age at time of new tumor presentation was 9 months, with 57% of new tumors developing within 4 months of carboplatin treatment. Kaplan-Meier analysis showed that children who were treated when younger than 6 months of age were more likely to have new tumors (60%) compared with those treated after 6 months of age (31%; P = 0.0182)., Conclusions: New intraocular tumors continue to develop after systemic carboplatin; most new tumors appeared within 4 months of treatment.

The article discusses the case of a 43-year-old man with uveal metastasis caused by nonsmall cell lung carcinoma who was treated with erlotinib. He started taking erlotinib when his chemotherapy with carboplatin and taxol failed to prevent the growth of uveal metastasis. Days after taking erlotinib, his choroidal lesion shrinked. The following three months, his tumor completely disappeared along with his improved vision.

Background: Intravenous etoposide is widely used in multiagent chemotherapy regimens for intraocular retinoblastoma despite the lack of phase 11 data documenting its efficacy. Because oral etoposide has been found to he highly effective in patients with relapsed medulloblastoma and neuroblastoma who had previously received intravenous etoposide, we investigated its use for intraocular retinoblastoma. Procedure: A pilot trial of oral eloposide (50mg/m²/ day for 21 days) in five children (6 eyes) with relapsed refractory intraocular retinoblastoma was performed. All had previously received chemotherapy, including intravenous etoposide in four patients, and all had received radiation therapy. Three patients (3 eves) had vitreous seeds. Response was evaluated after one cycle. Results: No serious acute toxicity was encountered, and no responses were noted. Four patients (5 eyes) had progressive disease. Stable disease was noted in one eye without vitreous disease. One patient developed secondary acute myeloid leukemia 30 months after exposure to oral etoposide. Conclusions: Oral etoposide was not an effective agent in this population. The role of etoposide in the treatment of higher risk intraocular retinoblastoma deserves further study. [ABSTRACT FROM AUTHOR]

Previous studies of the penetration of carboplatininto the vitreous have depended on unaffected animals or on animal modelsfor other cancers. The objective of this study was to determine the intraocularlevels of carboplatin following intravenous administration of carboplatinin the treatment of human intraocular retinoblastoma. Eight patients withbilateral intraocular retinoblastoma were treated in a consistent fashionwith intravenous carboplatin. One additional patient was similarly treated,but enucleated one month later. Samples were taken from those nine eyes afterenucleation one to two hours after the administration of 18.7 mg/kg (560 mg/m[sup 2] for patients more than 12 kg) of intravenous carboplatin, and carboplatinconcentrations in the aqueous and vitreous were then measured by atomic absorptionspectrometry. The mean concentration measured in the aqueous was 5.13 μg/mland in the vitreous 4.05 μg/ml, and vitreal concentrations were an averageof 80% of aqueous concentrations. In one patient, a vitreous concentrationof carboplatin was detected after an interval of one month that was 10% ofthe levels found in the samples enucleated one hour post-administration. Theseconcentrations are much higher than previous animal studies would predict,and are similar to levels measured in unaffected animals when the drug isgiven after the use of cryotherapy. The concentration also approaches levelspreviously shown to be toxic to the retina. This elevation in carboplatinconcentration may be due to disruption of the blood-vitreous barrier by activetumor. [ABSTRACT FROM AUTHOR]