Publications by authors named "Jasmine H Francis"

145 Publications

Orbital Retinoblastoma Treated with Intra-arterial Chemotherapy.

Ophthalmology 2021 10;128(10):1437

Weill-Cornell Medical Center, New York, New York.

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http://dx.doi.org/10.1016/j.ophtha.2021.03.018DOI Listing
October 2021

Association of Plasma Circulating Tumor DNA With Diagnosis of Metastatic Uveal Melanoma.

JAMA Ophthalmol 2021 Nov;139(11):1244-1245

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1001/jamaophthalmol.2021.3708DOI Listing
November 2021

Loss of polycomb repressive complex 1 activity and chromosomal instability drive uveal melanoma progression.

Nat Commun 2021 09 13;12(1):5402. Epub 2021 Sep 13.

Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA.

Chromosomal instability (CIN) and epigenetic alterations have been implicated in tumor progression and metastasis; yet how these two hallmarks of cancer are related remains poorly understood. By integrating genetic, epigenetic, and functional analyses at the single cell level, we show that progression of uveal melanoma (UM), the most common intraocular primary cancer in adults, is driven by loss of Polycomb Repressive Complex 1 (PRC1) in a subpopulation of tumor cells. This leads to transcriptional de-repression of PRC1-target genes and mitotic chromosome segregation errors. Ensuing CIN leads to the formation of rupture-prone micronuclei, exposing genomic double-stranded DNA (dsDNA) to the cytosol. This provokes tumor cell-intrinsic inflammatory signaling, mediated by aberrant activation of the cGAS-STING pathway. PRC1 inhibition promotes nuclear enlargement, induces a transcriptional response that is associated with significantly worse patient survival and clinical outcomes, and enhances migration that is rescued upon pharmacologic inhibition of CIN or STING. Thus, deregulation of PRC1 can promote tumor progression by inducing CIN and represents an opportunity for early therapeutic intervention.
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http://dx.doi.org/10.1038/s41467-021-25529-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438051PMC
September 2021

Clinical and Morphologic Characteristics of Fibroblast Growth Factor Receptor Inhibitor-Associated Retinopathy.

JAMA Ophthalmol 2021 Oct;139(10):1126-1130

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Fibroblast growth factor receptor (FGFR) 1 to 4 inhibitors are approved by the US Food and Drug Administration and suppress the mitogen-activated protein kinase (MAPK) pathway, with a potential for treatment-related retinopathy. To date, implications of FGFR inhibitor-associated ocular toxic effects are poorly described. Therefore, more detailed clinical descriptions of this ocular toxic effect could help explain visual symptoms while receiving drug therapy.

Objective: To describe the clinical and morphologic characteristics of serous retinal disturbances associated with FGFR inhibitors.

Design, Setting, And Participants: In this retrospective case series, 146 patients receiving FGFR inhibitors as cancer treatment at a single tertiary referral center were included. This study included 40 eyes of 20 patients with retinopathy by optical coherence tomography (OCT). OCTs were obtained on the remaining patients and the results were judged normal. Patients were recruited from March 2012 to January 2021.

Main Outcomes And Measures: Characteristics of treatment-emergent choroidal and retinal OCT abnormalities as compared with baseline OCT, associated with visual acuity at presentation and at fluid resolution.

Results: A total of 20 of 146 patients (13.7%) exhibited FGFR inhibitor-associated retinopathy. Of these 20 patients, 11 (55%) were female, and the median (range) age was 62.6 (42.7-86.0) years. The median (range; mean) time from medication start to initial subretinal fluid detection was 21 (5-125; 32) days. The median (interquartile range [IQR]) baseline logMAR best-corrected visual acuity (BCVA) was 0 (0-0.1). At fluid accumulation, 11 eyes had decreased vision: the median (IQR) subgroup baseline BCVA was 0 (0-0.1); and the median (IQR) BCVA change from baseline to accumulation was -0.1 (-0.2 to -0.1). For 26 eyes (65%) with follow-up, the subretinal fluid resolved without medical intervention or drug interruption in all but 1 patient. At fluid resolution, the median (IQR) BCVA was 0.1 (0-0.1), and the change in median (IQR) BCVA from baseline to fluid resolution was 0 (-0.03 to 0). No patient discontinued drug therapy on account of their retinopathy.

Conclusions And Relevance: FGFR inhibitors result in subretinal fluid foci similar to other drugs that inhibit the MAPK pathway. In this series, FGFR inhibitors did not cause irreversible loss of vision; the retinopathy was self-limited and did not require medical intervention. These results may explain visual symptoms while taking the drug, although the precise frequency or magnitude of this adverse effect cannot be determined with certainty from this retrospective investigation.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.3331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414363PMC
October 2021

Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.

Nat Cancer 2021 Mar 15;2:357-365. Epub 2021 Feb 15.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York, 10065, USA.

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and downstream clinical use (clinicaltrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low, moderate, and high penetrance dominant or recessive genes, or 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use, and use of targeted therapies. Germline testing should be considered for all children with cancer.
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http://dx.doi.org/10.1038/s43018-021-00172-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8294573PMC
March 2021

Increased Risk of Skin Cancer in 1,851 Long-Term Retinoblastoma Survivors.

J Invest Dermatol 2021 Dec 18;141(12):2849-2857.e3. Epub 2021 Jun 18.

Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA.

Patients with hereditary retinoblastoma are at risk for developing cutaneous melanoma, but little is known about the role of sun exposure or other factors, and the incidence of nonmelanoma skin cancer (NMSC) is poorly understood. We investigated the incidence of melanoma and NMSC in a cohort of 1,851 White, long-term retinoblastoma survivors (1,020 hereditary and 831 nonhereditary) diagnosed during 1914‒2006. During follow-up through 2016, 33 hereditary and 7 nonhereditary survivors developed melanoma, and 26 hereditary and 9 nonhereditary survivors developed NMSC. Most NMSCs were on the head/neck, whereas melanomas were more broadly distributed with patterns similar to melanoma-prone families. For both outcomes, the median age at diagnosis was ~20 years younger among hereditary survivors than among nonhereditary survivors. At 50 years after retinoblastoma diagnosis, the cumulative incidence in hereditary survivors was 4.5% for melanoma and 3.7% for NMSC; for nonhereditary survivors, it was 0.7% and 1.5%, respectively. Sun sensitivity and phenotypic characteristics generally did not vary by skin cancer status. Hereditary retinoblastoma survivors have an increased risk for melanoma and NMSC that occurred earlier than that observed among nonhereditary survivors, likely reflecting genetic factors. These findings among White retinoblastoma survivors support consensus-based recommendations for skin cancer screening and sun protection starting at young ages and continuing long term.
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http://dx.doi.org/10.1016/j.jid.2021.05.021DOI Listing
December 2021

Immune checkpoint inhibitor associated ocular hypertension (from presumed trabeculitis).

Am J Ophthalmol Case Rep 2021 Sep 24;23:101125. Epub 2021 May 24.

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Immune checkpoint inhibitors (ICIs) are associated with a range of immune-related adverse ophthalmic events. To date, there are scant reports of ocular hypertension coupled with ICI-associated uveitis. However, in instances of ocular hypertension in the context of only mild uveitic reaction and absence of synechiae, trabeculitis is considered. This series describes our observations of presumed trabeculitis in the setting of ICI therapy and investigates the clinical findings, treatment and outcome of these patients.

Observations: Two eyes of 2 patients (both male aged 65 and 43) developed a mild anterior uveitis and elevated intraocular pressure (IOP) with open angles and no evidence of peripheral anterior synechiae in association with ICI treatment for their malignancy; and were considered to have presumed unilateral trabeculitis. The patients underwent 10 cycles (6.53 months) and 2 cycles (3.33 months) respectively of ICI therapy before developing ophthalmic symptoms. Neither patient was on systemic or topical steroid treatment at time of diagnosis and there was no suspicion of a viral etiology for the inflammation. Following management, the anterior uveitis resolved and IOP rapidly returned to normal in both eyes: ICI therapy was discontinued in both patients (and uneventfully re-challenged at a lower dose in one patient) and both eyes were treated with a combination of topical and/or oral glaucoma medications and topical steroids.

Conclusions And Importance: Uveitic ocular hypertension has been described with ICI. However, another immune-related mechanism for ocular hypertension with unique clinical characteristics, includes trabeculitis. We describe two cases of trabeculitis in the setting of ICI-therapy. The intraocular inflammation and elevated intraocular pressure which characterizes trabeculitis often responds rapidly to conservative treatment. In both patients checkpoint inhibitor therapy was discontinued and, in one patient, was re-challenged at a lower dose without recurrence. Immunotherapy is now more widely used for cancer treatment and its potential ocular manifestations should be shared with the ophthalmic community.
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http://dx.doi.org/10.1016/j.ajoc.2021.101125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175271PMC
September 2021

Clinical and Morphologic Characteristics of Extracellular Signal-Regulated Kinase Inhibitor-Associated Retinopathy.

Ophthalmol Retina 2021 Jun 5. Epub 2021 Jun 5.

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Ophthalmology, Weill-Cornell Medical Center, New York, New York.

Purpose: To investigate clinical and morphologic characteristics of serous retinal disturbances in patients taking extracellular signal-regulated kinase (ERK) inhibitors.

Design: Single-center retrospective study of prospectively collected data.

Participants: Of 61 patients receiving ERK inhibitors for treatment of metastatic cancer, this study included 40 eyes of 20 patients with evidence of retinopathy confirmed by OCT.

Methods: Clinical examination, fundus photography, and OCT were used to evaluate ERK inhibitor retinopathy. The morphologic features, distribution, and location of fluid foci were evaluated serially. Visual acuity (VA) and choroidal thickness measurements were compared at baseline, fluid accumulation, and resolution.

Main Outcome Measures: Characteristics of treatment-emergent choroid and retinal OCT abnormalities as compared with baseline OCT findings and the impact of toxicity on VA.

Results: Of 20 patients with retinopathy, most showed fluid foci that were bilateral (100%), multifocal in each eye (75%), and with at least 1 focus involving the fovea (95%). All subretinal fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. No statistical difference was found in choroidal thickness at fluid accumulation and resolution compared with baseline. Forty-five percent of eyes showed evidence of concomitant intraretinal edema localized to the outer nuclear layer. At the time of fluid accumulation, 57.5% eyes showed a decline in VA (mainly by 1-2 lines from baseline). For all eyes with follow-up, the subretinal fluid and intraretinal edema were reversible and resolved without medical intervention, and best-corrected VA at fluid resolution was not statistically different from baseline. Concomitant intraretinal fluid was not associated with worsening of VA. No patient discontinued or decreased drug dose because of retinopathy.

Conclusions: This study showed that ERK inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics. The observed foci were similar to mitogen-activated protein kinase kinase (MEK) inhibitor-associated retinopathy and distinct from central serous chorioretinopathy. However, unlike with MEK inhibitors, an increased occurrence of concomitant intraretinal fluid without significant additive visual impact seems to occur with ERK inhibitors. In this series, ERK inhibitors did not cause irreversible loss of vision or serious eye damage; retinopathy was self-limited and did not require medical intervention.
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http://dx.doi.org/10.1016/j.oret.2021.06.001DOI Listing
June 2021

Fundus albipunctatus photoreceptor microstructure revealed using adaptive optics scanning light ophthalmoscopy.

Am J Ophthalmol Case Rep 2021 Jun 16;22:101090. Epub 2021 Apr 16.

Icahn School of Medicine at Mount Sinai and New York Eye and Ear Infirmary of Mount Sinai, Department of Ophthalmology, New York, NY, USA.

Purpose: Fundus albipunctatus is an inherited cause of congenital stationary night blindness. The objective of this report is to describe structural changes occurring in a macular phenotype of a novel RDH5 mutation producing fundus albipunctatus using high-resolution imaging. A 62-year-old male with longstanding night blindness underwent imaging and genetic evaluation. High-resolution images of the photoreceptor mosaic were compared to those of a healthy subject. Results of a comprehensive ophthalmic evaluation and genetic testing with imaging including fundus photography, spectral-domain optical coherence tomography (OCT), fluorescein angiography (FA), OCT angiography (OCT-A), and adaptive optics scanning light ophthalmoscopy (AOSLO) are described.

Observations: The patient presented with visual acuity of 20/25 in both eyes and longstanding poor dark adaptation. Anterior segment examination was unremarkable. Fundoscopy revealed well circumscribed bilateral perifoveal mottling and atrophy in both eyes. Discrete white-yellow flecks were present beyond the vascular arcades extending to the far periphery. Genetic testing revealed a novel compound heterozygous RDH5 mutation (c.388C > T, p.Gln130*; c.665T > C, p.Leu222Pro). OCT demonstrated perifoveal photoreceptor and outer retinal irregularities, which corresponded to a window defect with late staining on FA. OCT-A demonstrated normal retinal vasculature with patchy areas of non-perfusion in the choriocapillaris. Macular abnormalities in both eyes were imaged using AOSLO to assess cone and rod photoreceptor architecture. While clinical features are consistent with a primary rod disorder, confocal AOSLO showed a paucity of normal cones with a small spared central island in both eyes. Rods appeared larger and more irregular throughout the macula. Non-confocal split detection AOSLO imaging revealed the presence of cone inner segments in dark regions of confocal imaging, indicating some degree of photoreceptor preservation.

Conclusions And Importance: The AOSLO imaging of this particular macular phenotype of fundus albipunctatus demonstrates some of the structural photoreceptor abnormalities that occur in this condition, adding insight to the variable presentation of RDH5 retinopathy. The presence of preserved inner segment architecture suggests the possibility that gene therapy could play a future role in treating this condition.
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http://dx.doi.org/10.1016/j.ajoc.2021.101090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082516PMC
June 2021

Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis.

Neurology 2021 06 12;96(23):1091-1093. Epub 2021 May 12.

From the Ophthalmic Oncology Service (J.H.F., D.H.A.) and Departments of Neurology (R.A.N., E.L.D.), Radiology (G.A.U., V.H.), and Epidemiology and Statistics (K.P.), Memorial Sloan Kettering Cancer Center; Department of Neurosurgery (Y.P.G., J.K., K.S., A.P.), Weill Cornell Medical Center, New York; and Molecular Imaging and Therapy (G.A.U.), Hoag Family Cancer Institute, Newport Beach, CA.

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http://dx.doi.org/10.1212/WNL.0000000000012070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205455PMC
June 2021

Bilateral diffuse uveal melanocytic proliferation with multifocal diffuse integumentary melanocytic proliferation paraneoplastic syndrome: A case report.

Australas J Dermatol 2021 Aug 11;62(3):386-389. Epub 2021 May 11.

Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Bilateral diffuse uveal melanocytic proliferation (B-DUMP) is a rare paraneoplastic syndrome typically presenting with bilateral visual loss. B-DUMP is associated with extraocular systemic malignancies with the most common being lung cancer in males and uro-gynaecological cancer in females (mainly ovarian cancer). Cutaneous and/or mucosal involvement in patients with B-DUMP has been reported but it is not well characterised. Herein, we present a female in her 70s with diagnosis of stage IV vaginal clear-cell carcinoma and metastatic melanoma of unknown primary that developed progressive bilateral loss of visual acuity compatible with 'B-DUMP'. Simultaneously, she developed multifocal bilateral bluish-greyish patches on the skin that were shown to have a proliferation of dermal melanocytes. We propose that the clinical and histopathologic cutaneous findings seen in patients with B-DUMP be termed 'diffuse integumentary melanocytic proliferation (DIMP)'.
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http://dx.doi.org/10.1111/ajd.13617DOI Listing
August 2021

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study.

Br J Ophthalmol 2021 May 10. Epub 2021 May 10.

Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA

Background: Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.

Methods: Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction.

Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.

Results: Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.

Conclusions: Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.
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http://dx.doi.org/10.1136/bjophthalmol-2020-318529DOI Listing
May 2021

Prognostic value of [F]FDG PET/CT in patients with CNS lymphoma receiving ibrutinib-based therapies.

Eur J Nucl Med Mol Imaging 2021 11 8;48(12):3940-3950. Epub 2021 May 8.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: Current clinical and imaging tools remain suboptimal for predicting treatment response and prognosis in CNS lymphomas. We investigated the prognostic value of baseline [F]FDG PET in patients with CNS lymphoma receiving ibrutinib-based treatments.

Methods: Fifty-three patients enrolled in a prospective clinical trial and underwent brain PET before receiving single-agent ibrutinib or ibrutinib in combination with methotrexate with or without rituximab. [F]FDG uptake in these lesions was quantified by drawing PET volumes of interest around up to five [F]FDG-avid lesions per patient (with uptake greater than surrounding brain). We measured standardized uptake values (SUV), metabolic tumor volumes, total lesion glycolysis (TLG), and the sum thereof in these lesions. We analyzed the relationship between PET parameters and mutation status, overall response rates, and progression-free survival (PFS).

Results: Thirty-eight patients underwent single-agent therapy and 15 received combination therapy. On PET, 15/53 patients had no measurable disease. In the other 38 patients, a total of 71 lesions were identified on PET. High-intensity [F]FDG uptake and a larger volume of [F]FDG-avid disease were inversely related to treatment outcome (p ≤ 0.005). In univariable analysis, PFS was linearly correlated with all PET parameters, with stronger association when sum-values were used. A multivariable model showed that risk of progression increased by 9% for every 5-unit increase in sumSUV (hazard ratio = 1.09 [95% CI: 1.04 to 1.14]).

Conclusion: Higher lesional metabolic parameters are inversely related to outcome in patients undergoing ibrutinib-based therapies, and sumSUV emerged as a strong independent prognostic factor.

Trial Registration: NCT02315326; https://clinicaltrials.gov/ct2/show/NCT02315326?term=NCT02315326&draw=2&rank=1.
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http://dx.doi.org/10.1007/s00259-021-05386-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484020PMC
November 2021

Benign Tumors in Long-Term Survivors of Retinoblastoma.

Cancers (Basel) 2021 Apr 8;13(8). Epub 2021 Apr 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Hereditary retinoblastoma survivors have substantially increased risk of subsequent malignant neoplasms (SMNs). The risk of benign neoplasms, a substantial cause of morbidity, is unclear. We calculated the cumulative incidence of developing benign tumors at 60 years following retinoblastoma diagnosis among 1128 hereditary (i.e., bilateral retinoblastoma or unilateral with family history, mutation testing was not available) and 924 nonhereditary retinoblastoma survivors diagnosed during 1914-2006 at two US medical centers with follow-up through 2016. Using Cox proportional hazards regression, we compared benign tumor risk by hereditary status and evaluated the association between benign tumors and SMNs. There were 100 benign tumors among 73 hereditary survivors (cumulative incidence = 17.6%; 95% confidence interval [CI] = 12.9-22.8%) and 22 benign tumors among 16 nonhereditary survivors (cumulative incidence = 3.9%; 95%CI = 2.2-6.4%), corresponding to 4.9-fold (95%CI = 2.8-8.4) increased risk for hereditary survivors. The cumulative incidence after hereditary retinoblastoma was highest for lipoma among males (14.0%; 95%CI = 7.7-22.1%) and leiomyoma among females (8.9%; 95%CI = 5.2-13.8%). Among hereditary survivors, having a prior SMN was associated with 3.5-fold (95%CI = 2.0-6.1) increased risk of developing a benign tumor; the reciprocal risk for developing an SMN after a benign tumor was 1.8 (95%CI = 1.1-2.9). These large-scale, long-term data demonstrate an increased risk for benign tumors after hereditary versus nonhereditary retinoblastoma. If confirmed, the association between benign tumors and SMNs among hereditary patients may have implications for long-term surveillance.
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http://dx.doi.org/10.3390/cancers13081773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068196PMC
April 2021

Prelaminar and Postlaminar Invasion of Retinoblastoma.

Ophthalmol Retina 2021 04;5(4):387

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.oret.2020.12.015DOI Listing
April 2021

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Cancers (Basel) 2021 Feb 8;13(4). Epub 2021 Feb 8.

National Scientific and Technical Research Council, CONICET, Buenos Aires 1425, Argentina.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.
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http://dx.doi.org/10.3390/cancers13040673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915502PMC
February 2021

General cancer screening practices among adult survivors of retinoblastoma: Results from the Retinoblastoma Survivor Study.

Pediatr Blood Cancer 2021 04 26;68(4):e28873. Epub 2021 Jan 26.

Department of Epidemiology and Biostatistics, MSKCC, Memorial Sloan Kettering Cancer Center, New York, NY, United States.

We assessed breast, cervical, and colorectal cancer screening practices in adult retinoblastoma (Rb) survivors and non-Rb controls. We found that most Rb survivors adhered to general population cancer screening recommendations. Rates did not differ among Rb survivors and non-Rb controls, or among survivors by laterality, even though bilateral survivors reported higher levels of concern about future health and cancer risk. Older age, being overweight/obese, and lack of recent contact with medical personnel were independently associated with decreased utilization of Pap smear among female Rb survivors. Future studies are warranted to determine whether these associations might provide an opportunity for intervention.
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http://dx.doi.org/10.1002/pbc.28873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904654PMC
April 2021

Molecular Changes in Retinoblastoma beyond : Findings from Next-Generation Sequencing.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

This investigation uses hybridization capture-based next-generation sequencing to deepen our understanding of genetics that underlie retinoblastoma. Eighty-three enucleated retinoblastoma specimens were evaluated using a MSK-IMPACT clinical next-generation sequencing panel to evaluate both somatic and germline alterations. Somatic copy number variations (CNVs) were also identified. Genetic profiles were correlated to clinicopathologic characteristics. inactivation was found in 79 (97.5%) patients. All specimens had additional molecular alterations. The most common non- gene alteration was in 19 (22.9%). Five (11.0%) had pathogenic germline mutations in other non- cancer predisposition genes. Significant clinicopathologic correlations included: vitreous seeds associated with 1q gains and 16q loss of heterozygosity (BH-corrected -value = 0.008, 0.004; OR = 12.6, 26.7, respectively). mutations were associated with poor prognosis, specifically metastases-free survival (MFS) (nominal -value 0.03). Furthermore, retinoblastoma patients can have non- germline mutations in other cancer-associated genes. No two specimens had the identical genetic profile, emphasizing the individuality of tumors with the same clinical diagnosis.
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http://dx.doi.org/10.3390/cancers13010149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796332PMC
January 2021

Intravitreal melphalan hydrochloride vs propylene glycol-free melphalan for retinoblastoma vitreous seeds: Efficacy, toxicity and stability in rabbits models and patients.

Exp Eye Res 2021 03 11;204:108439. Epub 2021 Jan 11.

Division of Ocular Oncology and Pathology, Department of Ophthalmology and Visual Sciences, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA; Program in Cancer Biology, Vanderbilt University, Nashville, TN, USA; Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5 μg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p = 0.009), and 88% by MH (p = 0.004; PGFM vs. MH: p = 0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5 μg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 h of reconstitution) vs. 4 h after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, who were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical difference between formulations. Comparing those patient eyes treated exclusively with PGFM versus those treated exclusively with MH, efficacy for tumor control and globe salvage was equivalent (PGFM vs. MH: 96.2% vs. 93.8%, p = 0.56), but PGFM-treated eyes received fewer injections than MH-treated eyes (average 3.2 ± 1.9 vs. 6.4 ± 2.1 injections, p < 0.0001). Taken together, these rabbit experiments and our clinical experience in retinoblastoma patients demonstrate that MH and PGFM have equivalent efficacy and toxicity. PGFM was more stable, with no decreased efficacy or increased toxicity even 4 h after reconstitution. We therefore now use PGFM over traditional MH for our patients for intravitreal treatment of retinoblastoma.
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http://dx.doi.org/10.1016/j.exer.2021.108439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117559PMC
March 2021

Successful Treatment of Massive Choroidal Invasion in Retinoblastoma with Intra-arterial Chemotherapy (Ophthalmic Artery Chemosurgery).

Ophthalmol Retina 2021 09 29;5(9):936-939. Epub 2020 Dec 29.

Memorial Sloan Kettering Cancer Center, New York, New York; Weill Cornell Medical Center, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.oret.2020.12.018DOI Listing
September 2021

An In Utero Presentation of Trilateral Retinoblastoma.

Ophthalmol Retina 2021 08 26;5(8):831-832. Epub 2020 Dec 26.

Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Ophthalmology, Weill Cornell Medical Center, New York, New York.

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http://dx.doi.org/10.1016/j.oret.2020.12.017DOI Listing
August 2021

Retinoblastoma management in 13q deletion syndrome patients using super-selective chemotherapies and other cancer-directed interventions.

Pediatr Blood Cancer 2021 05 23;68(5):e28845. Epub 2020 Dec 23.

Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

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.
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http://dx.doi.org/10.1002/pbc.28845DOI Listing
May 2021

Reply.

Retina 2021 02;41(2):e24

Vitreous Retina Macula Consultants of New York, New York, New York.

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http://dx.doi.org/10.1097/IAE.0000000000003034DOI Listing
February 2021

Combined Inhibition of Gα and MEK Enhances Therapeutic Efficacy in Uveal Melanoma.

Clin Cancer Res 2021 03 23;27(5):1476-1490. Epub 2020 Nov 23.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gα) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gα have shown promising preclinical results, but their therapeutic activity in distinct Gα mutational contexts and have remained elusive.

Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in (e.g., G48V, R183Q, Q209L) and (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used and in xenograft studies to assess the efficacy of Gα inhibition as a single agent and in combination with MEK inhibition.

Results: We demonstrate that the Gα inhibitor YM-254890 inhibited downstream signaling and growth in all mutants. , YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition and tumor shrinkage .

Conclusions: These data suggest that the combination of Gα and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gα in uveal melanoma..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086191PMC
March 2021

A decision process for drug discovery in retinoblastoma.

Invest New Drugs 2021 04 16;39(2):426-441. Epub 2020 Nov 16.

Precision Medicine, Hospital de Pediatría JP Garrahan, 1245, Buenos Aires, Argentina.

Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.
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http://dx.doi.org/10.1007/s10637-020-01030-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488950PMC
April 2021

Unilateral Retinoblastoma Metastatic to the Skull and Both Orbits.

Ophthalmol Retina 2020 10;4(10):1021

Ophthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.oret.2020.04.019DOI Listing
October 2020

Optical Coherence Tomography Characteristics of the Choroid Underlying Congenital Hypertrophy of the Retinal Pigment Epithelium.

Ocul Oncol Pathol 2020 Aug 27;6(4):238-243. Epub 2020 Feb 27.

Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

Purpose: This study evaluates and characterizes the choroid underlying congenital hypertrophy of the retinal pigment epithelium (CHRPE).

Methods: Retrospective observational study of CHRPE at least 2 mm in diameter. Choroidal vascular architecture was qualitatively examined. Choroidal thickness was measured by 2 independent observers using enhanced depth imaging spectral domain optical coherence tomography.

Results: Forty-six eyes of 46 patients with CHRPE were included. Thirty-two lesions had imaging sufficient for analysis. Haller's layer was healthy in 18 (56%), thin in 13 (41%), and absent in 1 (2%). Sattler's layer was atrophic in 30 (94%), and choriocapillaris was atrophic in 31 (97%). CHRPE with thinned Haller's layer had significantly larger diameter. The mean sub-CHRPE choroidal thickness was 82.4 ± 7.9 µm, compared to a thickness of 148.4 ± 9.6 µm in the normal adjacent choroid ( < 0.0001). Mean retinal thickness overlying the CHRPE was 77.3 ± 4.3 µm, compared to a retinal thickness of 137.8 ± 2.9 µm overlying the normal adjacent choroid ( < 0.0001). Sub-CHRPE choroidal thickness was a mean of 56.2 ± 3.1% of the adjacent normal choroidal thickness.

Conclusion: The underlying choroid CHRPE is thinner than the adjacent normal choroid. All layers of the choroid can be thin with a preference of the inner Sattler's and choriocapillaris layers.
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http://dx.doi.org/10.1159/000504712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506233PMC
August 2020

Clinical, Genomic, and Pharmacological Study of -Amplified Wild-Type Metastatic Retinoblastoma.

Cancers (Basel) 2020 09 22;12(9). Epub 2020 Sep 22.

Precision Medicine, Hospital de Pediatría JP Garrahan, Buenos Aires 1245, Argentina.

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in gene with high-level amplification of (ampl+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of ampl+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common high amplification and chromosome 16q and 17p loss. A somatic mutation in , in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient's poor response but sensitivity to the synergistic effects of panobinostat-bortezomib and carboplatin-panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic ampl+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.
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http://dx.doi.org/10.3390/cancers12092714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565107PMC
September 2020
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