Acta Ophthalmologica 2015
developed reduced visual acuity in the first decade of life. A further recent paper detailed a consanguinous family with early onset cone-rod dystrophy due to splice site mutations in ADAM9 (El-Haig et al. 2014). We report the detailed clinical phenotype in a child with retinal disease caused by a homozygous mutation in ADAM9. A male patient presented at age 3 years. He was noted in infancy to have a right convergent squint with poor vision and eccentric fixation. There was no nystagmus. He was otherwise well with normal development. The parents were from Pakistan and were first cousins. At last review, age 7, the vision was right 1.0 logMAR (Snellen 6/60), left 0.88 logMAR (Snellen 6/48) with a hyperopic, astigmatic refractive error of R + 4.00/2.50 9 20 L + 4.00/2.00 9 180. There was a moderate left divergent squint with eccentric fixation. Early posterior subcapsular cataract was noted. Fundus examination showed posterior pole atrophy with a white-speckled appearance, which extended to the arcades and encompassed the optic disc (Fig. 1). Retinal imaging demonstrated reduced autofluorescence in the posterior pole with atrophy of the outer retina on optical coherence tomography (Fig. 1). Pattern and flash electroretinography (PERG; ERG) performed at the age of 3 years using surface electrodes revealed an undetectable PERG and borderline photopic and scotopic ERGs. At the age of 7 years, the PERG and full-field ERG were performed using corneal electrodes to ISCEV standards. The PERG was undetectable in keeping with severe macular dysfunction, and mildly abnormal full-field ERGs were consistent with cone-rod dystrophy (Fig. 1). Whole exome sequencing was performed (AROS Applied Biotechnology, Aarhus, Denmark), which identified a novel, homozygous mutation in ADAM9, c.967delT; p.Ser323Glnfs*33, which on direct Sanger sequencing was shown to segregate in the family with both parents heterozygous for this mutation (Fig. 1). Non-syndromic, autosomal recessive CORD is rare and usually associated with biallelic mutations in ABCA4 (Bocquet et al. 2013). In the previous reports of CORD due to ADAM9, five families were identified with mutations leading to either aberrant splicing or
premature truncation codons. Similar to our patient, all had poor vision in their first decade of life, no nystagmus and outer retinal atrophy of the macula. Most were also noted to have discrete white patches in the posterior pole and around the disc and a peripheral pigmentary retinopathy, which is not present in our patient. Retinal imaging in a previous report of the index family demonstrated posterior pole atrophy in two patients in their 40s with a similar appearance to our patient (Danciger et al. 2001). Electrophysiology in these two patients demonstrated severe loss of both cone and rod function. In the recent report of a single family, the youngest patient assessed was 17 years (El-Haig et al. 2014). Posterior pole atrophy was noted, and in the retinal images this also encompassed the disc. No electrophysiology was available. Given the young age of our patient, we have been able to demonstrate the electrophysiological phenotype of severe loss of macular function in the early stages with relatively mild peripheral retinal dysfunction. In both a canine and mouse model, there are cone and rod photoreceptor abnormalities on electrophysiology which are not apparent in very young animals but develop with time (Parry et al. 2009; Goldstein et al. 2010). In both models, histopathology localized the primary defect to the apical microvilli of the retinal pigment epithelium potentially mediated by failure of normal photoreceptor outer segment phagocytosis. These animal models show early preservation of photoreceptor structure despite dysfunction. This together with relatively good peripheral photoreceptor function in early human disease as illustrated by this case suggests that there is a therapeutic window for gene therapy in patients with mutations in ADAM9.
References Bocquet B, Lacroux A, Surget MO et al. (2013): Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management. Ophthalmic Epidemiol 20: 13–25. Danciger M, Hendrickson J, Lyon J et al. (2001): CORD9 a new locus for arCRD: mapping to 8p11, estimation of frequency,
evaluation of a candidate gene. Invest Ophthalmol Vis Sci 42: 2458–2465. El-Haig WM, Jakobsson C, Favez T, Schorderet DF & Abouzeid H (2014): Novel ADAM9 homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract. Br J Ophthalmol 98: 1718–1723. Goldstein O, Mezey JG, Boyko AR et al. (2010): An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9. Mol Vis 16: 1549–1569. Parry DA, Toomes C, Bida L et al. (2009): Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet 84: 683–691.
Correspondence: Anthony T. Moore, MA, FRCOphth Inherited Eye Diseases UCL Institute of Ophthalmology 11-43 Bath St London EC1V 9EL, UK Tel: +44 20 7566 2260 Fax: +44 20 7608 6830 Email: [email protected] The National Institute for Health Research (UK) and Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, The Foundation Fighting Blindness (USA), Fight For Sight, Moorfields Eye Hospital Special Trustees, RP Fighting Blindness, Rosetrees Trust.
Efficacy and safety of SNJ-1656 in primary openangle glaucoma or ocular hypertension Toshihiro Inoue,1 Hidenobu Tanihara,1 Hideki Tokushige2 and Makoto Araie3 1
Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; 2Senju Pharmaceutical Co, Ltd, Osaka, Japan; 3 Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan doi: 10.1111/aos.12641
Editor, he results of phase 1 trial of SNJ-1656, an ophthalmic solution of a Rho-associated kinase (ROCK)
T
e393
Acta Ophthalmologica 2015
inhibitor, were reported previously (Tanihara et al. 2008). Here, we report the results of a randomized, double-masked, multicentre, phase 2 clinical study of SNJ-1656. Subjects with primary openangle glaucoma (POAG) or ocular hypertension (OHT), aged 20–74 years, with intraocular pressure (IOP) 22– 31 mm Hg and corrected visual acuity ≥20/40 were included. After screening examination, IOP-lowering drugs were washed out, and subjects received either 0.03%, 0.05% or 0.1% of SNJ-1656 or placebo twice daily (between 8:30 and 10:30 AM, and between 8:00 and 10:00 PM) in both eyes for 7 days. The eye with the higher IOP at the initial visit (right eye if the IOPs were the same) was chosen as the study eye for efficacy. Safety was evaluated in both eyes. Ophthalmologic findings and physiologic conditions were examined at the visit for starting administration of SNJ-1656 and the final visit during the trials, and
the conjunctiva and cornea were examined with slit-lamp microscopy before and 2 hr after administration at each visit. By calculation, at 2.5% of significance level and 90% of statistical power, 13 subjects per group were required to achieve the probability of the estimates of treatment differences between the groups. Unless otherwise indicated, data are expressed as mean SD. P value of less than 0.05 was considered statistically significant, which were analysed by SAS for Windows Release 9.13 (SAS Inc, Cary, NC, USA). In total, 66 subjects were enrolled, of which 63 subjects completed the study. Non-completing subjects were discontinued due to hyperaemia in 2 subjects, and headache and foreign body sensation in 1 subject treated with 0.05% SNJ-1656. There were no differences in the characteristics of the population among the groups (Fig. 1A). After 7-day instillation of placebo or 0.03%,
0.05% or 0.1% SNJ-1656, changes in IOP from the baseline just before instillation of the morning eyedrops were 2.2 1.9, 3.8 2.7, 4.3 2.3 and 4.0 2.5 mm Hg, respectively (Fig. 1B). The corresponding values 2 hr after instillation of the morning eyedrops were 1.5 2.2, 5.0 2.4, 4.4 2.7 and 4.5 1.9 mm Hg, respectively (Fig. 1C; p = 0.0002, 0.0025 and 0.0010 for the 0.03%, 0.05% and 0.1% solution, respectively). Seventy-five treatmentrelated adverse events in 41 subjects were reported in a total of 66 patients: 15 treated with 0.03% SNJ-1656, 31 with 0.05% SNJ-1656, 28 with 0.1% SNJ-1656, and 1 in the placebo group, which were different among groups (p < 0.0001). Conjunctival hyperaemia was the most frequently reported adverse event: 9, 15 and 15 subjects, that were moderate in 1, 3 and 3 subjects, treated with 0.03%, 0.05%
(B)
(A)
(C)
Fig. 1. (A) The characteristics of the population among the groups. (B) IOP levels just before instillation of the morning eyedrops. (C) IOP levels 2 hr after instillation of the morning eyedrops. Values are shown as mean SD (16 subjects in placebo group, 15 subjects in 0.03%, 14 subjects in 0.05% and 18 subjects in 0.1% SNJ-1656 group). The significance of findings was evaluated by Dunnett’s test (2-sided). *p < 0.05 compared with the placebo group.
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and 0.1% SNJ-1656, respectively. Punctate keratitis was observed in 1 subject treated with 0.03% SNJ1656 and in 1 subject with 0.1% SNJ-1656. One subject had mild hepatic dysfunction after 0.05% SNJ1656 instillation. All adverse events were mild to moderate except in 1 case: hyperaemia in 1 subject treated with 0.03% SNJ-1656. Adverse events requiring treatment were headache and abdominal pain, conjunctival hyperaemia and nasopharyngitis in 1 subject each, all of which recovered. There was no abnormal value in haematologic and urine examinations, except in 1 subject for 0.05% SNJ-1656 with mild hepatic dysfunction, recovered after the cessation of SNJ-1656 without treatment. Systolic blood pressure was not different between day 0 and 7 in any of the groups before and after instillation except the placebo group before instillation, which were 131.6 20.2 and 126.3 18.7 mm Hg on day 0 and 7, respectively (p = 0.007).
Reference Tanihara H, Inatani M, Honjo M, Tokushige H, Azuma J & Araie M (2008): Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch Ophthalmol 126: 309–315.
Correspondence: Hidenobu Tanihara, MD Department of Ophthalmology Faculty of Life Sciences Kumamoto University 1-1-1 Honjo, Chuo-Ku Kumamoto 860-8556, Japan Tel: +81 96 373 5247 Fax: +81 96 373 5249 Email: [email protected] The research was supported by Senju Pharmaceutical Co, Ltd, Osaka, Japan. Senju participated in the design of the study, conduct of the study, data collection, data management, data analysis, interpretation of the data, and preparation, review, and approval of the manuscript. HT1 has received consulting fees from Kowa, and MSD, and board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan. TI has no financial interest. HT2 is employee of Senju Pharmaceutical. MA has received consulting fees from Kowa, MSD, Topcon, and Allergan Japan, and board member-
ship fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan and lecture fees from Carl Zeiss Japan, and has patents of Topcon. No company shown above writes or influences directly the wording of the manuscript.This research was supported by the National Natural Science Foundation of China (81371008), the Science and Technology Planning Project of Guangdong Province, China (No. 2012B031800353) and the Science and Research Project of Xiangnan University, China (No. 2013YJ67).
Relapse of acute lymphoblastic leukaemia (ALL) Nils A. Eide,1 Thomas P. Bærland,1 Ellen Sauesund,1 Jon Lømo,2 Marius LundIversen 2 and Sigurd Liestøl3 1
Department of Ophthalmology, Oslo University Hospital –HF and University of Oslo, Oslo, Norway; 2Department of Pathology, Oslo University Hospital – HF and University of Oslo, Oslo, Norway; 3Department of Haematology, Oslo University Hospital –HF and University of Oslo, Oslo, Norway doi: 10.1111/aos.12619
Editor, xtramedullary leukaemia remains an important complication of acute lymphoblastic leukaemia (ALL). Side-effects of treatment are observed more frequently than ocular infiltration of tumour cells (Sharma et al. (2004). The outcome for patients with ALL continues to improve with event-free survival (EFS) rates approaching 80% (Barredo et al. 2006). Involvement of the anterior segment is a rare (Patel et al. 2003; Sharma et al. 2004), but well documented manifestation, usually with a simultaneous relapse in the central nervous system. The prognosis for patients with isolated CNS recurrences is poor. It has been attempted to tailor the CNS radiation during intensified systemic therapy. The goal is to reduce the risk of long-term neurocognitive deficits and secondary brain neoplasms (Barredo et al. 2006). The aim of this letter was to stress the need for eye evaluation before stem cell transplantation (SCT) and the importance of new signs after SCT.
E
In March 2011, a 22-year-old man noticed weight loss and dyspnoea. In May 2011, enlarged lymph glands, hepatosplenomegaly and petechiae located on neck and lower extremities were detected. Abnormal values of leucocytes: 52 9 109/l, thrombocytes: 24 9 109/l, Hb: 8.3 g/dl and LD: 807 were measured. A maximal cell-rich bone marrow biopsy showed lymphoblast domination and flow cytometry revealed a B-lymphoblastic leukaemia, (83%) with the following immunophenotype: CD45+, CD34+, CD19+, CD20/+ (weak), CD10+ (strong) and Tdt+. Cytogenetic examination showed no abnormalities. Cerebrospinal fluid contained no blasts. A common B-cell ALL was diagnosed. Treatment according to the Hammersmith protocol was started. SCT was not indicated due to a good response to induction treatment with minimal residual disease. Episodes of uveitis in his left eye were treated by ophthalmologists at the University hospital and at the local eye department in the time between the primary treatment and a CNS relapse diagnosed in January 2013. Cerebrospinal fluid at this point was turbid and contained 165 blasts. Preconditioning prior to SCT was started with seven intrathecal methotrexate injections and radiotherapy to the CNS axis (given with 6 MeV photon beams, 10 doses of 1.8 Gy 5 days a week (total 18 Gy) to the brain and seven doses of 1.8 Gy 5 days a week (12.6 Gy) to the medullary cord, eyes not included) and hyper-CVAD block (cyclophosfamide, vincristine, antracycline and doxorubicin), which was given twice. In June 2013, allogenic SCT was performed with an unrelated, HLAcompatible female donor. Their blood groups were mismatched (donor A+, recipient B+). The result was good haematological reconstitution with >99% donor chimerism. In September 2013, an ocular relapse of was considered because of multiple, bilateral chorioretinal lesions (Fig. 1) and massive infiltration of iris in the left eye (Fig. 2). The eyes showed a poor response to intensive local steroid treatment. Magnetic resonance imaging (MRI) (orbital and cerebral), cerebrospinal fluid and BM-aspirate and BMbiopsy were normal. Pathology was documented using ultrasound biomicroscopy, wide-field fundus photographs
e395
developed reduced visual acuity in the first decade of life. A further recent paper detailed a consanguinous family with early onset cone-rod dystrophy due to splice site mutations in ADAM9 (El-Haig et al. 2014). We report the detailed clinical phenotype in a child with retinal disease caused by a homozygous mutation in ADAM9. A male patient presented at age 3 years. He was noted in infancy to have a right convergent squint with poor vision and eccentric fixation. There was no nystagmus. He was otherwise well with normal development. The parents were from Pakistan and were first cousins. At last review, age 7, the vision was right 1.0 logMAR (Snellen 6/60), left 0.88 logMAR (Snellen 6/48) with a hyperopic, astigmatic refractive error of R + 4.00/2.50 9 20 L + 4.00/2.00 9 180. There was a moderate left divergent squint with eccentric fixation. Early posterior subcapsular cataract was noted. Fundus examination showed posterior pole atrophy with a white-speckled appearance, which extended to the arcades and encompassed the optic disc (Fig. 1). Retinal imaging demonstrated reduced autofluorescence in the posterior pole with atrophy of the outer retina on optical coherence tomography (Fig. 1). Pattern and flash electroretinography (PERG; ERG) performed at the age of 3 years using surface electrodes revealed an undetectable PERG and borderline photopic and scotopic ERGs. At the age of 7 years, the PERG and full-field ERG were performed using corneal electrodes to ISCEV standards. The PERG was undetectable in keeping with severe macular dysfunction, and mildly abnormal full-field ERGs were consistent with cone-rod dystrophy (Fig. 1). Whole exome sequencing was performed (AROS Applied Biotechnology, Aarhus, Denmark), which identified a novel, homozygous mutation in ADAM9, c.967delT; p.Ser323Glnfs*33, which on direct Sanger sequencing was shown to segregate in the family with both parents heterozygous for this mutation (Fig. 1). Non-syndromic, autosomal recessive CORD is rare and usually associated with biallelic mutations in ABCA4 (Bocquet et al. 2013). In the previous reports of CORD due to ADAM9, five families were identified with mutations leading to either aberrant splicing or
premature truncation codons. Similar to our patient, all had poor vision in their first decade of life, no nystagmus and outer retinal atrophy of the macula. Most were also noted to have discrete white patches in the posterior pole and around the disc and a peripheral pigmentary retinopathy, which is not present in our patient. Retinal imaging in a previous report of the index family demonstrated posterior pole atrophy in two patients in their 40s with a similar appearance to our patient (Danciger et al. 2001). Electrophysiology in these two patients demonstrated severe loss of both cone and rod function. In the recent report of a single family, the youngest patient assessed was 17 years (El-Haig et al. 2014). Posterior pole atrophy was noted, and in the retinal images this also encompassed the disc. No electrophysiology was available. Given the young age of our patient, we have been able to demonstrate the electrophysiological phenotype of severe loss of macular function in the early stages with relatively mild peripheral retinal dysfunction. In both a canine and mouse model, there are cone and rod photoreceptor abnormalities on electrophysiology which are not apparent in very young animals but develop with time (Parry et al. 2009; Goldstein et al. 2010). In both models, histopathology localized the primary defect to the apical microvilli of the retinal pigment epithelium potentially mediated by failure of normal photoreceptor outer segment phagocytosis. These animal models show early preservation of photoreceptor structure despite dysfunction. This together with relatively good peripheral photoreceptor function in early human disease as illustrated by this case suggests that there is a therapeutic window for gene therapy in patients with mutations in ADAM9.
References Bocquet B, Lacroux A, Surget MO et al. (2013): Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management. Ophthalmic Epidemiol 20: 13–25. Danciger M, Hendrickson J, Lyon J et al. (2001): CORD9 a new locus for arCRD: mapping to 8p11, estimation of frequency,
evaluation of a candidate gene. Invest Ophthalmol Vis Sci 42: 2458–2465. El-Haig WM, Jakobsson C, Favez T, Schorderet DF & Abouzeid H (2014): Novel ADAM9 homozygous mutation in a consanguineous Egyptian family with severe cone-rod dystrophy and cataract. Br J Ophthalmol 98: 1718–1723. Goldstein O, Mezey JG, Boyko AR et al. (2010): An ADAM9 mutation in canine cone-rod dystrophy 3 establishes homology with human cone-rod dystrophy 9. Mol Vis 16: 1549–1569. Parry DA, Toomes C, Bida L et al. (2009): Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet 84: 683–691.
Correspondence: Anthony T. Moore, MA, FRCOphth Inherited Eye Diseases UCL Institute of Ophthalmology 11-43 Bath St London EC1V 9EL, UK Tel: +44 20 7566 2260 Fax: +44 20 7608 6830 Email: [email protected] The National Institute for Health Research (UK) and Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, The Foundation Fighting Blindness (USA), Fight For Sight, Moorfields Eye Hospital Special Trustees, RP Fighting Blindness, Rosetrees Trust.
Efficacy and safety of SNJ-1656 in primary openangle glaucoma or ocular hypertension Toshihiro Inoue,1 Hidenobu Tanihara,1 Hideki Tokushige2 and Makoto Araie3 1
Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; 2Senju Pharmaceutical Co, Ltd, Osaka, Japan; 3 Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, Japan doi: 10.1111/aos.12641
Editor, he results of phase 1 trial of SNJ-1656, an ophthalmic solution of a Rho-associated kinase (ROCK)
T
e393
Acta Ophthalmologica 2015
inhibitor, were reported previously (Tanihara et al. 2008). Here, we report the results of a randomized, double-masked, multicentre, phase 2 clinical study of SNJ-1656. Subjects with primary openangle glaucoma (POAG) or ocular hypertension (OHT), aged 20–74 years, with intraocular pressure (IOP) 22– 31 mm Hg and corrected visual acuity ≥20/40 were included. After screening examination, IOP-lowering drugs were washed out, and subjects received either 0.03%, 0.05% or 0.1% of SNJ-1656 or placebo twice daily (between 8:30 and 10:30 AM, and between 8:00 and 10:00 PM) in both eyes for 7 days. The eye with the higher IOP at the initial visit (right eye if the IOPs were the same) was chosen as the study eye for efficacy. Safety was evaluated in both eyes. Ophthalmologic findings and physiologic conditions were examined at the visit for starting administration of SNJ-1656 and the final visit during the trials, and
the conjunctiva and cornea were examined with slit-lamp microscopy before and 2 hr after administration at each visit. By calculation, at 2.5% of significance level and 90% of statistical power, 13 subjects per group were required to achieve the probability of the estimates of treatment differences between the groups. Unless otherwise indicated, data are expressed as mean SD. P value of less than 0.05 was considered statistically significant, which were analysed by SAS for Windows Release 9.13 (SAS Inc, Cary, NC, USA). In total, 66 subjects were enrolled, of which 63 subjects completed the study. Non-completing subjects were discontinued due to hyperaemia in 2 subjects, and headache and foreign body sensation in 1 subject treated with 0.05% SNJ-1656. There were no differences in the characteristics of the population among the groups (Fig. 1A). After 7-day instillation of placebo or 0.03%,
0.05% or 0.1% SNJ-1656, changes in IOP from the baseline just before instillation of the morning eyedrops were 2.2 1.9, 3.8 2.7, 4.3 2.3 and 4.0 2.5 mm Hg, respectively (Fig. 1B). The corresponding values 2 hr after instillation of the morning eyedrops were 1.5 2.2, 5.0 2.4, 4.4 2.7 and 4.5 1.9 mm Hg, respectively (Fig. 1C; p = 0.0002, 0.0025 and 0.0010 for the 0.03%, 0.05% and 0.1% solution, respectively). Seventy-five treatmentrelated adverse events in 41 subjects were reported in a total of 66 patients: 15 treated with 0.03% SNJ-1656, 31 with 0.05% SNJ-1656, 28 with 0.1% SNJ-1656, and 1 in the placebo group, which were different among groups (p < 0.0001). Conjunctival hyperaemia was the most frequently reported adverse event: 9, 15 and 15 subjects, that were moderate in 1, 3 and 3 subjects, treated with 0.03%, 0.05%
(B)
(A)
(C)
Fig. 1. (A) The characteristics of the population among the groups. (B) IOP levels just before instillation of the morning eyedrops. (C) IOP levels 2 hr after instillation of the morning eyedrops. Values are shown as mean SD (16 subjects in placebo group, 15 subjects in 0.03%, 14 subjects in 0.05% and 18 subjects in 0.1% SNJ-1656 group). The significance of findings was evaluated by Dunnett’s test (2-sided). *p < 0.05 compared with the placebo group.
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Acta Ophthalmologica 2015
and 0.1% SNJ-1656, respectively. Punctate keratitis was observed in 1 subject treated with 0.03% SNJ1656 and in 1 subject with 0.1% SNJ-1656. One subject had mild hepatic dysfunction after 0.05% SNJ1656 instillation. All adverse events were mild to moderate except in 1 case: hyperaemia in 1 subject treated with 0.03% SNJ-1656. Adverse events requiring treatment were headache and abdominal pain, conjunctival hyperaemia and nasopharyngitis in 1 subject each, all of which recovered. There was no abnormal value in haematologic and urine examinations, except in 1 subject for 0.05% SNJ-1656 with mild hepatic dysfunction, recovered after the cessation of SNJ-1656 without treatment. Systolic blood pressure was not different between day 0 and 7 in any of the groups before and after instillation except the placebo group before instillation, which were 131.6 20.2 and 126.3 18.7 mm Hg on day 0 and 7, respectively (p = 0.007).
Reference Tanihara H, Inatani M, Honjo M, Tokushige H, Azuma J & Araie M (2008): Intraocular pressure-lowering effects and safety of topical administration of a selective ROCK inhibitor, SNJ-1656, in healthy volunteers. Arch Ophthalmol 126: 309–315.
Correspondence: Hidenobu Tanihara, MD Department of Ophthalmology Faculty of Life Sciences Kumamoto University 1-1-1 Honjo, Chuo-Ku Kumamoto 860-8556, Japan Tel: +81 96 373 5247 Fax: +81 96 373 5249 Email: [email protected] The research was supported by Senju Pharmaceutical Co, Ltd, Osaka, Japan. Senju participated in the design of the study, conduct of the study, data collection, data management, data analysis, interpretation of the data, and preparation, review, and approval of the manuscript. HT1 has received consulting fees from Kowa, and MSD, and board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan. TI has no financial interest. HT2 is employee of Senju Pharmaceutical. MA has received consulting fees from Kowa, MSD, Topcon, and Allergan Japan, and board member-
ship fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan and lecture fees from Carl Zeiss Japan, and has patents of Topcon. No company shown above writes or influences directly the wording of the manuscript.This research was supported by the National Natural Science Foundation of China (81371008), the Science and Technology Planning Project of Guangdong Province, China (No. 2012B031800353) and the Science and Research Project of Xiangnan University, China (No. 2013YJ67).
Relapse of acute lymphoblastic leukaemia (ALL) Nils A. Eide,1 Thomas P. Bærland,1 Ellen Sauesund,1 Jon Lømo,2 Marius LundIversen 2 and Sigurd Liestøl3 1
Department of Ophthalmology, Oslo University Hospital –HF and University of Oslo, Oslo, Norway; 2Department of Pathology, Oslo University Hospital – HF and University of Oslo, Oslo, Norway; 3Department of Haematology, Oslo University Hospital –HF and University of Oslo, Oslo, Norway doi: 10.1111/aos.12619
Editor, xtramedullary leukaemia remains an important complication of acute lymphoblastic leukaemia (ALL). Side-effects of treatment are observed more frequently than ocular infiltration of tumour cells (Sharma et al. (2004). The outcome for patients with ALL continues to improve with event-free survival (EFS) rates approaching 80% (Barredo et al. 2006). Involvement of the anterior segment is a rare (Patel et al. 2003; Sharma et al. 2004), but well documented manifestation, usually with a simultaneous relapse in the central nervous system. The prognosis for patients with isolated CNS recurrences is poor. It has been attempted to tailor the CNS radiation during intensified systemic therapy. The goal is to reduce the risk of long-term neurocognitive deficits and secondary brain neoplasms (Barredo et al. 2006). The aim of this letter was to stress the need for eye evaluation before stem cell transplantation (SCT) and the importance of new signs after SCT.
E
In March 2011, a 22-year-old man noticed weight loss and dyspnoea. In May 2011, enlarged lymph glands, hepatosplenomegaly and petechiae located on neck and lower extremities were detected. Abnormal values of leucocytes: 52 9 109/l, thrombocytes: 24 9 109/l, Hb: 8.3 g/dl and LD: 807 were measured. A maximal cell-rich bone marrow biopsy showed lymphoblast domination and flow cytometry revealed a B-lymphoblastic leukaemia, (83%) with the following immunophenotype: CD45+, CD34+, CD19+, CD20/+ (weak), CD10+ (strong) and Tdt+. Cytogenetic examination showed no abnormalities. Cerebrospinal fluid contained no blasts. A common B-cell ALL was diagnosed. Treatment according to the Hammersmith protocol was started. SCT was not indicated due to a good response to induction treatment with minimal residual disease. Episodes of uveitis in his left eye were treated by ophthalmologists at the University hospital and at the local eye department in the time between the primary treatment and a CNS relapse diagnosed in January 2013. Cerebrospinal fluid at this point was turbid and contained 165 blasts. Preconditioning prior to SCT was started with seven intrathecal methotrexate injections and radiotherapy to the CNS axis (given with 6 MeV photon beams, 10 doses of 1.8 Gy 5 days a week (total 18 Gy) to the brain and seven doses of 1.8 Gy 5 days a week (12.6 Gy) to the medullary cord, eyes not included) and hyper-CVAD block (cyclophosfamide, vincristine, antracycline and doxorubicin), which was given twice. In June 2013, allogenic SCT was performed with an unrelated, HLAcompatible female donor. Their blood groups were mismatched (donor A+, recipient B+). The result was good haematological reconstitution with >99% donor chimerism. In September 2013, an ocular relapse of was considered because of multiple, bilateral chorioretinal lesions (Fig. 1) and massive infiltration of iris in the left eye (Fig. 2). The eyes showed a poor response to intensive local steroid treatment. Magnetic resonance imaging (MRI) (orbital and cerebral), cerebrospinal fluid and BM-aspirate and BMbiopsy were normal. Pathology was documented using ultrasound biomicroscopy, wide-field fundus photographs
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