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We would like to add some data to this interesting discussion about the impact of ophthalmic artery chemosurgery or intra-arterial chemotherapy (OAC) in the occurrence of secondary malignancies in children with retinoblastoma with germline mutations of the Rb1 gene.
The discussion about the incidence of secondary leukemia is an important one. Secondary leukemias usually present early in the patient follow-up, usually around 2-3 years. Systemic chemotherapy has been implicated in their occurrence since, they were not identified as a common secondary malignancy in patients with retinoblastoma not receiving chemotherapy1. Their occurrence is low1, but as the case Dr Meadows and Lahey report are usually refractory to treatment and usually fatal. In our series of patients treated with systemic chemoreduction for conservative therapy from Argentina, secondary AML was the most common fatal secondary malignancy with a total of 2 out of 129 cases. We had a third case in a child receiving chemotherapy for extraocular disease, similarly to Dr Meadows and Lahey’s case2. In our current, yet unpublished results with ophthalmic artery chemosurgery, we had no case of secondary AML , in 71 consecutive cases with bilateral retinoblastoma treated with OAC with a median follow-up of 42 months. Secondary AML has been widely reported as a complication of systemic chemotherapy in pediatric oncology patients 3 including those receiving epipodophillotoxins 4and also alkylating agents5. Cum...
We would like to add some data to this interesting discussion about the impact of ophthalmic artery chemosurgery or intra-arterial chemotherapy (OAC) in the occurrence of secondary malignancies in children with retinoblastoma with germline mutations of the Rb1 gene.
The discussion about the incidence of secondary leukemia is an important one. Secondary leukemias usually present early in the patient follow-up, usually around 2-3 years. Systemic chemotherapy has been implicated in their occurrence since, they were not identified as a common secondary malignancy in patients with retinoblastoma not receiving chemotherapy1. Their occurrence is low1, but as the case Dr Meadows and Lahey report are usually refractory to treatment and usually fatal. In our series of patients treated with systemic chemoreduction for conservative therapy from Argentina, secondary AML was the most common fatal secondary malignancy with a total of 2 out of 129 cases. We had a third case in a child receiving chemotherapy for extraocular disease, similarly to Dr Meadows and Lahey’s case2. In our current, yet unpublished results with ophthalmic artery chemosurgery, we had no case of secondary AML , in 71 consecutive cases with bilateral retinoblastoma treated with OAC with a median follow-up of 42 months. Secondary AML has been widely reported as a complication of systemic chemotherapy in pediatric oncology patients 3 including those receiving epipodophillotoxins 4and also alkylating agents5. Cumulative systemic exposure to chemotherapy , along with genetic predisposition, seem to play a major role in its occurrence4, 5. In the case, Dr Meadows and Lahey report, the doses of alkylating agents received for the treatment with high dose chemotherapy should have been significantly higher than those from intra-arterial melphalan. We have estimated from our pharmacokinetic study of melphalan in patients receiving OAC for the treatment of retinoblastoma that systemic exposure is at least 10 times lower compared to systemic doses which are regularly used for preparation for high dose therapy and stem cell rescue as Dr Meadows and Lahey’s case6. Additionally, since OAC regimens do not include epipodophillotoxins, secondary leukemias caused by exposure to these drugs are eliminated. So, while it is likely that the significantly lower systemic exposure to chemotherapy obtained by OAC6 might add some risk of secondary leukemia to these predisposed patients, date presented up to the present time suggest that, compared to systemic chemotherapy a lower incidence of secondary leukemia or in fact no cases in children only treated with OAC are seen.
The discussion about the potential prevention of metastatic dissemination and the role of systemic versus OAC in it is also an open one. While it is likely that lower systemic chemotherapy levels achieved with OAC might provide a lower protection against systemic dissemination, on the other hand OAC provides a significantly higher exposure to chemotherapy in the optic nerve, which is a major source of dissemination for retinoblastoma to the CNS. Dissemination to this critical compartment is usually fatal7. If we apply the rationale proposed by Dr Lahey and Meadows of thinking that a higher exposure to chemotherapy would be more effective in preventing metastasis in minimally disseminated disease, OAC would be more effective in preventing dissemination through the optic nerve compared to systemic chemotherapy.
References
1. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114: 1378-1383.
2. Chantada GL, Fandino AC, Raslawski EC, et al. Experience with chemoreduction and focal therapy for intraocular retinoblastoma in a developing country. Pediatr Blood Cancer. 2005;44: 455-460.
3. Hijiya N, Ness KK, Ribeiro RC, Hudson MM. Acute leukemia as a secondary malignancy in children and adolescents: current findings and issues. Cancer. 2009;115: 23-35.
4. Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. N Engl J Med. 1991;325: 1682-1687.
5. Davies SM. Therapy-related leukemia associated with alkylating agents. Med Pediatr Oncol. 2001;36: 536-540.
6. Schaiquevich P, Buitrago E, Taich P, et al. Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci. 2012;53: 4205-4212.
7. Taich P, Requejo F, Asprea M, et al. Topotecan Delivery to the Optic Nerve after Ophthalmic Artery Chemosurgery. PLoS One. 2016;11: e0151343.
Dear Editor,
We have read with interest the paper by Klimova et al. Some statements in the paper are confusing and may even mislead the readers.
The authors claim in the survival section of the paper that: "Vitreoretinal lymphoma is a life-threatening disease, with a 5-year survival rate of 71% in our study". Vitreoretinal lymphoma (VRL) may affect vision, and in very advanced cases that we rarely see in recent years, may destroy the eye. However, VRL per se is not what that kills the patients, but the associated brain lymphoma or in some case the systemic lymphoma.
According to the results in this study (and the title of the paper), "Combined (local and systemic) treatment in patients with PVRL showed favorable results in comparison with local therapy alone (p=0.695). However, the statistical significance was not reached". It is no wonder that they claim that combined treatment is better than local treatment when they have 60% relapses. However, no other study of intra-vitreal (IVit) Methotrexate showed such a high relapse rate. In our experience, the relapse rate is extremely low with IVit methotrexate alone. Actually, in summarizing our ten years results we had no recurrence of the intraocular disease (2) and summarizing now our 20-year experience with 113 eyes, we had only two cases of recurrences (unpublished data). It is difficult to explain the poor results of the authors’ patients, using either intravitreal methotrexate al...
Dear Editor,
We have read with interest the paper by Klimova et al. Some statements in the paper are confusing and may even mislead the readers.
The authors claim in the survival section of the paper that: "Vitreoretinal lymphoma is a life-threatening disease, with a 5-year survival rate of 71% in our study". Vitreoretinal lymphoma (VRL) may affect vision, and in very advanced cases that we rarely see in recent years, may destroy the eye. However, VRL per se is not what that kills the patients, but the associated brain lymphoma or in some case the systemic lymphoma.
According to the results in this study (and the title of the paper), "Combined (local and systemic) treatment in patients with PVRL showed favorable results in comparison with local therapy alone (p=0.695). However, the statistical significance was not reached". It is no wonder that they claim that combined treatment is better than local treatment when they have 60% relapses. However, no other study of intra-vitreal (IVit) Methotrexate showed such a high relapse rate. In our experience, the relapse rate is extremely low with IVit methotrexate alone. Actually, in summarizing our ten years results we had no recurrence of the intraocular disease (2) and summarizing now our 20-year experience with 113 eyes, we had only two cases of recurrences (unpublished data). It is difficult to explain the poor results of the authors’ patients, using either intravitreal methotrexate alone or in combination with systemic high dose methotrexate.
In their discussion, the authors write that "Vitreoretinal lymphomas are considered to be systemic disease….". It should be emphasized that this disease is in most cases a unique type of lymphoma that affects immune-privileged organs: the brain, the eye, and the testis, and only in some cases (17% in our experience), the eye disease accompanies systemic lymphoma.
References
1) Klimova A, Heissigerova J, Rihova E, et al. Combined treatment of primary vitreoretinal lymphomas significantly prolongs the time to first relapse. Br J Ophthalmol 2018, doi: 10.1136/bjophthalmol-2017-311574
2) Frenkel S, Hendler K, Siegal T, et al. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol 2008;92:383-8.
Sincerely Yours,
Jacob Pe'er, M.D.
Shahar Frenkel, M.D., Ph.D.
Ocular Oncology Service
Department of Ophthalmology
Hadassah – Hebrew University Medical center
Jerusalem, Israel
Dear Editor,
We have read with interest the recently published article by Al Arrayedh H, Collum L, Murphy CC (1). The authors concluded that a poor outcome was seen after PKP for CHED in Irish population, which arises from a combination of dense amblyopia and a high risk of graft failure in the long term. This is an important study which has a unique cohort of only autosomal recessive cases from a large Irish consanguineous family.
We want to highlight some points in this article that were not clearly described .
Author reported 2 previously diagnosed congenital glaucoma cases, which also affects the visual outcome of the surgery and may skew results of this study. But they had not mentioned clearly about this.
In the figure 2 , the failed DSEK case also received regrafting twice but that was not shown in the legend.Also 32 eyes received penetrating keratoplasty as per the text but in that figure , 33 was mentioned.
In some previous studies 12 years of age (2,3) has been mentioned as the demarcation for outcome of penetrating keratoplasty in congenital hereditary endothelial dystrophy . This was not analysed in this very important study (maybe because of small numbers) but it could have been a useful clinical hint for timing of surgery in these patients.
Thanks
1. AlArrayedh H, Collum L, Murphy CC. Outcomes of penetrating keratoplasty in congenital hereditary endothelial dystrophy. Br J Ophthalmol. 2018 Jan;102(1):19-25 ...
Dear Editor,
We have read with interest the recently published article by Al Arrayedh H, Collum L, Murphy CC (1). The authors concluded that a poor outcome was seen after PKP for CHED in Irish population, which arises from a combination of dense amblyopia and a high risk of graft failure in the long term. This is an important study which has a unique cohort of only autosomal recessive cases from a large Irish consanguineous family.
We want to highlight some points in this article that were not clearly described .
Author reported 2 previously diagnosed congenital glaucoma cases, which also affects the visual outcome of the surgery and may skew results of this study. But they had not mentioned clearly about this.
In the figure 2 , the failed DSEK case also received regrafting twice but that was not shown in the legend.Also 32 eyes received penetrating keratoplasty as per the text but in that figure , 33 was mentioned.
In some previous studies 12 years of age (2,3) has been mentioned as the demarcation for outcome of penetrating keratoplasty in congenital hereditary endothelial dystrophy . This was not analysed in this very important study (maybe because of small numbers) but it could have been a useful clinical hint for timing of surgery in these patients.
Thanks
1. AlArrayedh H, Collum L, Murphy CC. Outcomes of penetrating keratoplasty in congenital hereditary endothelial dystrophy. Br J Ophthalmol. 2018 Jan;102(1):19-25
2. Özdemir B, Kubaloğlu A, Koytak A, Coskun E, Çinar Y, Sari ES, Özertürk Y. Penetrating keratoplasty in congenital hereditary endothelial dystrophy. Cornea. 2012 Apr;31(4):359-65
3. Schaumberg DA, Moyes AL, Gomes JA, Dana MR. Corneal transplantation in young children with congenital hereditary endothelial dystrophy. Multicenter Pediatric Keratoplasty Study. Am J Ophthalmol. 1999 Apr;127(4):373-8
We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.
1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radia...
We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.
1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radiation affects the development of second cancers in germline affected retinoblastomas-but that is not the explanation for these cancers in our report.
2) In the many large series published worldwide on second cancers in retinoblastoma patients secondary AML does not appear to be a cancer that develops2,3 unless systemic chemotherapy is used4. In fact there are published series of secondary AML in retinoblastoma patients published prior to the introduction of OAC and in each case systemic chemotherapy was implicated as the cause. There has not been an increase in sAML in our patients treated with OAC and no other center has suggested or reported an increase in sAML after adopting OAC.
3) Drs. Leahey and Meadows imply that the Melphalan given for OAC is responsible for the secondary AML but that seems unlikely and is not consistent with the published, peer review literature. The Japanese used similar doses of Melphalan in their series of patients treated with intra-arterial chemotherapy (published in 2011) between 1988 and 2007.5 In their 343 patients they meticulously pointed out that long-term follow-up of these patients did not reveal an increase in second cancers and in fact all of the second cancers but one they attributed to the use of external beam radiation combined with chemotherapy. The one patient they had who developed secondary AML they attributed to the four courses of systemic chemotherapy utilizing Vincristine, Carboplatin and Etoposide. We don’t understand why Dr. Leahey and Meadows implicate the Melphalan but not the seven cycles of multiagent systemic chemotherapy they delivered. This child did not have AML while under our care. Finally, FLT3 mutations (present in this child) have usually been associated with topoisomerase induced sAML and de novo (no prior chemotherapy) sAML and not sAML from alkylating agents (e.g. Melphalan). 6 Their child’s sAML may be unrelated to any chemotherapy but more likely the systemic chemotherapy (with doses a hundred times the small amount of Melphalan delivered by OAC) is the culprit.
4) Secondary AML from chemotherapy is well known in pediatric oncology and well known by Drs. Leahey and Meadows. It is a devastating and often lethal complication of systemic chemotherapy and was the subject of a paper by Drs. Leahey and Meadows in 1999.7 They described this complication as a…”late effect of chemotherapy” in their cohort of 228 patients. We agree that secondary AML can be a late and devastating effect of systemic chemotherapy and that is why we have abandoned it for intraocular retinoblastoma and one of the reasons we developed OAC.
5) Drs. Leahey and Meadows correctly state that the goal of retinoblastoma is to cure the child of cancer (and suggest that OAC does not do that). A large, collaborative manuscript (which included their patients) was published a December 2017 on the worldwide experience with OAC8 since we introduced it in 20069. In 1139 patients who received 4396 infusions only three patients died of metastatic disease (all from Argentina and all had prior systemic chemotherapy). The conclusion is clear: using OAC to save children’s eyes and vision does not compromise patient survival.
6) Drs. Leahey and Meadows and the Philadelphia retinoblastoma team have considerable experience with OAC over the past 10 years and have published more than 20 papers on the subject. They have not published on their second tumor experience in the OAC era. We challenge them to collect and publish their data on second cancers in germline patients treated with OAC alone. If they have additional sAML cases we suggest their use of multi-agent systemic chemotherapy for retinoblastoma is the cause (as we abandoned that 12 years ago because of that well documented adverse effect).
7) We are saddened by this patient’s course but have no way of evaluating the risk/benefit discussion that Drs. Leahey and Meadows had with the family when they decided to use adjuvant multiagent chemotherapy which may have induced resistance and then a total of seven cycles of multiagent chemotherapy which are proven to cause secondary AML. The conclusion from this case is that we should all avoid systemic chemotherapy in retinoblastoma if there is a better option…and for intraocular disease fortunately there is: OAC.
References
1. Habib LA, Francis JH, Fabius AW, Gobin PY, Dunkel IJ, Abramson DH. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol. 2018;102(2):272–275. doi:10.1136/bjophthalmol-2017-310328.
2. Kleinerman RA, Yu C-L, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950–957. doi:10.1200/JCO.2011.37.0239.
3. Abramson DH, Frank CM. Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology. 1998;105(4):573–9–discussion579–80. doi:10.1016/S0161-6420(98)94006-4.
4. Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology. 2007;114(7):1378–1383. doi:10.1016/j.ophtha.2007.03.074.
5. Suzuki S, Yamane T, Mohri M, Kaneko A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology. 2011;118(10):2081–2087. doi:10.1016/j.ophtha.2011.03.013.
7. Leahey AM, Teunissen H, Friedman DL, Moshang T, Lange BJ, Meadows AT. Late effects of chemotherapy compared to bone marrow transplantation in the treatment of pediatric acute myeloid leukemia and myelodysplasia. Med Pediatr Oncol. 1999;32(3):163–169.
8. Abramson DH, Shields CL, Jabbour P, et al. Metastatic deaths in retinoblastoma patients treated with intraarterial chemotherapy (ophthalmic artery chemosurgery) worldwide. Int J Retina Vitreous. 2017;3:40. doi:10.1186/s40942-017-0093-8.
9. Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology. 2008;115(8):1398–404–1404.e1. doi:10.1016/j.ophtha.2007.12.014.
We read the excellent paper ‘Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement’ by Eade et al.1 with great interest. The authors reviewed the pathology in extraocular muscle biopsies performed over a 25-year period and reported the clinical and radiological features that might distinguish between benign and malignant diseases. As the authors note, it is imperative for the orbital surgeon to consider a muscle biopsy when the diagnosis is in doubt. With this in mind we would like to highlight two relevant cases of simulated extraocular muscle enlargement seen radiologically due to deviated ocular position rather than a pathological process related to the muscle itself. In both cases this confused the clinical picture and nearly resulted in needless surgery.
In case 1, a 42-year-old woman was referred to the oculoplastic clinic with diplopia, reduced vision in the right eye associated with retro-bulbar pain and facial paraesthesia. On examination, there was evidence of a right esotropia with a reduction of abduction (consistent with a 6th cranial nerve palsy) associated with reduced sensation involving the V1 and V2 distribution. Optic nerve function was normal. Investigations revealed an elevated serum IgG subclass 4 (1.18 g/L) and normal serum ACE. The MRI report confirmed increased girth of the right medial rectus muscle in conjunction with enlargement and pathological enhancement of right cavernous sinus extending into...
We read the excellent paper ‘Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement’ by Eade et al.1 with great interest. The authors reviewed the pathology in extraocular muscle biopsies performed over a 25-year period and reported the clinical and radiological features that might distinguish between benign and malignant diseases. As the authors note, it is imperative for the orbital surgeon to consider a muscle biopsy when the diagnosis is in doubt. With this in mind we would like to highlight two relevant cases of simulated extraocular muscle enlargement seen radiologically due to deviated ocular position rather than a pathological process related to the muscle itself. In both cases this confused the clinical picture and nearly resulted in needless surgery.
In case 1, a 42-year-old woman was referred to the oculoplastic clinic with diplopia, reduced vision in the right eye associated with retro-bulbar pain and facial paraesthesia. On examination, there was evidence of a right esotropia with a reduction of abduction (consistent with a 6th cranial nerve palsy) associated with reduced sensation involving the V1 and V2 distribution. Optic nerve function was normal. Investigations revealed an elevated serum IgG subclass 4 (1.18 g/L) and normal serum ACE. The MRI report confirmed increased girth of the right medial rectus muscle in conjunction with enlargement and pathological enhancement of right cavernous sinus extending into the superior ophthalmic fissure. The patient was considered for orbital biopsy of the enlarged medial rectus muscle to ascertain the diagnosis and specifically to consider IgG4 related-disease. The MRI scan was subsequently reviewed in the regional skull-base multidisciplinary team meeting. At this stage the extraocular muscle findings were re-interpreted as being due to unopposed medial rectus contraction (i.e. the eye was in adduction at the time of the scan) secondary to a 6th cranial nerve palsy rather than pathological enlargement. This was supported by the lack of confluence between the two pathologies with sparing of the tendinous ring. The proposed orbital biopsy was therefore cancelled. Staging imaging of the chest confirmed asymmetric left hilar and borderline mediastinal lymphadenopathy which was confirmed as non-caseating granulomatous change on biopsy. A diagnosis of systemic sarcoidosis was confirmed, with cavernous sinus involvement, and the patient was successfully treated with oral prednisolone with resolution of the 6th nerve palsy.
In case 2, orbital imaging (CT) demonstrated enlargement of the inferior and horizontal recti as well as superior oblique bilaterally. There was no clear cut diagnosis of thyroid eye diease and an orbital biopsy was considered. An MRI was requested for preoperative planning which revealed the extraocular muscles to be of normal size. The biopsy was subsequently cancelled. The radiology team retrospectively noted that the patient had been in down-gaze during the CT, looking toward the radiographer’s control room, giving another false positive of extraocular muscle enlargement.
Several studies have shown that the ocular position influences the size of the extraocular muscles, specifically the thickness and volume of the muscles increases on contraction.2-4 We recommend that the interpretation of extraocular muscle size on radiological imaging should be accompanied by an assessment of the ocular position to minimise the risk of unnecessary orbital biopsy. Local discussion with radiology departments regarding the possibility of target fixation during scans may also be warranted.
1. Eade EL, Hardy TG, McKelvie PA, McNab AA. Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement. Br J Ophthalmol. 2018 Jan 19. pii: bjophthalmol-2017-311147. doi: 10.1136/bjophthalmol-2017-311147.
2. Tian S, Nishida Y, Isberg B, Lennerstrand G. MRI measurements of normal extraocular muscles and other orbital structures. Graefes Arch Clin Exp Ophthalmol. 2000;238(5):393-404.
3. Clark, RA. Demer, JL. Changes in Extraocular Muscle Volume During Ocular Duction. Investigative Ophthalmology & Visual Science. 2016;57:1106-1111.
4. Loba P, Laudanska-Olszewska I, Majos A, Stefańczyk L, Broniarczyk-Loba A. Morphometric parameters of extraocular rectus muscles evaluated by dynamic-multipositional magnetic resonance. Eur J Ophthalmol 2015;25(5):373-378.
Having read the article of secondary primary malignancies (SPM) in patients treated with ophthalmic artery chemosurgery (OAC) (1), we wish to update Dr. Habib’s report. A patient with unilateral Group D heritable retinoblastoma (RB) treated by their team with 5 OAC treatments in 2012 through 2013 developed acute myeloid leukemia (AML) on 4/26/2017 and died 3 months later.
Following an intraocular recurrence after OAC and subsequent enucleation the patient’s care was transferred to our institution. Despite adjuvant chemotherapy he developed widespread bone and marrow metastases 8 months after enucleation. He then underwent intensive chemotherapy and an autologous stem cell transplant. Twenty eight months later he developed AML with a fms-like tyrosine kinase 3 (FLT3) mutation. Melphalan administered during all OAC treatments and the drugs administered following that failure must be implicated in this outcome (2). By failing to eradicate retinoblastoma, metastatic disease ensued requiring further treatment and subsequently, AML.
The author’s report is profoundly misleading with regard to the risk of SPMs following OAC. Although the maximum period of follow-up is 12 years, the median is 2.5 years. Patients failing OAC required radiation therapy and are known to be 3 times more likely to develop additional cancers (3). We await that follow-up.
The goal of RB care is cure. This patient’s course illustrates the danger of failing to prevent metastatic disease wi...
Having read the article of secondary primary malignancies (SPM) in patients treated with ophthalmic artery chemosurgery (OAC) (1), we wish to update Dr. Habib’s report. A patient with unilateral Group D heritable retinoblastoma (RB) treated by their team with 5 OAC treatments in 2012 through 2013 developed acute myeloid leukemia (AML) on 4/26/2017 and died 3 months later.
Following an intraocular recurrence after OAC and subsequent enucleation the patient’s care was transferred to our institution. Despite adjuvant chemotherapy he developed widespread bone and marrow metastases 8 months after enucleation. He then underwent intensive chemotherapy and an autologous stem cell transplant. Twenty eight months later he developed AML with a fms-like tyrosine kinase 3 (FLT3) mutation. Melphalan administered during all OAC treatments and the drugs administered following that failure must be implicated in this outcome (2). By failing to eradicate retinoblastoma, metastatic disease ensued requiring further treatment and subsequently, AML.
The author’s report is profoundly misleading with regard to the risk of SPMs following OAC. Although the maximum period of follow-up is 12 years, the median is 2.5 years. Patients failing OAC required radiation therapy and are known to be 3 times more likely to develop additional cancers (3). We await that follow-up.
The goal of RB care is cure. This patient’s course illustrates the danger of failing to prevent metastatic disease with initial therapy. As Dr. Desjardins wrote in her recent review “ local administration [via OAC] cannot be used to treat micrometastases in advanced forms of the disease “ (4). Although metastatic RB can be treated if it develops (5), not all patients survive.
References:
1. Habib LA, Francis JH, Fabius A et al. Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years. Br J Ophthalmol 2018; 102: 272-5.
2. Levine EG and Bloomfield CO. Leukemias and myelodysplastic syndromes secondary to drugs, radiation and environmental exposures. Semin Oncol 1982; 19: 471-84.
3. Kleinerman RA, Tucker MA, Tarone RE, et al. Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 2005; 23: 2272-9.
4. Kassoux N, Lumbroso L, Levy-Gabriel C et al. Retinoblastoma: updates on current management. Asia-Pac J Ophthalmol 2017; 6: 290-5.
5. Dunkel IJ, Khakoo Y, Kernan NA et al. Intensive multi-modal therapy for patients with stage 4A metastatic retinoblastoma. Pediatr Blood Cancer 201; 55: 55-9.
We read with interest the report by Sradhanjali et al(1) demonstrating more effective antifungal activity of combination of Natamycin and voriconazole than single-use in vitro treatment. It should be noted, however, that given the small sample size, these results should be confirmed with a larger dataset.
Caution should be exercised when inferring results from in vitro studies because it always do not translate to in vivo models and are inconsistent. In our hands, we found treatment success when adding topical voriconazole 1% with natamycin 5% in recalcitrant full thickness infiltrate cases of fungal keratitis. This may be because topical natamycin acts superficially whereas voriconazole, though not as effective as Natamycin, takes care of the deeper infiltration because it has better penetration than Natamycin. Sharma et al (2) also concluded that topical voriconazole seems to be a useful adjunct to natamycin in fungal keratitis not responding to topical natamycin. Debridement of ulcer also helps in these cases giving way for the drug to act and reducing the fungal load.
Given the poor susceptibility and clinical outcomes among Fusarium ulcers treated with voriconazole, Sun et al(3) recommended against using voriconazole as a first-line therapy for Fusarium keratitis. Li et al(4) recommends against combination therapy because of possible interactions in mechanism of drugs. We believe that combination therapy as a first line of treatment may compound the pr...
We read with interest the report by Sradhanjali et al(1) demonstrating more effective antifungal activity of combination of Natamycin and voriconazole than single-use in vitro treatment. It should be noted, however, that given the small sample size, these results should be confirmed with a larger dataset.
Caution should be exercised when inferring results from in vitro studies because it always do not translate to in vivo models and are inconsistent. In our hands, we found treatment success when adding topical voriconazole 1% with natamycin 5% in recalcitrant full thickness infiltrate cases of fungal keratitis. This may be because topical natamycin acts superficially whereas voriconazole, though not as effective as Natamycin, takes care of the deeper infiltration because it has better penetration than Natamycin. Sharma et al (2) also concluded that topical voriconazole seems to be a useful adjunct to natamycin in fungal keratitis not responding to topical natamycin. Debridement of ulcer also helps in these cases giving way for the drug to act and reducing the fungal load.
Given the poor susceptibility and clinical outcomes among Fusarium ulcers treated with voriconazole, Sun et al(3) recommended against using voriconazole as a first-line therapy for Fusarium keratitis. Li et al(4) recommends against combination therapy because of possible interactions in mechanism of drugs. We believe that combination therapy as a first line of treatment may compound the problem of drug resistance. Though increasing azole resistance is common, resistance to natamycin is not observed(5). So, we woud like to drive the point that topical Natamycin should be the standard first line of drug in treating fungal keratitis and topical voricanazole can serve as adjunctive therapy in recalcitrant cases. Studies to measure aqueous humor concentrations of drugs may be needed to compare with the MIC to find correlation between in vivo and in vitro studies.
Reference
1. Sradhanjali S, Yein B, Sharma S, Das S. In vitro synergy of natamycin and voriconazole against clinical isolates of Fusarium, Candida, Aspergillus and Curvularia spp. Br J Ophthalmol. 2018; 102(1):142-145.
2. Sharma N, Chacko J, Velpandian T, Titiyal JS, Sinha R, Satpathy G, Tandon R, Vajpayee RB. Comparative evaluation of topical versus intrastromal voriconazole as an adjunct to natamycin in recalcitrant fungal keratitis. Ophthalmology. 2013; 120(4):677-81.
3. Sun CQ, Lalitha P, Prajna NV, Karpagam R, Geetha M, O'Brien KS, Oldenburg CE, Ray KJ, McLeod SD, Acharya NR, Lietman TM. Association between in vitro susceptibility to natamycin and voriconazole and clinical outcomes in fungal keratitis. Ophthalmology. 2014; 121(8):1495-500.
4. Li L, Wang Z, Li R, Luo S, Sun X. In vitro evaluation of combination antifungal activity against Fusarium species isolated from ocular tissues of keratomycosis patients. American journal of ophthalmology. 2008; 146(5):724-8.
5. Prajna NV, Lalitha P, Rajaraman R, Krishnan T, Raghavan A, Srinivasan M, O’Brien KS, Zegans M, McLeod SD, Acharya NR, Keenan JD. Changing Azole Resistance: A Secondary Analysis of the MUTT I Randomized Clinical Trial. JAMA ophthalmology. 2016; 134(6):693-6.
We thank the authors for their comments and insights on our paper ‘Pterygia are indicators of an increased risk of developing cutaneous melanomas’.
We agree that there was selection bias within the pterygium cases. All cases were identified as hospital in-patients and therefore represent that small select portion of the population who were receiving treatment for (or removal of) their pterygium. We made no assumptions about whether these cases were more or less severe than untreated pterygia or whether the removals were performed for cosmetic or other reasons. The strengths of this study are that it included all in-hospital cases treated in Western Australia over a 30 year time period, without prejudice.
While melanoma is an uncommon problem in China, it is a major health issue in Australia and New Zealand. The clinical relevance of this study should be viewed against the background of the world’s highest incidence rates of cutaneous melanoma that currently exist, with up to 60 cases per 100,000 population1-3 in Australia and New Zealand. Contrast this with the incidence rates of East Asian countries of approximately 0.7 cases per 100,000 population.4 Both non-melanoma and melanoma skin cancers are a major health priority for cancer prevention research. We are not suggesting that pterygium be used as the sole indicator for a population wide screening program. There are well established major screening and surveillance programs in place in Australia. Our study a...
We thank the authors for their comments and insights on our paper ‘Pterygia are indicators of an increased risk of developing cutaneous melanomas’.
We agree that there was selection bias within the pterygium cases. All cases were identified as hospital in-patients and therefore represent that small select portion of the population who were receiving treatment for (or removal of) their pterygium. We made no assumptions about whether these cases were more or less severe than untreated pterygia or whether the removals were performed for cosmetic or other reasons. The strengths of this study are that it included all in-hospital cases treated in Western Australia over a 30 year time period, without prejudice.
While melanoma is an uncommon problem in China, it is a major health issue in Australia and New Zealand. The clinical relevance of this study should be viewed against the background of the world’s highest incidence rates of cutaneous melanoma that currently exist, with up to 60 cases per 100,000 population1-3 in Australia and New Zealand. Contrast this with the incidence rates of East Asian countries of approximately 0.7 cases per 100,000 population.4 Both non-melanoma and melanoma skin cancers are a major health priority for cancer prevention research. We are not suggesting that pterygium be used as the sole indicator for a population wide screening program. There are well established major screening and surveillance programs in place in Australia. Our study adds a new variable to the calculation of risk for individuals (along with skin colour, hair colour, latitude and sun exposure). We do not believe our findings will cause increased anxiety to people who develop pterygium but will be a useful aid to increasing awareness of the health risks associated with high levels of solar radiation that are a part of life in Australia.
Table 5 age groups are correct as shown but could also be written as: <50 (aged 0 to 49.99) years and ≥50 (aged 50 or more) years.
The suggested correction (>50 years and <49 years) would exclude all people aged 50 years which would be incorrect for the data shown.
Julie Crewe
Tim Threlfall
Antony Clark
Paul Sanfilippo
Professor David Mackey
References
1 MacLennan R, Green AC, McLeod GRC, Martin NG. Increasing Incidence of Cutaneous Melanoma in Queensland, Australia. JNCI: Journal of the National Cancer Institute. 1992;84(18):1427-32 DOI:10.1093/jnci/84.18.1427
2 Marks R. The Changing Incidence and Mortality of Melanoma in Australia. In: Dummer R, Nestle FO, Burg G, editors. Cancers of the Skin: Proceedings of the 8th World Congress. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. p. 113-21.
3 Garbe C, Leiter U. Melanoma epidemiology and trends. Clinics in Dermatology. 2009;27(1):3-9 https://doi.org/10.1016/j.clindermatol.2008.09.001
4 Makredes M, Hui SK, Kimball AB. Melanoma in Hong Kong between 1983 and 2002: a decreasing trend in incidence observed in a complex socio–political and economic setting. Melanoma Research. 2010;20(5):427-30 DOI:10.1097/CMR.0b013e3283281072
Chan et al report on marked elevations in serum IgG2 that are observed in patients with orbital IgG4 related disease (IgG4-RD), with or without systemic involvement.
Using ROC area under the curve comparisons, the authors show that the serum IgG2 concentration has a higher AUC (0.9) than serum IgG4 (0.8) in detecting IgG4-RD in their cohort (comprised of 33 subjects: 20 with orbital IgG4-RD with or without systemic involvement, and 13 with non-IgG4-RD orbital inflammation).
Our group has noted this paper by Chan et al with interest as we have observed the same phenomenon of marked serum IgG2 elevations in patients with IgG4-RD, who have concomitantly low serum IgG4 concentrations. Like the patients presented by Chan et al, our IgG4-RD patients uniformly had serum IgG2 concentrations that were greater than the serum IgG4 concentration, even when the serum IgG4 concentration was very high.
Our interpretation of the apparent superior clinical utility of the serum IgG2 test in this context, is that this observation is only made when using an immunonephelometric methodology subject to two different types of analytical error:
i) antigen excess, leading to falsely low serum IgG4 measurement in a patient who in fact has a marked elevation of serum IgG4 [2] and
ii) cross reactivity of the reagent used to measure IgG2 with serum IgG4, leading to falsely high serum IgG2 measurement (this may be due to a direct and specific recognition of IgG4 epitop...
Chan et al report on marked elevations in serum IgG2 that are observed in patients with orbital IgG4 related disease (IgG4-RD), with or without systemic involvement.
Using ROC area under the curve comparisons, the authors show that the serum IgG2 concentration has a higher AUC (0.9) than serum IgG4 (0.8) in detecting IgG4-RD in their cohort (comprised of 33 subjects: 20 with orbital IgG4-RD with or without systemic involvement, and 13 with non-IgG4-RD orbital inflammation).
Our group has noted this paper by Chan et al with interest as we have observed the same phenomenon of marked serum IgG2 elevations in patients with IgG4-RD, who have concomitantly low serum IgG4 concentrations. Like the patients presented by Chan et al, our IgG4-RD patients uniformly had serum IgG2 concentrations that were greater than the serum IgG4 concentration, even when the serum IgG4 concentration was very high.
Our interpretation of the apparent superior clinical utility of the serum IgG2 test in this context, is that this observation is only made when using an immunonephelometric methodology subject to two different types of analytical error:
i) antigen excess, leading to falsely low serum IgG4 measurement in a patient who in fact has a marked elevation of serum IgG4 [2] and
ii) cross reactivity of the reagent used to measure IgG2 with serum IgG4, leading to falsely high serum IgG2 measurement (this may be due to a direct and specific recognition of IgG4 epitopes, or to non-specific “novel rheumatoid factor” interaction) [3, 4].
Both types of error are directly mediated by the magnitude of the serum IgG4 concentration, and therefore distort the diagnostic utility of both serum IgG2 (falsely increased diagnostic accuracy) and serum IgG4 (falsely decreased diagnostic accuracy) for IgG4-RD. In order, to fairly compare the two serum biomarkers, it is necessary to use a methodology, such as mass spectrometry, which is impervious to both types of error [4].
As the serum biomarker measurement methodology was not specified in the Chan paper, and some testing was performed as early as 2002, when the error of antigen excess in this circumstance had not yet been reported in the literature, there is a high probability that both types of error affected their results. Therefore, we question the implications that were derived from their observations. Given consideration to updated information on the measurement of IgG subclasses [4], we interpret the presented serum findings as representative of analytic artifact and consider serum IgG4 to be the preferred biomarker for IgG4-RD.
References
1. Chan ASY, Mudhar H, Shen SY, Lang SS, Fernando M, Hilmy MH, et al. Serum IgG2 and tissue IgG2 plasma cell elevation in orbital IgG4-related disease (IgG4-RD): Potential use in IgG4-RD assessment. Br J Ophthalmol 2017;101(11):1576-82.
2. Khosroshahi A, Cheryk LA, Carruthers MN, Edwards JA, Bloch DB, Stone JH. Brief report: Spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease. Arthritis Rheumatol 2014;66(1):213-7.
3. Ito T, Kitahara K, Umemura T, Ota M, Shimozuru Y, Kawa S, et al. A novel heterophilic antibody interaction involves IgG4. Scand J Immunol 2010;71(2):109-14.
4. van der Gugten G, DeMarco ML, Chen LYC, Chin A, Caruthers M, Holmes DT, et al. Resolution of spurious immunonephelometric IgG subclass measurement discrepancies by LC-MS/MS. Clinical Chemistry 2018 (in press).
The article in question：
Crewe JM, Threlfall T, Clark A, Sanfilippo PG, Mackey DA. Pterygia are indicators of an increased risk of developing cutaneous melanomas. Br J Ophthalmol 2017.
Authors:
Jingjing Shen
Minqian Shen
Yuanzhi Yuan
Corresponding author:
Yuanzhi Yuan
Address：#180 Fenglin Rd., Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, P.R. China
Email: yuan.yuanzhi@zs.hospital.sh.cn
Phone: +86-186 1688 1220 or +86-21-64041990 ext. 2684
Dear Editor,
We read with great interest the paper by Crewe et al.1 The authors showed that patients with pterygium had higher risk of cutaneous melanomas (CM) in a large retrospective matched-cohort study in Western Australia (WA), and suggested pterygium as an indicator for CM. The finding was interesting. However, we doubt the conclusion and its clinical relevance and public health significance.
Compared to control group, patients with pterygium had a 20% or 24% increased risk of developing CM in terms of odds ratio(OR) or incidence rate ratio (IRR), respectively. The incidence rate difference（IRD）, however, was only 27.7/100 000 person-years (PY) (Table 5., by subtracting the IR of the control group from that of the pterygium group, i.e. (186.5-158.8)/100 000 PY). The rate difference corres...
The article in question：
Crewe JM, Threlfall T, Clark A, Sanfilippo PG, Mackey DA. Pterygia are indicators of an increased risk of developing cutaneous melanomas. Br J Ophthalmol 2017.
Authors:
Jingjing Shen
Minqian Shen
Yuanzhi Yuan
Corresponding author:
Yuanzhi Yuan
Address：#180 Fenglin Rd., Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, P.R. China
Email: yuan.yuanzhi@zs.hospital.sh.cn
Phone: +86-186 1688 1220 or +86-21-64041990 ext. 2684
Dear Editor,
We read with great interest the paper by Crewe et al.1 The authors showed that patients with pterygium had higher risk of cutaneous melanomas (CM) in a large retrospective matched-cohort study in Western Australia (WA), and suggested pterygium as an indicator for CM. The finding was interesting. However, we doubt the conclusion and its clinical relevance and public health significance.
Compared to control group, patients with pterygium had a 20% or 24% increased risk of developing CM in terms of odds ratio(OR) or incidence rate ratio (IRR), respectively. The incidence rate difference（IRD）, however, was only 27.7/100 000 person-years (PY) (Table 5., by subtracting the IR of the control group from that of the pterygium group, i.e. (186.5-158.8)/100 000 PY). The rate difference corresponds to a number needed to harm (NNH) of 3610 (the reciprocal of the rate difference), which means that if 3610 individuals with pterygium that needed to be excised are followed for one year, approximately one additional CM could be detected. However, the annual cases of pterygium treatment in WA were less than 1/3 of this NNH value (figure 2; around 1000 pterygium cases were treated in WA hospitals in 2013) 1. In other words, only one person could gain benefit if all cases of pterygium treatment in WA be carefully followed up for more than 3 years. It could potentially result in unnecessary biopsies, lead to overdiagnosis and overtreatment, and cause enormous waste of resources,2 not to mention the considerable anxiety exposed to the patients and their relatives year by year.
Giving the strategy of the exposure group (the patients with pterygium) sampling, there was obvious selection bias in Crewe’s study. The reported population prevalence of pterygium varies from 2.8% to 7.8% in Australia.3-5 But only the cases with hospital treated pterygium were included in the study, which overrepresented the serious pterygium cases with higher cumulative risk of ultraviolet radiation exposure, thus may be predisposed to CM. On the other hand, patients may have their pterygia removed for cosmetic reasons. An increased detection rate for CM could also be observed in such patients as they might be alert to any changes of their appearance. Thus, the selection of the exposure group in this cohort study could falsely increase the association between pterygium and CM. As acknowledged in the paper, only a small proportion of pterygium cases were included in the study. If, however, the potentially biased conclusion be extrapolated to general pterygium cases, it could do even more harm than good.
A real-world study with big data is appealing because of its representation of the wider population. However, even a small effect, if any, can be statistically significant with a large sample size. Caution should especially be taken in interpreting the findings and their clinical relevance and significance.
Moreover, a typo in Table 5 needs to be corrected. The age groups should be labeled as “>50 years” and “<49 years.”
1. Zhongshan Hospital Affiliated to Fudan University
2. Center for Evidence-based Medicine, Fudan University
Financial Disclosures: The authors have no financial disclosures.
Reference:
1. Crewe JM, Threlfall T, Clark A, Sanfilippo PG, Mackey DA. Pterygia are indicators of an increased risk of developing cutaneous melanomas. Br J Ophthalmol 2017.
2. Force USPST, Bibbins-Domingo K, Grossman DC, et al. Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 2016;316(4):429-35.
3. Pham TQ, Wang JJ, Rochtchina E, Mitchell P. Pterygium, pinguecula, and 5-year incidence of cataract. Am J Ophthalmol 2005;139(6):1126-8.
4. Landers J, Henderson T, Craig J. Prevalence of pterygium in indigenous Australians within central Australia: the Central Australian Ocular Health Study. Clin Exp Ophthalmol 2011;39(7):604-6.
5. McCarty CA, Fu CL, Taylor HR. Epidemiology of pterygium in Victoria, Australia. Br J Ophthalmol 2000;84(3):289-92.
We would like to add some data to this interesting discussion about the impact of ophthalmic artery chemosurgery or intra-arterial chemotherapy (OAC) in the occurrence of secondary malignancies in children with retinoblastoma with germline mutations of the Rb1 gene.
Show MoreThe discussion about the incidence of secondary leukemia is an important one. Secondary leukemias usually present early in the patient follow-up, usually around 2-3 years. Systemic chemotherapy has been implicated in their occurrence since, they were not identified as a common secondary malignancy in patients with retinoblastoma not receiving chemotherapy1. Their occurrence is low1, but as the case Dr Meadows and Lahey report are usually refractory to treatment and usually fatal. In our series of patients treated with systemic chemoreduction for conservative therapy from Argentina, secondary AML was the most common fatal secondary malignancy with a total of 2 out of 129 cases. We had a third case in a child receiving chemotherapy for extraocular disease, similarly to Dr Meadows and Lahey’s case2. In our current, yet unpublished results with ophthalmic artery chemosurgery, we had no case of secondary AML , in 71 consecutive cases with bilateral retinoblastoma treated with OAC with a median follow-up of 42 months. Secondary AML has been widely reported as a complication of systemic chemotherapy in pediatric oncology patients 3 including those receiving epipodophillotoxins 4and also alkylating agents5. Cum...
Dear Editor,
We have read with interest the paper by Klimova et al. Some statements in the paper are confusing and may even mislead the readers.
The authors claim in the survival section of the paper that: "Vitreoretinal lymphoma is a life-threatening disease, with a 5-year survival rate of 71% in our study". Vitreoretinal lymphoma (VRL) may affect vision, and in very advanced cases that we rarely see in recent years, may destroy the eye. However, VRL per se is not what that kills the patients, but the associated brain lymphoma or in some case the systemic lymphoma.
According to the results in this study (and the title of the paper), "Combined (local and systemic) treatment in patients with PVRL showed favorable results in comparison with local therapy alone (p=0.695). However, the statistical significance was not reached". It is no wonder that they claim that combined treatment is better than local treatment when they have 60% relapses. However, no other study of intra-vitreal (IVit) Methotrexate showed such a high relapse rate. In our experience, the relapse rate is extremely low with IVit methotrexate alone. Actually, in summarizing our ten years results we had no recurrence of the intraocular disease (2) and summarizing now our 20-year experience with 113 eyes, we had only two cases of recurrences (unpublished data). It is difficult to explain the poor results of the authors’ patients, using either intravitreal methotrexate al...
Show MoreDear Editor,
We have read with interest the recently published article by Al Arrayedh H, Collum L, Murphy CC (1). The authors concluded that a poor outcome was seen after PKP for CHED in Irish population, which arises from a combination of dense amblyopia and a high risk of graft failure in the long term. This is an important study which has a unique cohort of only autosomal recessive cases from a large Irish consanguineous family.
We want to highlight some points in this article that were not clearly described .
Author reported 2 previously diagnosed congenital glaucoma cases, which also affects the visual outcome of the surgery and may skew results of this study. But they had not mentioned clearly about this.
In the figure 2 , the failed DSEK case also received regrafting twice but that was not shown in the legend.Also 32 eyes received penetrating keratoplasty as per the text but in that figure , 33 was mentioned.
In some previous studies 12 years of age (2,3) has been mentioned as the demarcation for outcome of penetrating keratoplasty in congenital hereditary endothelial dystrophy . This was not analysed in this very important study (maybe because of small numbers) but it could have been a useful clinical hint for timing of surgery in these patients.
Thanks
1. AlArrayedh H, Collum L, Murphy CC. Outcomes of penetrating keratoplasty in congenital hereditary endothelial dystrophy. Br J Ophthalmol. 2018 Jan;102(1):19-25
Show More...
Dear Sir,
We are writing this letter in response to a “letter to the editor” from Drs. Leahey and Meadows about our recently published paper “Second primary malignancies in retinoblastoma patients treated with intra-arterial chemotherapy: the first 10 years”.1 There are a number of incorrect statements in their letter and we hope this letter will clarify those errors made by them.
1) Drs. Leahey and Meadows state that…”the author’s report is profoundly misleading with regard to the risk of SPMs following OAC”. To prove that they then state that the median follow-up range is 2.5 years with a maximum follow-up of 12 years. How is that “profoundly misleading”? In the same paragraph they then state that patients failing OAC required radiation therapy and suggest that all of these second neoplasms are a consequence of radiation. That is not true. In our paper (page 273, Table 3) we documented that not one of the children who developed a second tumor had received radiation. How could radiation be the cause of a second tumor if the patients never received radiation? Dr. Leahey and Meadows also wrote that…”patients failing OAC require radiation”. That’s not true. On page 272 we stated that…”patients who received external beam radiation prior to presentation at our clinic were excluded from analysis”. None of the patients in this series received radiation after OAC and no patient in our center has received radiation in the past 10 years. We do not dispute that radia...
Show MoreWe read the excellent paper ‘Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement’ by Eade et al.1 with great interest. The authors reviewed the pathology in extraocular muscle biopsies performed over a 25-year period and reported the clinical and radiological features that might distinguish between benign and malignant diseases. As the authors note, it is imperative for the orbital surgeon to consider a muscle biopsy when the diagnosis is in doubt. With this in mind we would like to highlight two relevant cases of simulated extraocular muscle enlargement seen radiologically due to deviated ocular position rather than a pathological process related to the muscle itself. In both cases this confused the clinical picture and nearly resulted in needless surgery.
In case 1, a 42-year-old woman was referred to the oculoplastic clinic with diplopia, reduced vision in the right eye associated with retro-bulbar pain and facial paraesthesia. On examination, there was evidence of a right esotropia with a reduction of abduction (consistent with a 6th cranial nerve palsy) associated with reduced sensation involving the V1 and V2 distribution. Optic nerve function was normal. Investigations revealed an elevated serum IgG subclass 4 (1.18 g/L) and normal serum ACE. The MRI report confirmed increased girth of the right medial rectus muscle in conjunction with enlargement and pathological enhancement of right cavernous sinus extending into...
Show MoreHaving read the article of secondary primary malignancies (SPM) in patients treated with ophthalmic artery chemosurgery (OAC) (1), we wish to update Dr. Habib’s report. A patient with unilateral Group D heritable retinoblastoma (RB) treated by their team with 5 OAC treatments in 2012 through 2013 developed acute myeloid leukemia (AML) on 4/26/2017 and died 3 months later.
Show MoreFollowing an intraocular recurrence after OAC and subsequent enucleation the patient’s care was transferred to our institution. Despite adjuvant chemotherapy he developed widespread bone and marrow metastases 8 months after enucleation. He then underwent intensive chemotherapy and an autologous stem cell transplant. Twenty eight months later he developed AML with a fms-like tyrosine kinase 3 (FLT3) mutation. Melphalan administered during all OAC treatments and the drugs administered following that failure must be implicated in this outcome (2). By failing to eradicate retinoblastoma, metastatic disease ensued requiring further treatment and subsequently, AML.
The author’s report is profoundly misleading with regard to the risk of SPMs following OAC. Although the maximum period of follow-up is 12 years, the median is 2.5 years. Patients failing OAC required radiation therapy and are known to be 3 times more likely to develop additional cancers (3). We await that follow-up.
The goal of RB care is cure. This patient’s course illustrates the danger of failing to prevent metastatic disease wi...
We read with interest the report by Sradhanjali et al(1) demonstrating more effective antifungal activity of combination of Natamycin and voriconazole than single-use in vitro treatment. It should be noted, however, that given the small sample size, these results should be confirmed with a larger dataset.
Caution should be exercised when inferring results from in vitro studies because it always do not translate to in vivo models and are inconsistent. In our hands, we found treatment success when adding topical voriconazole 1% with natamycin 5% in recalcitrant full thickness infiltrate cases of fungal keratitis. This may be because topical natamycin acts superficially whereas voriconazole, though not as effective as Natamycin, takes care of the deeper infiltration because it has better penetration than Natamycin. Sharma et al (2) also concluded that topical voriconazole seems to be a useful adjunct to natamycin in fungal keratitis not responding to topical natamycin. Debridement of ulcer also helps in these cases giving way for the drug to act and reducing the fungal load.
Given the poor susceptibility and clinical outcomes among Fusarium ulcers treated with voriconazole, Sun et al(3) recommended against using voriconazole as a first-line therapy for Fusarium keratitis. Li et al(4) recommends against combination therapy because of possible interactions in mechanism of drugs. We believe that combination therapy as a first line of treatment may compound the pr...
Show MoreWe thank the authors for their comments and insights on our paper ‘Pterygia are indicators of an increased risk of developing cutaneous melanomas’.
Show MoreWe agree that there was selection bias within the pterygium cases. All cases were identified as hospital in-patients and therefore represent that small select portion of the population who were receiving treatment for (or removal of) their pterygium. We made no assumptions about whether these cases were more or less severe than untreated pterygia or whether the removals were performed for cosmetic or other reasons. The strengths of this study are that it included all in-hospital cases treated in Western Australia over a 30 year time period, without prejudice.
While melanoma is an uncommon problem in China, it is a major health issue in Australia and New Zealand. The clinical relevance of this study should be viewed against the background of the world’s highest incidence rates of cutaneous melanoma that currently exist, with up to 60 cases per 100,000 population1-3 in Australia and New Zealand. Contrast this with the incidence rates of East Asian countries of approximately 0.7 cases per 100,000 population.4 Both non-melanoma and melanoma skin cancers are a major health priority for cancer prevention research. We are not suggesting that pterygium be used as the sole indicator for a population wide screening program. There are well established major screening and surveillance programs in place in Australia. Our study a...
Chan et al report on marked elevations in serum IgG2 that are observed in patients with orbital IgG4 related disease (IgG4-RD), with or without systemic involvement.
Using ROC area under the curve comparisons, the authors show that the serum IgG2 concentration has a higher AUC (0.9) than serum IgG4 (0.8) in detecting IgG4-RD in their cohort (comprised of 33 subjects: 20 with orbital IgG4-RD with or without systemic involvement, and 13 with non-IgG4-RD orbital inflammation).
Our group has noted this paper by Chan et al with interest as we have observed the same phenomenon of marked serum IgG2 elevations in patients with IgG4-RD, who have concomitantly low serum IgG4 concentrations. Like the patients presented by Chan et al, our IgG4-RD patients uniformly had serum IgG2 concentrations that were greater than the serum IgG4 concentration, even when the serum IgG4 concentration was very high.
Our interpretation of the apparent superior clinical utility of the serum IgG2 test in this context, is that this observation is only made when using an immunonephelometric methodology subject to two different types of analytical error:
Show Morei) antigen excess, leading to falsely low serum IgG4 measurement in a patient who in fact has a marked elevation of serum IgG4 [2] and
ii) cross reactivity of the reagent used to measure IgG2 with serum IgG4, leading to falsely high serum IgG2 measurement (this may be due to a direct and specific recognition of IgG4 epitop...
Title Page
Title:
Letter to the Editor
The article in question：
Crewe JM, Threlfall T, Clark A, Sanfilippo PG, Mackey DA. Pterygia are indicators of an increased risk of developing cutaneous melanomas. Br J Ophthalmol 2017.
Authors:
Jingjing Shen
Minqian Shen
Yuanzhi Yuan
Corresponding author:
Yuanzhi Yuan
Address：#180 Fenglin Rd., Department of Ophthalmology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, P.R. China
Email: yuan.yuanzhi@zs.hospital.sh.cn
Phone: +86-186 1688 1220 or +86-21-64041990 ext. 2684
Dear Editor,
We read with great interest the paper by Crewe et al.1 The authors showed that patients with pterygium had higher risk of cutaneous melanomas (CM) in a large retrospective matched-cohort study in Western Australia (WA), and suggested pterygium as an indicator for CM. The finding was interesting. However, we doubt the conclusion and its clinical relevance and public health significance.
Compared to control group, patients with pterygium had a 20% or 24% increased risk of developing CM in terms of odds ratio(OR) or incidence rate ratio (IRR), respectively. The incidence rate difference（IRD）, however, was only 27.7/100 000 person-years (PY) (Table 5., by subtracting the IR of the control group from that of the pterygium group, i.e. (186.5-158.8)/100 000 PY). The rate difference corres...
Show MorePages