Hemodynamic and Anatomic Variations Require an Adaptable Approach during Intra-Arterial Chemotherapy for Intraocular Retinoblastoma: Alternative Routes, Strategies, and Follow-Up.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy for retinoblastoma is not always a straightforward procedure, and it may require an adaptable approach. This study illustrates strategies used when the ophthalmic artery is difficult to catheterize or not visible, and it ascertains the effectiveness and safety of these strategies. MATERIALS AND METHODS: A retrospective study was performed on a series of 108 eyes affected by intraocular retinoblastoma and selected for intra-arterial chemotherapy (follow-up range, 6-82 months). We recognized 3 different patterns of drug delivery: a fixed pattern through the ophthalmic artery, a fixed pattern through branches of the external carotid artery, and a variable pattern through either the ophthalmic or the external carotid artery. RESULTS: We performed 448 sessions of intra-arterial chemotherapy, 83.70% of them through the ophthalmic artery and 16.29% via the external carotid artery. In 24.52% of eyes, the procedure was performed at least once through branches of the external carotid artery. In 73 eyes, the pattern of drug delivery was fixed through the ophthalmic artery; for 9 eyes, it was fixed through branches of the external carotid artery; and for 17 eyes, the pattern was variable. Statistical analysis did not show any significant difference in the clinical outcome of the eyes (remission versus enucleation) treated with different patterns of drug delivery. Adverse events could not be correlated with any particular pattern. CONCLUSIONS: Alternative routes of intra-arterial chemotherapy for intraocular retinoblastoma appear in the short term as effective and safe as the traditional drug infusion through the ophthalmic artery.

Detection of calcifications in retinoblastoma using gradient-echo MR imaging sequences: comparative study between in vivo MR imaging and ex vivo high-resolution CT.

BACKGROUND AND PURPOSE: Intratumoral calcifications are very important in the diagnosis of retinoblastoma. Although CT is considered superior in detecting calcification, its ionizing radiation, especially in patients with hereditary retinoblastoma, should be avoided. The purpose of our study was to validate T2*WI for the detection of calcification in retinoblastoma with ex vivo CT as the criterion standard. MATERIALS AND METHODS: Twenty-two consecutive patients with retinoblastoma (mean age, 21 months; range, 1-71 months) with enucleation as primary treatment were imaged at 1.5T by using a dedicated surface coil. Signal-intensity voids indicating calcification on T2*WI were compared with ex vivo high-resolution CT, and correlation was scored by 2 independent observers as poor, good, or excellent. Other parameters included the shape and location of the signal-intensity voids. In 5 tumors, susceptibility-weighted images were evaluated. RESULTS: All calcifications visible on high-resolution CT could be matched with signal-intensity voids on T2*WI, and correlation was scored as excellent in 17 (77%) and good in 5 (23%) eyes. In total, 93% (25/27) of the signal-intensity voids inside the tumor correlated with calcifications compared with none (0/8) of the signal-intensity voids outside the tumor. Areas of nodular signal-intensity voids correlated with calcifications in 92% (24/26), and linear signal-intensity voids correlated with hemorrhage in 67% (6/9) of cases. The correlation of signal-intensity voids on SWI was better in 4 of 5 tumors compared with T2*WI. CONCLUSIONS: Signal-intensity voids on in vivo T2*WI correlate well with calcifications on ex vivo high-resolution CT in retinoblastoma. Gradient-echo sequences may be helpful in the differential diagnosis of retinoblastoma. The combination of funduscopy, sonography, and high-resolution MR imaging with gradient-echo sequences should become the standard diagnostic approach for retinoblastoma.

Is CT still useful in the study protocol of retinoblastoma?

BACKGROUND AND PURPOSE: Intralesional calcium deposition is considered a key element for differentiating retinoblastoma from simulating lesions. Our aim was to assess whether MR imaging associated with ophthalmologic investigations (ophthalmoscopy and ultrasonography) could replace CT in the detection of diagnostic intralesional calcifications in retinoblastoma. MATERIALS AND METHODS: Ophthalmoscopic findings, MR images, CT scans, and histologic examination of 28 retinoblastomas from 23 consecutive children (11 males, 12 females; age range at admission, 1-35 months; mean age, 11 months; median age, 9 months) were retrospectively evaluated. Ultrasonography was performed in 18 patients with 21 retinoblastomas. MR imaging included T2-weighted spin-echo and gradient-echo images, fluid-attenuated inversion recovery images, and T1-weighted spin-echo images with and without contrast enhancement. Clinical data were integrated with MR imaging data to evaluate the utility of both approaches to discover calcifications; particularly, a correlation between intralesional signal-intensity void spots on MR imaging and hyperattenuating areas on CT scans was performed. RESULTS: Ophthalmoscopy detected calcifications in 12 of 28 eyes (42.85%). Ultrasonography detected calcifications in 20 of 21 eyes (95.23%). CT showed hyperattenuating intralesional areas consistent with calcifications in 27 of 28 eyes (96.42%). MR imaging showed intralesional signal-intensity void spots in 25 of 28 eyes (89.28%). All spots detected with MR imaging matched the presence of calcifications on CT scans. Gradient-echo T2*-weighted and fast spin-echo T2-weighted images showed the highest degree of correlation with CT. When we put together ophthalmoscopy, ultrasonography, and MR imaging data, no calcifications detected on CT were missed, and the differential diagnosis was thorough. CONCLUSIONS: A combination of clinical data and MR images may remove potentially harmful ionizing radiation from the study protocol of retinoblastoma.

A case of coloboma in a newborn to a woman taking mycophenolate mofetil in pregnancy after kidney transplantation.

Recently, mycophenolate mofetil (MMF) has been introduced in the immunosuppressive strategy after kidney transplantation. Recently, the existence of a MMF associated embriopathy has been hypothesized, namely, multiple craniofacial malformations. Only 1 report has described chorioretinal coloboma. We report a case of woman who used MMF throughout pregnancy after kidney transplantation. Her newborn developed coloboma of the right eye associated with an ocular cyst without any other malformation. The other drugs used by our patient are not considered teratogenic. Therefore, it seems reasonable to conclude a causal relationship between MMF and the malformation observed in this newborn.

Retinoblastoma epidemiology: does the evidence matter?

It has been proposed that retinoblastoma is 'caused' by two sequential mutations affecting the RB1 gene, but this is a rather outdated view of cancer aetiology that does not take into account a large amount of new acquisitions such as chromosomal and epigenetic alterations. Retinoblastoma remains probably the only cancer in which the rather simplistic 'two hit' mutational model is still considered of value, although cancer is known to be associated with genomic and microsatellite instability, defects of the DNA mismatch repair system, alterations of DNA methylation and hystone acethylation/deacethylation, and aneuploidy. Moreover, as it is shown herein, the predictions made by the 'two hit' model, are not fulfilled by the clinical and epidemiological data reported so far. Moreover, while the role of mutational events in cancer has been largely questioned in the more recent literature, no serious effort has been done to investigate the role of epigenetic alterations and aneuploidy in retinoblastoma. Through the analysis of the specialised literature and a set of original epidemiological and biological data concerning retinoblastoma, the authors illustrate the evidences arguing against the 'two hit' hypothesis and propose that epigenetic factors and aneuploidy play central roles in the disease.

Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH.

We describe three patients with retinoblastoma, dysmorphic features and developmental delay. Patients 1 and 2 have high and broad forehead, deeply grooved philtrum, thick anteverted lobes and thick helix. Patient 1 also has dolicocephaly, sacral pit/dimple and toe crowding; patient 2 shows intrauterine growth retardation and short fifth toe. Both patients have partial agenesis of corpus callosum. Patient 3 has growth retardation, microcephaly, thick lower lip and micrognathia. Using array-comparative genomic hybridization (CGH), we identified a 13q14 de novo deletion in patients 1 and 2, while patient 3 had a 7q11.21 maternally inherited deletion, probably not related to the disease. Our results confirm that a distinct facial phenotype is related to a 13q14 deletion. Patients with retinoblastoma and malformations without a peculiar facial phenotype may have a different deletion syndrome or a casual association of mental retardation and retinoblastoma. Using array-CGH, we defined a critical region for mental retardation and dysmorphic features. We compared this deletion with a smaller one in a patient with retinoblastoma (case 4) and identified two distinct critical regions, containing 30 genes. Four genes appear to be good functional candidates for the neurological phenotype: NUFIP1 (nuclear fragile X mental retardation protein 1), HTR2A (serotonin receptor 2A), PCDH8 (prothocaderin 8) and PCDH17 (prothocaderin 17).

Phthisis bulbi and buphthalmos as presenting signs of retinoblastoma: a report of two cases and literature review.

PURPOSE: To report two cases of bilateral retinoblastoma (RB) with unusual presentations. METHODS: The medical records of 321 patients from the Retinoblastoma Referral Center in Siena were reviewed. A total of 111 patients had bilateral RB, 2 of them presenting with phthisis bulbi and buphthalmos. Both patients underwent bilateral enucleation. Clinical features, imaging studies, and histopathology were reviewed. RESULTS: These 2 cases represent 0.62% (2/321) in our series. Histopathology did not reveal viable tumor cells in the phthisical eyes; in both buphthalmic eyes the tumor was active, infiltrating the choroid and optic nerve. CONCLUSIONS: Phthisis bulbi and buphthalmos are unusual presenting signs of RB. This very rare combination of these two signs in different eyes of the same patient is probably due to a delay in diagnosis.

Retinocytoma associated with calcified vitreous deposits.

PURPOSE: To report a case of bilateral retinocytoma associated with calcified vitreous deposits. METHODS: Case report. RESULTS: On routine examination, a 35-year-old asymptomatic father of a child with bilateral retinoblastoma presented bilateral retinocytoma associated with vitreous calcifications, in the vicinity of the retinocytoma in his left eye. Fundus photographic documentation and fluorescein angiography were performed. The patient has been followed up for 10 years. CONCLUSIONS: The lesions in both eyes have remained stable without signs of growth or malignant transformation. Calcified vitreous deposits are a recently described feature of retinocytoma in addition to the three classic features: translucent retinal mass, retinal pigment epithelial alteration, and calcification.

Pleomorphic adenoma of the lacrimal gland in an 18-year-old girl irradiated for bilateral retinoblastoma.

PURPOSE: To report a case of pleomorphic adenoma of the lacrimal gland following irradiation for bilateral retinoblastoma. MATERIALS AND METHODS: Case report. A 4-month-old girl, with bilateral retinoblastoma, underwent enucleation of the right eye, systemic chemotherapy and bilateral external beam irradiation with a lateral field. The right anophthalmic socket (because of infiltration of the optic nerve) and the left eye (for relapse) were irradiated;. 17 years later, she developed a mass in the superotemporal quadrant of the left orbit. The mass was completely excised. RESULTS: Pleomorphic adenoma is rare in children and teenagers; it usually presents as a painless, slow growing mass in healthy adults. In this case, it developed as a second primary tumor after irradiation for retinoblastoma.

Hypertelorism, ptosis, and myopia associated with drug-resistant epilepsy, mental delay, growth deficiency, ectodermal defects, and osteopenia.

We report a 30-year-old woman with hypertelorism, ptosis, and myopia associated with drug-resistant epilepsy (DRE, Lennox-Gastaut syndrome), mental delay, growth deficiency, ectodermal defects, and osteopenia. To the best of our knowledge, this patient has an unusual combination of symptoms not previously described, associated with severe central nervous system dysfunction. The ectodermal defects were present in a very intriguing form, were difficult to diagnose, and did not conform to any classification or previous description.

Coats disease: smaller volume of the affected globe.

PURPOSE: To determine whether a significant smaller volume of the affected globe, compared with that of the normal globe, is an additional feature of Coats disease. MATERIALS AND METHODS: Ocular globe volume was assessed in 13 children (11 boys, two girls; age range, 0.6-14 years; mean age, 4.1 years) with Coats disease and in 18 (eight boys, 10 girls; age range, 0.5-12 years; mean age, 3.6 years) with unilateral retinoblastoma. Orbital computed tomographic scans were available for all children; magnetic resonance images were available for 11 children-seven with Coats disease and four with retinoblastoma. For volume estimation, anteroposterior and equatorial diameters of ocular globes were measured. Statistical analysis was conducted with univariate and multivariate methods. RESULTS: In children with Coats disease, the mean volume of the affected globe was 4,877.03 mm(3) (range, 2,951.47-6,284.70 mm(3)) and that of the normal globe, 6,018.00 mm(3) (range, 4,062.32-7,509.26 mm(3)). In children with retinoblastoma, the mean volume of the affected globe was 4,557.06 mm(3) (range, 1,612.01-7,463.00 mm(3)) and that of the normal globe, 4,402.11 mm(3) (range, 1,360.46- 7,463.00 mm(3)). The Coats disease population had a significantly smaller volume of the affected globe (z = -3.1009; P =.002); the retinoblastoma population did not have a statistically significant trend toward a bigger affected globe volume (z = -1.7064; P =.088). The difference between the affected globe volume and the normal globe volume in children with Coats disease was the only significant independent variable (P =.005). CONCLUSION: A significantly smaller volume of the affected globe is an additional feature of Coats disease.

Corpus callosum agenesis, multiple cysts, skin defects, and subtle ocular abnormalities with a de novo mutation [45,XX,der(5), t(5;;14) (pter;q11.2)].

We report on a 2-year-old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single-locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region.

MOMO syndrome: a possible third case.

This report describes a 5-year-old girl, mildly mentally retarded, with the following characteristics: macrocephaly; severe obesity; ocular abnormalities (right optic disk coloboma and left choroidal coloboma); short stature; and recurvation of the femur. The case is sporadic with no consanguinity between the parents. The condition was diagnosed tentatively as MOMO syndrome (Macrosomia, Obesity, Macrocephaly, and Ocular Abnormalities) (MIM, 157980), because of the presence of short stature, in contrast with the large stature of the only two previously described cases. It is the third possible example of this rare syndrome to be described in the literature, with some new clinical findings presented.

Metachronous tumor development in unilateral retinoblastoma.

PURPOSE: A series of 205 retinoblastoma (RB) patients referred to the Department of Ophthalmology at the University of Siena (Italy) was evaluated in order to assess the proportion of unilateral cases later developing tumors in the companion eye ("metachronous" bilateral retinobastoma) (MBRB). METHODS: The total number of unilaterally affected patients developing tumors in the fellow eye was recorded and the risk factors assessed for the development of asynchronous bilateral retinoblastoma, i.e., family history, tumor multifocality and early age at diagnosis. RESULTS: Only two out of 133 (1.5%) unilateral retinoblastoma patients in our series could be considered affected by MBRB. CONCLUSIONS: The incidence of MBRB in our series was negligible (1.5% of all unilateral cases) compared to other reports. None of the reported risk factors for the development of tumors in the fellow eye was relevant in the present series. Although close follow-up of some unilateral cases is still recommended, thorough examination of the fellow eye, to search for lesions in the peripheral retina, is essential in all cases of unilateral RB. MBRB may be a distinctive clinical entity with specific clinical, genetic and prognostic features. However, all these aspects need to be better investigated in larger series.

Loss of heterozygosity on the long arm of chromosome 11 in orbital embryonal rhabdomyosarcoma (OERMS): a microsatellite study of seven cases.

OBJECTIVES. To investigate, by means of microsatellite analysis, regions of chromosome 11 involved in the genesis of embryonal rhabdomyosarcoma (ERMS) localized to the orbit. METHODS. Microsatellite analysis was carried out on seven cases of orbital ERMS by comparing the electrophoretic migration patterns of PCR-amplified microsatellites of chromosome 11 from both constitutional (blood) and tumor genotypes. Five of the tumors analyzed were samples frozen at the time of surgery, and two were paraffin embedded. RESULTS. Overall, microsatellites D11S1396 (11q13.1-q22.3) and D11S976 (11q) showed loss of heterozygosity (LOH) in all tumor samples, thus indicating the presence, on the long arm of chromosome 11, of one or more tumor suppressor genes with a possible role in the genesis of the disease. CONCLUSION. While the role of genes on the short arm of chromosome 11 in the genesis of ERMS is well established, much less is known of the possible involvement of tumor suppressor genes on the long arm of the same chromosome. This is the first report showing the possible involvement of tumor suppressor genes in this portion of the chromosome in ERMS localized to the orbit.

Design and implementation of a relational database used in the management of patients with retinoblastoma.

Clinical data are most useful in the management of patients with complex medical problems if they are accurate, reliable, and easily accessible by physicians and the medical community at large. Furthermore, the data are most valuable when they can be shared among cooperating institutions. We describe a computer system which exhibits a uniform taxonomy, an integrated on-line dictionary of clinical terms, a coherent temporal layout, and persistent spatial integrity with regard to the values of the variables. The system is user friendly and provides real time data access which can be retrieved by structured query language or may be programmed to be used as part of an international network in the management of patients with retinoblastoma, a malignant and potentially fatal tumor of childhood. Furthermore, because of its design flexibility, this system provides for potential application to other ophthalmic disorders, such as malignant uveal melanoma, and other areas of medicine as well.

The polymerase chain reaction (PCR) in the routine genetic characterization of retinoblastoma: a tool for the clinical laboratory.

The Polymerase Chain Reaction (PCR) is a highly innovative technique which allows for the generation of large amounts of DNA starting from minute quantities obtained from the blood or tissue of a patient. With the increasing knowledge concerning the structure of the human genome and the potential to amplify specific segments of DNA by the PCR technique, the molecular genetic characterization of many ocular disorders has been greatly facilitated. This is particularly true of retinoblastoma (RB) where the causative gene, RB1, gene has been identified and characterized. Using PCR technique, specific sequences of the RB1 gene can be amplified and analyzed to precisely define the genetic mutation in an affected individual. In addition, this technique can also be applied in order to characterize the genetic defect within the tumor itself. In this report we illustrate the use of the PCR technique in the genetic characterization of the RB1 gene and its application to the study of RB. These techniques are applicable even in a small clinical laboratory and can be extended to a number of ophthalmic disorders.

Italian register for retinoblastoma. Pros and cons of a retrospective statistical study.

In an attempt to verify some of the current conflicting results concerning the impact of relevant prognostic factors in the retinoblastoma therapy, the authors took into consideration, for statistical analysis, the series of 459 cases included in the Italian Registry for retrospective study of retinoblastoma. Although this series appears large enough, problems related to the continuously changing approaches to the disease and the consequent lack of standardization often make it difficult to draw significant conclusions. Hence, while historical (retrospective) analysis often allows the manipulation of a great number of data, particularly in the case of relatively rare diseases, prospective randomized controlled trials are strongly recommended to standardize definitely the relevant prognostic criteria. These and other problems related to retrospective analysis are discussed in detail.

Recurrent and new tumours during conservative treatment of bilateral retinoblastoma.

Conservative treatment of retinoblastoma is a combination of different therapeutic modalities: radiotherapy, photocoagulation, cryocoagulation, chemotherapy. The choice of the most suitable treatment depends on the stage of the disease. The evaluation of the regression and quiescence of tumoral foci after radiotherapy, Xenon photocoagulation or cryocoagulation is based on a purely subjective examination of the ophthalmoscopic aspects which are common to various types of treatment. Frequently, degenerative changes of the tumour mass are difficult to differentiate from actual recurrence. Recurrences generally start at the edge of the scar or within the scar, while new retinal tumours are observed far from the original tumour, sometimes near the ora serrata. The authors discuss the regression patterns and the ophthalmoscopic and clinical aspects of recurrent and new tumours and report their personal experience on the therapeutic approach.