Cases Of Retinoblastoma Research Articles

Parental Occupation and Risk of Childhood Retinoblastoma in Denmark.

Retinoblastoma is the most common primary intraocular tumor affecting children. We examine the role of parental occupational exposures and risk of retinoblastoma among offspring. Our population-based case-control study linked data from four nationwide Danish registries and included all cases of retinoblastoma diagnosed in Danish children (<5 y, n = 144) between 1975 and 2014. We focused on two biologically relevant time periods: 90 days preconception to conception for fathers; conception to birth for mothers. Parents were grouped into major industry headings created from Danish industry codes. We observed increased risk of all retinoblastoma for children of fathers in the food and drink industry and iron and metal industry. Bilateral disease was associated with paternal work in manufacturing and land transportation. Our results suggest that some occupational exposures may increase the risk of childhood sporadic retinoblastoma.

LINC-36. TRILATERAL RETINOBLASTOMA: A REPORT OF FOUR CASES

Retinoblastoma is the most common primary malignant intraocular cancer that usually develops in early childhood. About 5% of those patients are at risk of developing trilateral retinoblastoma (TRB). In developing countries, most of them came in the late stage; therefore, ocular and patient survival rates are lower than in developed countries. From 2015–2019, we found four cases of trilateral retinoblastoma. Two of them had bilateral retinoblastoma, and two had unilateral retinoblastoma. They all presented with leukocoria and had no family history of retinoblastoma. The mean age was 13.8 months (range 9–24 months of age). The diagnosis of trilateral retinoblastoma was made from initial head CT/MRI. They were treated conservatively with high dose VEC chemotherapy, and three of them have died during treatment. Trilateral retinoblastoma is usually fatal and needs multidisciplinary treatment care. In developing countries, it is important to evaluate distant metastasis. Head CT or MRI from the initial diagnosis to exclude the trilateral retinoblastoma.

Distantly Metastatic Retinoblastoma to Soft Tissue and Bone: A Challenging Diagnosis Highlighting the Utility of CRX.

Distant metastasis of retinoblastoma to sites outside the central nervous system is rare; such cases may present years following primary treatment. Diagnosis may be difficult given the rarity of such events and considerable histologic mimics. We describe the clinicopathologic features of 6 cases of metastatic retinoblastoma to distant bone and soft tissue sites from 2 large academic centers. Patients were 3 female and 3 male children; median age was 9.5 years (range: 5 to 15 y) with a mean interval from primary disease diagnosis of 8.0 years (range: 0.75 to 14 y). Metastasis to bones of the lower extremities was most common, occurring in 4 of 6 cases. Tumors showed typical histologic features of retinoblastoma, with sheets of primitive round cells with minimal cytoplasm and indistinct nucleoli; however, characteristic Flexner-Wintersteiner rosettes were absent. A subset of cases demonstrated an alveolar growth pattern, and 2 cases showed higher grade cytology with nuclear anaplasia and prominent nucleoli. Immunohistochemistry for CRX and RB1 showed uniform positivity and loss of expression, respectively. Metastatic retinoblastoma outside the central nervous system may present following long disease-free intervals. Immunohistochemistry for CRX is helpful to confirm this challenging diagnosis.

Retinoblastoma in Children Older than 6 Years of Age

Objective: The aim of this work was to study the clinical and histopathology features and treatment outcome in retinoblastoma cases presenting at an older age (>6 years). Design: This was a retrospective study. We recruited 48 retinoblastoma patients who were treated at our institute over 7 consecutive years and were older than 6 years at presentation. Methods: Medical records were reviewed for data, including age at diagnosis, gender, laterality, family history, lag time, first symptom, misdiagnosis, clinical findings, grade and stage of disease at diagnosis, treatment, outcome, and follow-up status. Histopathology slides were reviewed and assessed for the presence of histopathological high-risk features (HRF) for metastasis. The main outcome measures were the frequency of atypical clinical features like hyphema, pseudohypopyon, glaucoma, cataract, vitreous hemorrhage, and phthisis, and misdiagnosis, prior intervention, stage of disease at presentation, and treatment outcome. Results: In total, 48/610 (7.8%) patients were older than 6 years, with a median age of 7 years (range 6–31). Retinoblastoma was bilateral in 7 cases. The most common initial symptom was white reflex followed by a decrease in vision. The median lag time was 9 months. Fourteen cases (29.2%) were misdiagnosed, with endophthalmitis the most common misdiagnosis. Twenty-six (54%) patients had intraocular disease, 12 (25%) had locally advanced disease, and 10 (21%) had metastatic disease at presentation. Overall, 67% (14/21) of the eyes that were enucleated upfront for presumed intraocular disease had histopathological HRF. At last follow-up, 31/36 (86%) who were treated were alive and healthy, while 5 (14%) patients had disease progression. Conclusions: This is the largest study of older age retinoblastoma and shows that it forms a significant percentage of retinoblastoma in developing countries, is misdiagnosed in one-third of cases, and may present at an advanced stage in 46% of cases.

Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries

BackgroundThe travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed...

Screening for retinoblastoma: an evidence review of the validity and use of the red reflex test

Abstract Background Retinoblastoma is the most common intraocular malignancy of childhood, the most common presenting signs of which are leucocoria and strabismus. In Ireland, there are on average less than 5-7 cases annually. Early detection of this sight and life-threatening malignancy is important to enable urgent specialist ophthalmology referral for assessment. An evidence review was sought by the Health Service Executive Steering Group for the Revised Child Health Programme to examine the validity and use of the red reflex test in Ireland and internationally as a screening test for retinoblastoma. Methods An electronic literature search was conducted to identify relevant peer-reviewed publications using the database Pubmed. A hand search of reference lists of suitable articles was conducted to check for additional material. Publications pertaining to national and international retinoblastoma screening practices were sourced via internet searches using Google. The relevant grey literature was explored. Results There is very limited data on the validity of the red reflex test as a screening test for retinoblastoma. Despite potentially raising a high proportion of false positive results, it is a low-cost, non-invasive, quick and acceptable test. In Ireland and the UK, retinoblastoma is universally screened for using the red reflex test within 72 hours of birth and at 6-8 weeks of age. Detection of a white, absent or asymmetrical red reflex prompts urgent referral to a specialist ophthalmology service. Many cases of retinoblastoma in developed countries are brought to clinical attention after an eye abnormality is noticed by a parent. Conclusions The red reflex test is a valuable screening tool which is used internationally as part of newborn screening for eye pathology including retinoblastoma. The evidence synthesised in this review will inform educational initiatives in Ireland to improve awareness and detection of this malignancy among healthcare providers and parents. Key messages Early detection of retinoblastoma is important to enable urgent specialist ophthalmology referral for assessment. The red reflex test is a valuable screening tool which is used internationally as part of newborn screening for eye pathology including retinoblastoma.

High-risk features in primary versus secondary enucleated globes with advanced retinoblastoma: a retrospective histopathological study.

The management of bilateral advanced retinoblastoma (RB) cases is challenging with attempts to use neoadjuvant therapy salvaging of one of the globes. Our aim in this study was to demonstrate the effect of this primary therapy on the histopathological features and risk factors in secondary enucleated compared to primarily enucleated globes with groups D and E RB. We retrospectively reviewed all enucleated globes with advanced RB received in the pathology laboratories over a period of 5years. Patients were divided into two groups: one with primary enucleations and another with at least one secondary enucleated globe, and their demographic and clinical data were analyzed. The enucleated globes in the two groups were analyzed to compare the general histopathological features including tumor seeding, size, differentiation, growth pattern, mitotic figures, and focality. More importantly, high-risk features: choroidal invasion, optic nerve (ON) invasion, iris/anterior chamber invasion, ciliary body invasion, and scleral and extra-scleral extension, as well as the pathological classification of the tumor (pT) according to the American Joint Committee on Cancer 7th edition were also compared between the two groups. We had a total of 106 enucleated globes (78 primary and 28 secondary enucleations) from 99 patients with advanced RB (73 patients with primarily and 26 with secondarily enucleated globes). Demographic and clinical profiles of patients were similar in both, but the mean interval from presentation to enucleation was significantly longer in the secondary enucleations (P = 0.015). Rare/occasional mitotic figures were observed in secondary enucleations using multivariate analysis (P = 0.003). Primarily enucleated globes had higher risk of tumor seeding (P = 0.020), post-laminar/surgical margin ON invasion (P = 0.001), and massive choroidal invasion (P = 0.028). Half of the secondary enucleated globes had tumors confined to the globes without invasion (pT1) and statistically significant lower tumor classifications (pT1 or pT2a) compared to primary enucleations (P =0.001). However, 18% of the secondarily enucleated globes in 3 patients had unfavorable outcome with RB-related mortality after a period of 1-4years. Secondary enucleated globes with advanced RB show favorable histopathological findings mainly less mitosis. These eyes have significantly lower chance for harboring choroidal and ON invasion, thus mostly classified as pT1 or pT2a when compared to primarily enucleated globes. The decision for secondary enucleation was observed to be significantly delayed (8.0months ± 9.8). Prompt decision for needed enucleation based on the response to primary treatment and careful histopathological examination of enucleated globes are essential to prevent disease-related mortality.

Recommendations for Long-Term Follow-up of Adults with Heritable Retinoblastoma

To generate recommendations for long-term follow-up of adult survivors of heritable retinoblastoma. We convened a meeting of providers from retinoblastoma centers around the world to review the state of the science and to evaluate the published evidence. Retinoblastoma is a rare childhood cancer of the retina. Approximately 40% of retinoblastoma cases are heritable, resulting from a germline mutation in RB1. Dramatic improvements in treatment and supportive care have resulted in a growing adult survivor population. However, survivors of heritable retinoblastoma have a significantly increased risk of subsequent malignant neoplasms, particularly bone and soft tissue sarcomas, uterine leiomyosarcoma, melanomas, and radiotherapy-related central nervous system tumors, which are associated with excess morbidity and mortality. Despite these risks, no surveillance recommendations for this population currently are in place, and surveillance practices vary widely by center. Following the Institute of Medicine procedure for clinical practice guideline development, a PubMed, EMBASE, and Web of Science search was performed, resulting in 139 articles; after abstract and full-text review, 37 articles underwent detailed data abstraction to quantify risk and evidence regarding surveillance, if available. During an in-person meeting, evidence was presented and discussed, resulting in consensus recommendations. Diagnosis and mortality from subsequent neoplasm. Although evidence for risk of subsequent neoplasm, especially sarcoma and melanoma, was significant, evidence supporting routine testing of asymptomatic survivors was not identified. Skin examination for melanoma and prompt evaluation of signs and symptoms of head and neck disease were determined to be prudent. This review of the literature confirmed some of the common second cancers in retinoblastoma survivors but found little evidence for a benefit from currently available surveillance for these malignancies. Future research should incorporate international partners, patients, and family members.

A 20-year audit of retinoblastoma treatment outcomes.

ObjectivesTo evaluate the long-term treatment outcomes in intraocular retinoblastoma (RB) including the associated factors for eventual treatment with external beam radiotherapy (EBRT) and enucleation as well as to analyse the risk factors for metastasis and death in extraocular RB.MethodsRetrospective analysis of 390 eyes from 256 (89.8%) intraocular RB and 29 (10.2%) extraocular RB cases diagnosed and treated between October 1998 and May 2018 at one of the largest tertiary care centers in Turkey.ResultsOf 351 intraocular RB eyes, 53.3% had group D/E disease at presentation. 75 (21.4%) of 351 eyes underwent primary enucleation. Of the remaining 276 eyes undergoing eye-conserving treatments, 201 (72.8%) were salvaged. Most of these eyes were treated using intravenous chemotherapy and/or focal treatments [transpupillary thermotherapy (TTT) and cryotherapy] initially. EBRT was eventually required in 48 (17.4%) eyes and secondary enucleation in 75 (27.2%) eyes. At mean follow-ups of 76.7 and 39.7 months for intraocular and extraocular RB cohorts, respectively, 180 (46.2%) eyes underwent primary/secondary enucleation and exenteration. Overall, 13 cases developed metastasis and 9 died. Two patients with trilateral RB also expired. Multivariable risk factors for enucleation were the presence of vitreous seeds (p < 0.001), absence of EBRT administration (p = 0.033), 5–9 TTT applications compared with no TTT (p = 0.031), and each 1 mm increase in tumour base diameter (p < 0.001). Univariate factors predictive of metastasis were the presence of extraocular RB detected by imaging methods (p < 0.001) and extrascleral/optic nerve cut end involvement at histopathological examination (p < 0.001).ConclusionsIn our series, 72.8% of the intraocular RB eyes undergoing eye-conserving treatments were saved. The globe salvage rate for all intraocular and extraocular RB eyes was 53.8% and the overall survival rate was 96.1%.

Global Retinoblastoma Presentation and Analysis by National Income Level

Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Outcomes of Advanced Retinoblastoma Treated with Local Salvage Treatment; a Retrospective Case Series.

Retinoblastoma (RB) is the most common intraocular malignancy arising from the developing retina and occurs in approximately one of every 15,000-20,000 births. With the introduction of the intra-arterial chemotherapy (IAC), the 5-year overall survival of children with RB is 99%, though in low- and middle-income countries, it rarely exceeds 35% due to limited resources and lack of expertise. The aim of this study was to determine the outcome of local salvage in advanced RB. A retrospective analysis was conducted on children diagnosed with advanced RB that had local salvage therapy along with systemic chemotherapy from January 2015 to January 2018 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Fifteen patients were included in the study, among these 10 were male. The median age of presentation was 20 months (range 2-40 months). Among participants, 11 patients had bilateral RB. Fourteen patients received local control along with systemic chemotherapy. Relapse disease was seen in 12 patients and 2-year disease-free survival (DFS) was 20%. The results of the present study suggest that centres lacking the resources for IAC should treat advance cases of RB with an upfront or early enucleation.

The risk factor of metastatic status of retinoblastoma patient in Yogyakarta Tertiary Hospital

The metastases of the tumor become a serious problem malignancy including retinoblastoma. This study aimed to observe the correlation between several risk factors with the metastatic status of retinoblastoma patients in Yogyakarta Tertiary Hospital. Records of patients with retinoblastoma treated between 2011 and 2017 were obtained for observational analytic study. The gender, laterality, age, Body Mass Index (BMI) classification, BMI for age, type of retinoblastoma, and metastatic status were analyzed. The association was statistically analyzed by the correlation ratio of Eta test. Thirty-seven cases of retinoblastoma were enrolled in this study, with mean age 29.44 (±14.1) months; 14 females and 23 males. Ten patients (27.0%) have no metastases, while 27 patients (72.9%) exhibit metastases. The multivariate logistic regression analysis demonstrated that male gender (OR 8.3; 95% CI 1.07–64.5; p = 0.04) and age below 24 months (OR 17.6; 95% CI 1.26-248.31; p = 0.03) were a predictive of the metastatic status for retinoblastoma. On the other hand, the laterality, BMI classification, BMI for age, and types of retinoblastoma were not associated with the metastatic status of retinoblastoma. The gender and age were significantly associated with the metastatic status of retinoblastoma. Male patients and age below 24 months were more likely to have metastatic disease of retinoblastoma.

Fluorescein angiography findings in both eyes of a unilateral retinoblastoma case during intra-arterial chemotherapy with melphalan.

Fluorescein angiography findings in both eyes of a unilateral retinoblastoma case during intra-arterial chemotherapy with melphalan.

PEDT-04 SIX CASES OF RETINOBLASTOMA WITH CNS INVOLVEMENT

Although the survival rate of intraocular retinoblastoma (RB) is nearly 100%, the outcome of central nervous system (CNS) involvement or Trilateral retinoblastoma (TRb: very rare RB which associated with brain tumor) is dismal. We retrospectively reviewed our six cases of these rare tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 2). Only one had RB family history. Their affected eyes were bilateral 2, unilateral 3 and no 1. Their CNS diseases were suprasellar tumor 3, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Two of the suprasellar tumor patients had spinal metastasis. Three of the six patients were TRb. One TRb patient was treated with chemotherapy and high-dose chemotherapy without radiotherapy. Although he suffered with secondary osteosarcoma seven years later, he got complete remission and alive 5 years more without any tumor recurrence. The second TRb patient was treated with chemotherapy and local radiotherapy but relapsed 20 months later. The third TRb patient was chemotherapy resistant. Two CSF positive patients had optic nerve invasion. One patient with chiasm invasion died 11 months later because of treatment resistance. The other patient with optic nerve invasion before optic canal had no CNS tumor nor CSF involvement at diagnosis. Chemotherapy before enucleation was given to avoid dissemination. However, CSF cytology became positive after enucleation and remained even with intensified chemotherapy. Finally, he got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 3.8 years. The last patient had suprasellar genetically classified retinoblastoma tumor and cerebrospinal metastasis. This patient showed good chemotherapy response and is still under treatment. Even with "so called° fatal RB cases, some case could survive with intensified therapy. Data accumulation is necessary for better survival of these tumors.

LINC00858 promotes retinoblastoma cell proliferation, migration and invasion by inhibiting miR-3182.

The aim of the present study was to determine the role of long intergenic non-protein coding RNA 858 (LINC00858) in retinoblastoma (RB) and investigate the underlying molecular mechanisms. RB tissues and paracancerous tissues of 27 RB cases were obtained. RB cell lines (SO-RB50, Y79, HXO-RB44 and WERI-Rb1) and a normal retinal epithelial cell line (ARPE-19) were cultured for in vitro experiments. Batches of SO-RB50 and Y79 cells were assigned to groups transfected with small interfering RNA targeting LINC00858 (si-LINC00858 group), microRNA (miR)-3182 mimics or inhibitor, or the respective controls. A Cell Counting Kit-8 and Transwell assays were performed to assess the effect of the transfections on the proliferation, migration and invasion of SO-RB50 and Y79 cells. A luciferase reporter assay was performed using SO-RB50 cells to demonstrate the direct binding of LINC00858 and miR-3182. Reverse transcription-quantitative PCR was employed to detect LINC00858 and miR-3182 expression. Pearson correlation analysis was used to assess the correlation between the expression of LINC00858 and miR-3182. The results indicated that RB tissues and cells exhibited aberrantly elevated LINC00858 expression (P<0.05). Compared with those in the control-transfected group, SO-RB50 and Y79 cells of the si-LINC00858 group had a lower cell proliferation, as well as a lower number of migrated and invaded cells (all P<0.05). miR-3182 was proven to be a target gene of LINC00858, to be abnormally downregulated in RB tissues and cells (P<0.05) and to be negatively correlated with LINC00858 expression. Compared with those in the si-LINC00858 + inhibitor-negative control group, SO-RB50 and Y79 cells of the si-LINC00858 + miR-3182 inhibitor group exhibited a significantly higher relative proliferation, migration and invasion (all P<0.05). In conclusion, LINC00858 promoted RB cell proliferation, migration and invasion, at least partially by inhibiting miR-3182.

OCT and OCT‐A in pediatric ocular oncology

AbstractOver the last years, the use of optical coherence tomography in pediatric ocular oncology has become instrumental for the diagnosis and treatment of different tumors, by providing precise location of the lesions and documentation of growth or concomittant complications. In the specific case of retinoblastoma, the most common intraocular pediatric tumor, OCT allows (i) the early detection of new tumors or tumor recurrences, (ii) the monitoring of the treatment response, (iii) the evaluation of the retina and optic nerve status especially in cases of concomitant dense retrohyaloidal or epiretinal seeding and also (iv) the documentation of treatment‐related adverse effects affecting the macula or the choroid. Recently, the use of optical coherence tomography‐angiography has enabled to investigate changes in the foveal microvascular anatomy of different pediatric cases at diagnosis or after various treatments.

Unilateral unifocal advanced intraocular retinoblastoma: is reasonable to adopt intra‐arterial chemotherapy as single therapeutic choice?

AbstractPurposeTo report the outcome of 30 naive unilateral unifocal retinoblastoma cases treated with intra‐arterial chemotherapy alone.MethodsFrom 2008 to 2019, 192 eyes affected with retinoblastoma have been treated with intra‐arterial chemotherapy (IAC). 100 out of 192 (52%) eyes were naive advanced unilateral unifocal retinoblastoma (Group B‐E). 30 out of 100 (30%) received intra‐arterial chemotherapy alone. All patients underwent genetic testing at diagnosis. MR was performed at diagnosis, during treatment (when necessary), 3 months after last infusion and annually to evaluate eyeball growth.ResultsTumor control and globe salvage was achieved in 100% of the reported cases (follow‐up ranged from 11 years to 9 months). New tumors or relapse have not been detected. No further local or systemic therapies were necessary. Procedure complications and local and systemic effects are reported. No intraocular or orbital tumor recurrence or metastatic disease have been observed observed.ConclusionsThe outcome will be correlated to genetic analysis, doses and drugs used (alone or in combination) and number of infusions received.

Molecular subgrouping of primary pineal parenchymal tumors reveals distinct subtypes correlated with clinical parameters and genetic alterations.

Tumors of the pineal region comprise several different entities with distinct clinical and histopathological features. Whereas some entities predominantly affect adults, pineoblastoma (PB) constitutes a highly aggressive malignancy of childhood with a poor outcome. PBs mainly arise sporadically, but may also occur in the context of cancer predisposition syndromes including DICER1 and RB1 germline mutation. With this study, we investigate clinico-pathological subgroups of pineal tumors and further characterize their biological features. We performed genome-wide DNA methylation analysis in 195 tumors of the pineal region and 20 normal pineal gland controls. Copy-number profiles were obtained from DNA methylation data; gene panel sequencing was added for 93 tumors and analysis was further complemented by miRNA sequencing for 22 tumor samples. Unsupervised clustering based on DNA methylation profiling separated known subgroups, like pineocytoma, pineal parenchymal tumor of intermediate differentiation, papillary tumor of the pineal region and PB, and further distinct subtypes within these groups, including three subtypes within the core PB subgroup. The novel molecular subgroup Pin-RB includes cases of trilateral retinoblastoma as well as sporadic pineal tumors with RB1 alterations, and displays similarities with retinoblastoma. Distinct clinical associations discriminate the second novel molecular subgroup PB-MYC from other PB cases. Alterations within the miRNA processing pathway (affecting DROSHA, DGCR8 or DICER1) are found in about two thirds of cases in the three core PB subtypes. Methylation profiling revealed biologically distinct groups of pineal tumors with specific clinical and molecular features. Our findings provide a foundation for further clinical as well as molecular and functional characterization of PB and other pineal tumors, including the role of miRNA processing defects in oncogenesis.

Эффект родительского происхождения мутации в гене RB1 при наследственной ретинобластоме с низкой пенетрантностью

Актуальность. При наследственной ретинобластоме герминальная мутация в одном из аллелей гена RB1 обусловливает предрасположенность к заболеванию и его семейную передачу. Наследственная ретинобластома манифестирует в более раннем возрасте по сравнению со спорадической формой и носит в большинстве случаев мультифокальный и билатеральный характер. Однако некоторые семьи с ретинобластомой (два и более носителя одинаковой герминальной мутации в родословной) демонстрируют более мягкий фенотип с неполной пенетрантностью (у части носителей герминальной мутации заболевание не развивается) и вариабельной экспрессивностью (одинаковая мутация у разных членов семьи может проявляться уни- или билатеральной формой заболевания). Выявление низкопенетрантных мутаций в гене RB1 и изучение характера их наследования способствует пониманию механизмов, лежащих в основе развития наследственной ретинобластомы с низкой пенетрантностью, и крайне важно как для дальнейшего расширения знаний о молекулярной генетике ретинобластомы, так и для медико-генетического консультирования и последующего клинического ведения семей с такой формой заболевания. Цель. Установить спектр генетических нарушений в гене RB1 у больных с наследственной ретинобластомой с неполной пенетрантностью и вариабельной экспрессивностью в выборке российских пациентов и определить влияние родительского происхождения мутации в RB1 на её фенотипическое проявление. Методы. Методом высокопроизводительного параллельного секвенирования проведено молекулярно-генетическое обследование 332 неродственных больных с ретинобластомой. Для верификации выявленных точковых мутаций и анализа их сегрегации в родословных использовали секвенирование по Сэнгеру. Результаты. В группе пациентов без семейного анамнеза ретинобластомы у 3,5% больных определен наследственный характер заболевания, при котором один из родителей являлся бессимптомным носителем герминальной мутации в гене RB1. Выявлено 10 низкопенетрантных мутаций в гене RB1 и установлен спектр мутаций, приводящих к развитию наследственной ретинобластомы с низкой пенетрантностью. В 91,7% случаев наследственной ретинобластомы с низкой пенетрантностью мутантный аллель получен пробандом от отца, у которого отсутствовали клинические признаки заболевания или наблюдалась более легкая форма. Выводы. Полученные результаты подтверждают ранее высказанные предположения, что низкопенетрантные герминальные мутации в гене RB1, унаследованные от отца, чаще приводят к развитию ретинобластомы, и в более тяжелой форме по сравнению с таковыми, унаследованными от матери. Background. In hereditary retinoblastoma, a germline mutation in one of the alleles of the RB1 gene causes a predisposition to the disease and its transmission within the pedigree. Hereditary retinoblastoma manifests at an earlier age compared with the sporadic form and in most cases is multifocal and bilateral. However, some families with retinoblastoma (two or more carriers of the same germline mutation in the pedigree) exhibit a milder phenotype with incomplete penetrance (some carriers of the germline mutation are asymptomatic) and variable expressivity (the same mutation in different family members may manifest as either a unilateral or bilateral form). Identification of low-penetrant mutations in the RB1 gene and studying their inheritance in pedigrees contributes to understanding the mechanisms underlying the development of retinoblastoma with low penetrance. It is extremely important both for further expansion of knowledge in the field of molecular genetics of retinoblastoma, and for competent genetic counseling and subsequent clinical management of families with this form of the disease. Objective. To establish the spectrum of genetic disorders in the RB1 gene in Russian patients with hereditary retinoblastoma with incomplete penetrance and variable expressivity and to determine the effect of the parental origin of the RB1 mutation on its phenotypic manifestation. Methods. Using high-performance parallel sequencing, a molecular genetic survey of 332 unrelated patients with retinoblastoma was performed. Sanger sequencing was used to verify the identified point mutations and analyze their segregation in pedigrees. Results. In the group of patients without a family history of retinoblastoma, in 3.5% the hereditary nature of the disease was determined, where one of the parents was an asymptomatic carrier of a germline mutation in the RB1 gene. Ten low-penetrant mutations in the RB1 gene were identified. In 91.7% of cases of hereditary retinoblastoma with low penetrance, the mutant allele was obtained by a proband from a father with no clinical signs of the disease or with a milder form. Conclusion. The results confirm the previously suggested assumptions that low-penetrant germline mutations in the RB1 gene inherited from the father more often lead to the development of retinoblastoma, and in a more severe form than those inherited from the mother.

Endovascular Super-Selective Intra-Arterial Chemotherapy for Retinoblastoma: Systematic Review and Institutional Experience

Abstract INTRODUCTION Selective intra-arterial delivery of chemotherapy (IAC) via microcatheter infusion into the ophthalmic artery has become an increasingly popular treatment modality to accomplish globe salvage in children with retinoblastoma. While previously limited to highly specialized centers, interest in and popularity of this treatment are growing. Here, we provide a comprehensive review of available data in addition to our own experience. METHODS Systematic literature review was conducted using PRISMA guidelines and 22 studies were identified that met inclusion criteria. In our own series, consecutive patients undergoing IAC for retinoblastoma were identified between January 2009 and December 2016. Pertinent data, including tumor grade, enucleation vs globe salvage, and both ocular and systemic adverse events were recorded. RESULTS In all1593 total eyes were treated as reported in 22 studies published between 2011 and 2019. Among those in which tumor staging data was available, 396 (27.6%) were less advanced (Reese–Ellsworth A-C, or International Classification I-III) and 997 (69.4%) were more advanced (D-E, IV-V). A total of 21 studies included data on systemic and/or ocular complications, which with few exceptions were transient and resulted in no permanent morbidity. A single permanent neurological complication occurred. Analysis of our institutional experience demonstrated a globe salvage rate of 73% (identical to pooled data from the literature). In 442 procedures, our ocular and systemic complication rates were 10.6% and 13.8%, respectively; virtually all were transient phenomena including orbital edema, myelosuppression, and and brief intraprocedural bronchospasm/bradycardia during drug delivery. CONCLUSION Although reported predominantly in retrospective series, a systematic review of outcomes in selective IAC for retinoblastoma demonstrates efficacy (73% globe salvage rate) with minimal morbidity, even in advanced disease. Our own results reflect a similar experience and taken together, provide strong evidence that this treatment modality is safe and effective. The data support adoption of this technique as first-line therapy for globe salvage in selected cases of retinoblastoma.