How we approach conservative treatment of retinoblastoma in South America in the era of local ocular treatments: A consensus of the Grupo America Latina de Oncologia Pediatrica (GALOP).

Local therapies are increasingly used for ocular preservation in retinoblastoma. In middle-income countries, these techniques pose specific challenges mostly related to more advanced disease at diagnosis. The Grupo de America Latina de Oncología Pediátrica (GALOP) developed a consensus document for the management of conservative therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the preferred therapy, except for those with less advanced disease or age younger than 6 months. OAC allowed for a reduction in the use of external beam radiotherapy in our setting. Intravitreal chemotherapy is the preferred treatment for vitreous seeding. Enucleation is the treatment of choice for eyes with advanced disease.

Impact of COVID-19 in pediatric oncology care in Latin America during the first year of the pandemic.

BACKGROUND: The ongoing coronavirus 2019 disease (COVID-19) pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year. METHOD: Four cross-sectional surveys were electronically distributed among pediatric onco-hematologists in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners. RESULTS: Four hundred fifty-three pediatric onco-hematologists from 20 countries responded to the first survey, with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active ongoing patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (odds ratio [OR]: 1.84, 95% CI: 1.19-2.8), surgeries (OR: 3, 95% CI: 1.9-4.6) and radiotherapy (OR: 6, 95% CI: 3.5-10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR: 3, 95% CI: 1.4-6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR: 3.48, 95% CI: 1.6-7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability. CONCLUSION: Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic.

Immunohistochemistry of apoptosis-related proteins in retinoblastoma.

Retinoblastoma is the most common intraocular malignant neoplasia during childhood and results from the partial or total inactivity of the retinoblastoma protein (pRb). In the absence of pRb, the E2F transcription factors increase the levels of cell cycle proteins as well as some pro-apoptotic proteins. We intended to study the immunohistochemistry profile of apoptotic-related proteins in retinoblastoma. We also evaluated the association between the expression of apoptotic protein and stage of tumor or survivor after a 5year follow up. Apoptosis-related proteins (Apaf-1, Bak, Bax, Bcl-2, Bcl-xL, Bim-long, MDM2, p53, pro-caspase-3, PUMA, Smac/DIABLO and cleaved caspase-3) were evaluated using immunohistochemistry on tissue microarrays which contained samples of retinoblastoma tumors taken from ninety-three patients without any treatment previous to surgery. The immunohistochemistry reactions were evaluated using an optical microscope as well as the ACIS III® platform. The pro-apoptotic proteins (APAF-1, Bax, p53, PUMA, Smac/DIABLO) were more frequently expressed than the anti-apoptotic proteins (Bcl-2, Bcl-xL and MDM2). The protein Bcl-xL had a negative correlation with cleaved caspase-3, a marker of cell apoptosis. Bcl-xL may be implicated in an apoptosis block.

Sarcomas de partes moles no primeiro ano de vida / Soft tissue sarcomas during the first year

Os autores destacam a importância dos sarcomas de partes moles em crianças até um ano de idade, por suas características clínicas e resposta ao tratamento específico. Apresentam estatística própria de 13 casos e revisão da literatura, no que se refere ao diagnóstico e prognóstico dos principais tipos de sarcomas.

Ethnicity, race, and socioeconomic status influence incidence of Langerhans cell histiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease, and its etiology is not well understood. Population-based studies may contribute to etiologic research by defining incidence patterns. This study was designed to evaluate the descriptive epidemiology of disseminated LCH in the United States, using data from population-based cancer registries. PROCEDURE: We analyzed the incidence and survival of disseminated LCH in children and adolescents (0-19 years) from 18 SEER registries during 2000-2009. Age-standardized incidence rates (ASIR) per million and rate ratios (RR) were calculated by gender, race, ethnicity, age, and socioeconomic variables (crowding, rural/urban, education, and poverty) using the SEER*Stat software 8.0.1. Relative survival (RS) estimates were calculated using Ederer II method. RESULTS: One hundred forty-five cases of disseminated LCH were recorded; ASIR was 0.70/million per year. Lower ASIR was observed for blacks (vs. whites) (RR = 0.41, 95% CI 0.18-0.81), while higher ASIR was noted for Hispanics (vs. non-Hispanics) (RR = 1.63, 95% CI 1.15-2.29). Risk of LCH was higher in crowded counties (RR = 1.84, 95% CI 1.31-2.58) and also in areas with low educational level (RR = 1.49, 95% CI 1.02-2.22). Five-year relative survival was 90.0% (95% CI 83.0-94.2). Important differences in survival were noted according to gender (male: RS = 96.0 vs. female: RS = 83.4%, P = 0.029) and age (<1 year: RS = 78.5, 1-4 years: RS = 95.6%, 5-19 years: RS = 100%, P = 0.004). CONCLUSIONS: This population-based study shows significant variations in the incidence of disseminated LCH by race and ethnic group, as well as the influence of socioeconomic factors. These data may provide clues to causation and point toward the need for analytical epidemiologic studies.

Serum level of vitamin D3 in cutaneous melanoma / Nível sérico de vitamina D3 em portadores de melanoma cutâneo

Objective To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. Methods The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. Results A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. Conclusion Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma. .

Objetivo Comparar o nível de vitamina D3 em portadores de melanoma, em atividade de doença ou não, com os valores de referência e com pacientes de um hospital geral. Métodos Os níveis séricos de vitamina D3 foram dosados em portadores de melanoma cutâneo entre 22 a 80 anos, de ambos os sexos, de janeiro de 2010 a dezembro de 2013. As amostras do grupo dos pacientes gerais foram processadas no Hospital Israelita Albert Einstein (grupo controle). A análise dos dados foi realizada utilizando o software Statistica. Resultados Foram estudados 100 pacientes, sendo 54 homens, com média de idade 54,67 anos, e 95 brancos. Desses 100 pacientes, 17 apresentavam doença em atividade. A média dos níveis de vitamina D3 nos 100 pacientes foi inferior ao nível considerado suficiente, porém acima da média do grupo controle. A deficiência de vitamina D3 apresentou distribuição semelhante nos dois grupos com melanoma (em atividade de doença ou não). Conclusão Os níveis de vitamina D3 nos pacientes com melanoma foram superiores aos dos pacientes gerais e inferiores aos de referência. Se os valores de referência estão adequados, grande parte da população apresenta níveis insuficientes de vitamina D3, incluindo os portadores de melanoma, ou tal padrão precisa ser reavaliado. Não houve diferença dos níveis de vitamina D3 entre portadores de melanoma com ou sem atividade. Estudos relacionando vitamina D e melanoma devem ser aprofundados. .

Serum level of vitamin D3 in cutaneous melanoma.

OBJECTIVE: To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. METHODS: The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. RESULTS: A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. CONCLUSION: Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma.

Abnormal orbital growth in children submitted to enucleation for retinoblastoma treatment.

Enucleation is typically performed for the treatment of advanced retinoblastoma in children. After enucleation, the orbit undergoes abnormal development. In this study, orbital asymmetry was calculated using computed tomography measurements obtained from patients who experienced enucleation for unilateral retinoblastoma. Influence factors analyzed included: type of treatment, use of orbital implants, and patient's age at diagnosis. A total of 42 children underwent enucleation with a mean follow-up period of 4.8 years. For 28 patients, treatment included enucleation alone, 14 patients received enucleation plus radiation therapy. Thirty patients kept orbital implants long term. The mean orbital volume asymmetry for treated versus contralateral orbits was 16.8%. Mean asymmetry in orbital volume was greater for patients who underwent enucleation combined to radiation therapy (23.7% vs. 13.3%, P=0.05) and for patients without long-term maintenance of the prosthetic implants (29.3% vs. 11.8%, P<0.01). In conclusion, orbital volume is abnormally affected in children after enucleation of 1 eye for the treatment of retinoblastoma, and computed tomography can precisely quantify the asymmetry that develops. Orbital implants improve volumetric growth after enucleation, with 2-fold greater orbital asymmetry achieved without an implant.

Evaluation of ototoxicity in children treated for retinoblastoma: preliminary results of a systematic audiological evaluation.

BACKGROUND: The objective of this study was to identify the ocurrence of hearing loss in children treated for retinoblastoma using a multidisciplinary approach. PATIENTS AND METHODS: Thirty-two children were evaluated pre- and post-treatment. Eleven children were treated exclusively with enucleation, fifteen with carboplatin and six with cisplatin. Otoacoustic emissions were performed with the ILO 88, before and after the treatment. RESULTS: In our study we found 5 children (24%) with hearing loss among the 21 evaluated. However in the group of children treated with carboplatin (N=15), 1 case (6.6%) presented hearing loss, while among those treated with cisplatin (N=6) we found 4 cases (66.6%) with hearing loss (p=0.0114). CONCLUSION: We concluded that patients who are treated with cisplatin are at risk for developing hearing loss.

Low prevalence of HPV in Brazilian children with retinoblastoma.

Retinoblastoma is the most frequent intra-ocular malignant tumor of the childhood, occurring in 1 of 18,000-30,000 live births. Little is known about the causes of sporadic retinoblastoma and only a few authors have investigated the etiologic role of human papillomavirus (HPV), with controversial results. Formalin-fixed, paraffin-embedded tissue blocks containing retinoblastoma were retrieved from the archives of the Department of Pathology at Hospital A C Camargo, São Paulo, Brazil. All patients were treated with enucleation (21 children had both eyes enucleated). Retinoblastoma and, when possible, normal retina of each specimen, were micro-dissected under direct light microscopic visualization by using a PixCell II Laser Capture Micro-dissection System. The DNA quality was evaluated by polymerase chain reaction (PCR) amplification of 110 base pairs fragment of the human ß-globin gene using primers PCO3+/PCO4+. All globin positive specimens were analyzed by PCR for the presence of HPV DNA using consensus primers GP5+/GP6+. A total of 154 specimens were evaluated. Forty-four patients also had normal retinal specimens available for analysis of DNA HPV. The DNA HPV prevalence among all tumor specimens was 4.6% (95% CI 2.0; 8.8) (7 positive specimens/153 adequate specimens). Among normal retinal specimens, the DNA HPV prevalence was 9.1% (95% CI 2.9; 20.5) (4 positive specimens/44 specimens). There was no statistically significant difference between these rates (P = 0.318). Excluding any experimental failure, our results indicate a low prevalence of HPV DNA in retinoblastomas. We were therefore unable to conclude about the association between these oncogenic viruses and this rare pediatric neoplasm.

Low prevalence of HPV in Brazilian children with retinoblastoma

Retinoblastoma is the most frequent intra-ocular malignant tumor of the childhood, occurring in 1 of 18,000–30,000 live births. Little is known about the causes of sporadic retinoblastoma and only a few authors have investigated the etiologic role of human papillomavirus (HPV), with controversial results. Formalin-fixed, paraffin-embedded tissue blocks containing retinoblastoma were retrieved from the archives of the Department of Pathology at Hospital A C Camargo, São Paulo, Brazil. All patients were treated with enucleation (21 children had both eyes enucleated). Retinoblastoma and, when possible, normal retina of each specimen, were micro-dissected under direct light microscopic visualization by using a PixCell II Laser Capture Micro-dissection System. The DNA quality was evaluated by polymerase chain reaction (PCR) amplification of 110 base pairs fragment of the human β-globin gene using primers PCO3 +/PCO4+. All globin positive specimens were analyzed by PCR for the presence of HPV DNA using consensus primers GP5+/GP6+. A total of 154 specimens were evaluated. Forty-four patients also had normal retinal specimens available for analysis of DNA HPV. The DNA HPV prevalence among all tumor specimens was 4.6% (95% CI 2.0; 8.8) (7 positive specimens/153 adequate specimens). Among normal retinal specimens, the DNA HPV prevalence was 9.1% (95% CI 2.9; 20.5) (4 positive specimens/44 specimens). There was no statistically significant difference between these rates (P = 0.318). Excluding any experimental failure, our results indicate a low prevalence of HPV DNA in retinoblastomas. We were therefore unable to conclude about the association between these oncogenic viruses and this rare pediatric neoplasm

Familial retinoblastoma in developing countries.

BACKGROUND: Although screening for familial retinoblastoma has been shown to be beneficial we suspected that such screening programs may be less than optimal in developing countries (DC). METHODS: Retrospective cohort study comparing patients with familial retinoblastoma from five centers in DC (Argentina, Brazil, Turkey, Jordan, and Venezuela) versus a reference center in the USA. RESULTS: Ninety-two (32 from the USA and 60 from DC) patients were included. Forty-one (44.6%) patients avoided enucleation, 42 (45.7%) had 1 eye removed, and 9 (9.8%) underwent bilateral enucleation. Eleven (11.9%) had major pathology risk factors at enucleation. There were no cases of metastatic disease at diagnosis. Detection via screening was significantly less common in DC than in the USA (23.3% vs. 71.8%, P < 0.0001). Patients in DC were diagnosed at a significantly later age and with more advanced intraocular disease that led to increased risk of bilateral enucleation. Patients detected by screening in DC were significantly younger at diagnosis, had less advanced intraocular disease, better ocular preservation rates and survival results than those whose retinoblastoma was not detected via early screening. Five-year pEFS was 0.92 for the patients treated in the USA and 0.81 for the patients in DC (P = 0.42). Seven events occurred (extraocular relapse four in patients from DC and second malignancies in three). CONCLUSIONS: Patients with familial retinoblastoma are less likely to be diagnosed by screening in DC and had higher morbidity and mortality caused by recurrent extraocular retinoblastoma.

Retinoblastoma: one world, one vision.

Retinoblastoma is curable when diagnosed early and treated appropriately; however, the prognosis is dismal when the basic elements of diagnosis and treatment are lacking. In developing countries, poor education, lower socioeconomic conditions, and inefficient health care systems result in delayed diagnosis and suboptimal care. Furthermore, the complexity of multidisciplinary care required is seldom possible. Whereas ocular salvage is a priority in the Western world, death from retinoblastoma is still a major problem in developing countries. To bring the 2 ends of this spectrum together and provide a forum for discussion, the "One World, One Vision" symposium was organized, at which clinicians and researchers from various cultural, geographic, and socioeconomic backgrounds converged to discuss their experiences. Strategies for early diagnosis in developing countries were discussed. Elements of the development of retinoblastoma centers in developing countries were discussed, and examples of successful programs were highlighted. An important component in this process is twinning between centers in developing countries and mentor institutions in high-income countries. Global initiatives by nongovernmental organizations such as the International Network for Cancer Treatment and Research, Orbis International, and the International Agency for Prevention of Blindness were presented. Treatment of retinoblastoma in developing countries remains a challenge; however, it is possible to coordinate efforts at multiple levels, including public administrations and nonprofit organizations, to improve the diagnosis and treatment of retinoblastoma and to improve the outcome for these children.

The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement.

This study aimed to determine the impact of the addition of ifosfamide/etoposide to a regimen containing cisplatin/teniposide on the survival of patients with retinoblastoma with orbital involvement. Thirty patients were treated at the A. C. Camargo Hospital, Brazil, from 1986 to 2002. From 1986 to April 1992 (period I, n=12), treatment consisted of 3 cycles of induction chemotherapy with cisplatin and teniposide, followed by maintenance with same drugs alternating with cyclophosphamide, vincristine, and doxorubicin every 21 days for 60 weeks. Since April 1992 (period II, n=18), the treatment consisted of 3 cycles of ifosfamide and etoposide followed by maintenance with same drugs, alternating with cisplatin and teniposide every 21 days for 36 weeks. In both periods, children were submitted to exenteration with eyelid preservation and orbital radiation therapy with 45 cGy, and also received intrathecal therapy with methotrexate plus dexamethasone and cytarabine. Kaplan-Meier method was used for survival analysis. The median age was 31 months. Most patients (86.7%) presented unilateral tumors. The 3-year overall survival was 34.4% and 72.2%, respectively, for patients treated during periods I and II (P=0.061). The addition of ifosfamide/etoposide to chemotherapy with cisplatin/teniposide improves survival in these patients, but further studies are still necessary.

Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?

PURPOSE: To describe a series of patients with secondary acute myelogenous leukemia (sAML) and retinoblastoma (RB). DESIGN: Retrospective observational cases series. PARTICIPANTS: Ocular and pediatric oncologists at referral centers in Europe and the Americas and the RB databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center. METHODS: Physician survey, retrospective database review, and literature search. MAIN OUTCOME MEASURES: History of RB and development of sAML, management of RB (surgery, radiotherapy, chemotherapy), age at diagnosis of RB and leukemia, French-American-British (FAB) subtype, and current status of patient (alive or dead). RESULTS: Fifteen patients with sAML were identified; 13 occurred in childhood. Mean latent period from RB to AML diagnosis was 9.8 years (median, 42 months). Nine cases were of the M2 or M5 FAB subtypes. Twelve patients (79 %) had received chemotherapy with a topoisomerase II inhibitor, 8 (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. CONCLUSIONS: Acute myelogenous leukemia is a rare secondary malignancy among retinoblastoma patients, many of whom were treated with primary or adjuvant chemotherapy. Additional studies are needed to assess potential risk factors contributing to sAML development in this cohort.

Retinoblastoma in children older than 5 years of age.

BACKGROUND: Retinoblastoma is a malignant tumor of the embryonic neural retina. About 80% of cases are diagnosed before age 4, with a median age at diagnosis of 2 years. OBJECTIVE: To determine characteristics and prognosis of retinoblastoma in children older than 5 years. PROCEDURES: From 1986 to 2002, medical records of 16 patients out of 453 cases referred to Hospital do Câncer AC Camargo, São Paulo, Brazil. RESULTS: Median age at diagnosis was 73.7 months (range 65-144) and there was an equal gender distribution. Fifteen patients presented with unilateral disease. The mean time between first symptoms and diagnosis was 9.6 months (range 0-48). Most cases were diagnosed in advanced stages and 15 eyes were enucleated. Eleven patients presented with intraocular tumor (1 Reese II and 10 Reese V) and five presented with extraocular disease (one CCG II and four CCG III). Twelve patients are still alive with a median follow-up of 92 months (range 65-199). CONCLUSIONS: Because of its low incidence at this age, diagnosis of retinoblastoma is usually delayed due to low level of suspicion. Therefore, it is important that physicians are aware of this disease in order to perform an earlier diagnosis, and decrease treatment-related morbidity.

Trends in eye cancer mortality among children in Brazil, 1980-2002.

BACKGROUND: In the last few decades mortality from childhood cancers has shown substantial declines in industrialized countries, with smaller favorable trends in South America. OBJECTIVE: This study describes mortality trends in childhood eye cancer in Brazil from 1980 to 2002. PROCEDURE: Age-specific eye cancer death rates (0-4, 5-9, and 10-14 years) were calculated according to gender. Age-standardized mortality rates for children under 15 years were obtained through the direct method, using the 1960 world population as the standard. Trends in mortality were modeled using linear regression methods, with the age-standardized mortality coefficient (3-year centered moving average) as the dependent variable and the calendar year as the independent variable. RESULTS: The age-standardized mortality rates among the boys decreased from 0.14/100,000 habitants in 1981 and 1985 to 0.06 in 1994, whereas the observed corresponding decline among girls was from 0.17/100,000 habitants in 1982 and 1983 to 0.07 in 2001. Statistically significant declining trends in eye cancer mortality rates were observed for boys (r(2) adjusted = 0.54, P < 0.001) and also for girls (r(2) adjusted = 0.53, P < 0.001). When only subsite retina was analyzed a statistically significant decrease in mortality coefficients was also noted for males (r(2) adjusted = 0.55, P < 0.001) and females (r(2) adjusted = 0.32, P = 0.005). CONCLUSIONS: A consistent decrease in eye cancer mortality rates was noted in Brazil. In the absence of changes in incidence rates, this decline could be attributed to the improvement in treatment protocols and survival.