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.

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.

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.

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.

High-dose-rate brachytherapy as part of a multidisciplinary treatment of nasopharyngeal lymphoepithelioma in childhood.

BACKGROUND: Nasopharyngeal carcinoma in childhood is rare. Radiochemotherapy is considered the standard treatment and yields increased survival and local control rates. In this article, the authors report on the results from the multidisciplinary treatment of pediatric patients who had nasopharyngeal lymphoepithelioma with radiochemotherapy, including high-dose-rate brachytherapy of the primary tumor site. METHODS: Between May 1992 and May 2000, 16 children with nasopharyngeal lymphoepithelioma received neoadjuvant chemotherapy, conventional external beam radiotherapy, high-dose-rate brachytherapy, and adjuvant chemotherapy. Patients ranged in age from 7 years to 18 years, and 9 patients were male. Patient distribution according to clinical disease stage was as follows: Stage III, 1 patient; Stage IVA, 5 patients; Stage IVB, 9 patients; and Stage IVC, 1 patient. Three cycles of neoadjuvant and adjuvant chemotherapy in 3-week intervals were administered with cyclophosphamide, vincristine, doxorubicin, and cisplatin. The median doses of external beam radiotherapy to the primary tumor, positive lymph nodes, and subclinical areas of disease were 55 grays (Gy), 55 Gy, and 45 Gy, respectively. Children received 2 insertions of high-dose-rate brachytherapy at 5 Gy per insertion: These were performed with metallic applicators inserted through the transnasal access under local anesthesia. RESULTS: The median of follow-up was 54 months. At the time of last follow-up, 13 patients were alive without disease, 2 patients had died of disease, and 1 patient had died of treatment-related cardiac failure. Local control was achieved in 15 of 16 patients. Chemotherapy-related and radiotherapy-related acute toxicity was relevant but tolerable. CONCLUSIONS: In the current study, it was shown that the treatment was effective in the control of both local and distant disease, although there was relevant acute and late toxicity. High-dose-rate brachytherapy was deliverable on an outpatient basis with local anesthesia. Close follow-up of these patients was necessary to evaluate the significance of treatment-related late effects and their impact on quality of life.

Extraocular retinoblastoma: a 13-year experience.

BACKGROUND: The current study was performed to evaluate two regimens of treatment and to describe clinical and epidemiologic characteristics in patients with extraocular retinoblastoma. METHODS: Eighty-three patients with extraocular retinoblastoma according to Childrens Cancer Group (CCG) classification were admitted to the Pediatric Department of the A. C. Camargo between 1987-2000. The age, gender, race, lag time, first clinical presentation, staging, laterality, and treatment regimen were analyzed. Treatment was comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide during the first treatment period (1987-1991) or cisplatin and teniposide with alternating courses of ifosfamide and etoposide during the second treatment period (1992-2000). RESULTS: The mean age of the patients was 32.9 months (range, 2-145 months). The mean lag time was 10.5 months. Forty-three patients were treated in the first period and 40 patients were treated in the second period. Locally advanced tumors (Class I-III) were present in 83.1% of the patients. There was a positive correlation between lag time and age for unilateral tumors (correlation coefficient [r] = 0.35; P = 0.006), whereas the correlation was negative for bilateral tumors (r = -0.12; P = 0.63). The 5-year overall survival was 55.1% in the first treatment period and 59.4% in the second treatment period (P = 0.69). No significant differences with regard to survival rates were noted for unilateral tumors between the two treatment periods (44.6 noted for unilateral tumors vs. 59.1 noted for unilateral tumors). CONCLUSIONS: In the current study, the addition of ifosfamide and etoposide to a treatment regimen comprised of cisplatin, teniposide, vincristine, doxorubicin, and cyclophosphamide did not appear to improve the survival of patients with extraocular retinoblastoma. Patients with dissemination to the central nervous system or metastatic disease remain incurable and die of progressive disease, despite the aggressive treatment. A multicenter trial should be considered to evaluate the best strategy for these situations.

Evolução da terapêutica do retinoblastoma / Development in the treatment of retinoblastoma

OBJETIVO: Mostrar a evoluçäo do tratamento do retinoblastoma ao longo de uma década e suas implicaçöes na sobrevida global e na preservaçäo da visäo. MÉTODOS: Trezentos e dezenove pacientes foram avaliados no estudo. Analisamos 257 pacientes portadores de retinoblastoma admitidos no Hospital do Câncer, entre janeiro de 1986 a dezembro de 1996, divididos em dois grupos de acordo com tratamento a que foram submetidos (1986 a 1990 e 1991 a 1996). Analisamos ainda 62 pacientes portadores de retinoblastoma intra-ocular entre janeiro de 1996 e maio de 2000 que foram submetidos a quimiorreduçäo, aliada a medidas oftalmológicas, sem enucleaçäo ou radioterapia externa. RESULTADOS: Em pacientes com doença intra-ocular, nos dois períodos, näo houve significância estatística com relaçäo à sobrevida. Analisamos 59 pacientes com retinoblastoma extra-ocular, de acordo com a classificaçäo do CCG (Children´s Cancer Group), e a sobrevida global em 5 anos foi maior no 2º período, (63,7 por cento vs. 41 por cento; p= 0,059). Entre 1996 e 2000 analisamos 62 pacientes com retinoblastoma intra-ocular com visäo preservada, sendo 47 (75,8 por cento) com doença bilateral e 15 (24,2 por cento) com tumor unilateral. Os portadores de tumor bilateral tiveram uma taxa de preservaçäo de visäo de 49,8 por cento, versus 26,7 por cento para os pacientes com tumor unilateral. CONCLUSÖES: Tumores intra-oculares mantêm altas taxas de cura e preservaçäo da visäo. Novas combinaçöes de drogas poderäo melhorar a sobrevida dos extra-oculares. Quanto às perspectivas futuras, há pesquisas envolvendo terapia gênica/molecular e terapêutica anti-angiogênese. Apesar de toda a evoluçäo, o diagnóstico precoce é a arma mais poderosa, na cura dos portadores deste tumor

Retinoblastoma: análise da evolução clínica de pacientes portadores de retinoblastoma submetidos à tratamento multidisciplinar / Retinoblastoma: analysis of clinical outcomes in patients with retinoblastoma who underwent multidisciplinary treatment

257 pacientes portadores de retinoblastoma, admitidos no Depto. de Pediatria – Hospital do Câncer de SP, no período de 1986 a 1995, foram analisados. Dois protocolos terapêuticos foram seguidos em dois períodos, o primeiro entre os anos de 1986 até 1990 e o segundo entre os anos de 1991 a 1995. Foram estudadas as variáveis sociodemográficas, clínicas, as relacionadas ao tratamento e os fatores prognósticos que influenciaram a sobrevida desses pacientes. No primeiro período da análise, pacientes com tumores intra-oculares submetidos à enucleação, que apresentassem algum fator de risco no exame anatomopatológico, receberam 10 ciclos de quimioterapia com Ciclofosfamida e Vincristina. No segundo período, os pacientes com essas mesmas características foram sorteados para receberam ou não, tratamento quimioterápico. No segundo período da análise (1991-1995), observamos que a sobrevida livre de doenças para pacientes com tumores intra e extra-oculares não apresentou diferença estatisticamente significativa. Campanhas de esclarecimento, visando diagnosticar precocemente esse tumor é de fundamental importância. Através de diagnóstico precoce, mantém-se a visão e eleva-se a taxa de sobrevida desses pacientes

Análise e avaliaçäo de retinoblastoma no Hospital A. C. Camargo - Fundaçäo Antônio Prudente no período de agosto de 1979 a agosto de 1983 / Analysis and evaluation of retinoblastoma in the Hospital A. C. Camargo-Fundaçäo Antonio Prudente from August 1979 to August 1983

Analisa-se a evoluçäo de 48 pacientes portadores de retinoblastoma, com um total de 58 olhos afetados, atendidos no Hospital A.C. Camargo - Fundaçäo Antonio Prudente, Säo Paulo, no período de agosto de 1979 a agosto de 1983. Ao diagnóstico, 43,8% dos pacientes apresentavam tumores intra-oculares e 56,2%, extra oculares. A sobrevida foi respectivamente de 90,1% e 40,7%. Estes dados mostram a evidente piora do prognóstico nos casos avançados. A partir do estudo das faixas de incidência, das causas do diagnóstico tardio e da evoluçäo da doença, propöe-se a intensificaçäo da divulgaçäo desta moléstia entre pediatras, oftalmologistas, populaçäo leiga, principalmente profissionais que lidam com crianças com baixa idade, a fim de facilitar o diagnóstico precoce. Propöe-se ainda a introduçäo de novos esquemas terapêuticos para os casos avançados, com a utilizaçäo de drogas que atravessem a barreira hematencefálica

Cisticercose ocular simulando retinoblastoma / Ocular cysticercosis simulating retinoblastoma

É apresentado caso de menino de cinco anos, com história e quadro clínico ocular de retinoblastoma, e que após enucleaçäo, teve diagnóstico anátomo-patológico confirmado de cisticercose ocular. Chama-se atençäo para a necessidade de incluir esta patologia entre os diagnósticos diferenciais do retinoblastoma, principalmente nos países de baixo nível de saúde pública