Overall survival and cause-specific mortality in a hospital-based cohort of retinoblastoma patients in São Paulo, Brazil.

Studies are lacking on long-term effects among retinoblastoma patients in low- and middle-income countries. Therefore, we examined cause-specific mortality in a retrospective cohort of retinoblastoma patients treated at Antonio Candido de Camargo Cancer Center (ACCCC), São Paulo, Brazil from 1986 to 2003 and followed up through December 31, 2018. Vital status and cause of death were ascertained from medical records and multiple national databases. We estimated overall and cause-specific survival using the Kaplan-Meier survival method, and estimated standardized mortality ratios (SMRs) and absolute excess risk (AER) of death. This cohort study included 465 retinoblastoma patients (42% hereditary, 58% nonhereditary), with most (77%) patients diagnosed at advanced stages (IV or V). Over an 11-year average follow-up, 80 deaths occurred: 70% due to retinoblastoma, 22% due to subsequent malignant neoplasms (SMNs) and 5% to non-cancer causes. The overall 5-year survival rate was 88% consistent across hereditary and nonhereditary patients (p = .67). Hereditary retinoblastoma patients faced an 86-fold higher risk of SMN-related death compared to the general population (N = 16, SMR = 86.1, 95% CI 52.7-140.5), corresponding to 42.4 excess deaths per 10,000 person-years. This risk remained consistent for those treated with radiotherapy and chemotherapy (N = 10, SMR = 90.3, 95% CI 48.6-167.8) and chemotherapy alone (N = 6, SMR = 80.0, 95% CI 35.9-177.9). Nonhereditary patients had only two SMN-related deaths (SMR = 7.2, 95% CI 1.8-28.7). There was no excess risk of non-cancer-related deaths in either retinoblastoma form. Findings from this cohort with a high proportion of advanced-stage patients and extensive chemotherapy use may help guide policy and healthcare planning, emphasizing the need to enhance early diagnosis and treatment access in less developed countries.

International trends in incidence of osteosarcoma (1988-2012).

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. The etiology of OS is largely unknown but may be informed by comparisons of incidence and trends between geographic regions. Using the Cancer Incidence in Five Continents (CI5) data from 1988 to 2012, we present OS age-standardized incidence rates (ASRs; cases/million) and average annual percent change (AAPC) and 95% confidence interval (CI) by geographic region among the age groups 0-9, 10-19, 20-29, 30-59, 60-79, 0-79. Among the 10-19 age group, we also used the most recent data (2008-2012) to present the ASRs for each country. We observed little variation in OS incidence between geographic regions in 2008-2012 across all age groups. Overall, the ASR for 0-79 ranged from 2 cases per million in Southern Asia to 4.2 in Sub-Saharan Africa. A bimodal distribution in incidence was observed with peaks in the 10-19 and 60-79 age groups across all regions over time. Overall, OS incidence was relatively stable across 1988-2012 with the only statistically significant increases in the 0-79 age group observed in Eastern Asia (AAPC: 1.8; 95% CI: 0.6, 1.9) and Sub-Saharan Africa (AAPC: 3.1; 95% CI: 0.5, 5.8). The small variation in incidence between regions and the stability in incidence over time suggests that OS carcinogenesis is not influenced by environmental or time-varying exposures.

Handovers Among Staff Intensivists: A Study of Information Loss and Clinical Accuracy to Anticipate Events.

OBJECTIVES: Handovers are associated with medical errors, and our primary objective is to identify missed diagnosis and goals immediately after a shift handover. Our secondary objective is to assess clinicians' diagnostic accuracy in anticipating clinical events during the night shift. DESIGN: Single-center prospective observational cohort study. SETTING: Thirty-bed tertiary ICU in Sao Paulo, Brazil. PATIENTS: Three-hundred fifty-two patient encounters over 44 day-to-night handovers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used a multimethods approach to measure transmission of information among staff physicians on diagnoses and goals for the night shift. We surveyed clinicians immediately after a handover and identified clinical events through chart abstractions and interviews with clinicians the next morning. Nighttime clinicians correctly identified 454 of 857 diagnoses (53%; 95% CI 50-56) and 123 of 304 goals (40%; 95% CI, 35-46). Daytime clinicians were more sensitive (65% vs 46%; p < 0.01) but less specific (82% vs 91%; p < 0.01) than nighttime clinicians in anticipating clinical events at night, resulting in similar accuracy (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.79] vs 0.68 [95% CI 0.63-0.74]; p = 0.09). The positive predictive value of both daytime and nighttime clinicians was low (13% vs 17%; p = 0.2). Gaps in diagnosis and anticipation of events were more pronounced in neurologic diagnoses. CONCLUSIONS: Among staff intensivists, diagnoses and goals of treatment are either not conveyed or retained 50-60% of the cases immediately after a handover. Clinicians have limited ability to anticipate events, and the expectation that anticipatory guidance can inform handovers needs to be balanced against information overload. Handovers among staff intensivists showed more gaps in the identification of diagnostic uncertainty and for neurologic diagnoses, which could benefit from communication strategies such as cognitive checklists, prioritizing discussion of neurologic patients, and brief combined clinical examination at handover.

Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study.

BACKGROUND: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA). PROCEDURE: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence. RESULTS: In total, 7,814 cases (ASR = 25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR) = 1.95; P < 0.001) and a lower risk of developing CSTS (RR = 0.64, P < 0.001). Compared to whites, blacks have a lower incidence of melanoma (RR = 0.03, P < 0.001), and higher risk of CSTS (RR = 2.28, P < 0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC = 2.5, 95%CI = 1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC = 9.5, 95% CI = 6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC = -21.4, 95% CI -27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008 = -13.6, 95% CI = -22.4;-3.8), although with a notable racial disparity (whites, AAPC = -15.2, 95% CI = -23.2;-6.4; blacks, AAPC = -10.6, 95% CI = -13.2;-7.9). CONCLUSIONS: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies.

Linfoma de Hodgkin clássico na infância. Experiência de tratamento e fatores prognósticos / Classical Hodgkin?s lymphoma in childhood. Therapeutic experience and prognostic factors

Objetivos: Estimar as taxas de sobrevida global e livre de eventos em portadores de linfoma de Hodgkin (LH), bem como identificar fatores prognósticos. Métodos: Estudo de coorte retrospectivo, incluindo variáveis demográficas, laboratoriais, tipo histológico, estadiamento e tratamento de 107 pacientes menores de 18 anos de idade admitidos no Departamento de Pediatria do Centro de Tratamento e Pesquisa Hospital do Câncer, no período entre 1985 e 1995. Resultados: Dos pacientes, 81 (76%) eram do sexo masculino e 80% da raça branca. A média de idade foi 10 anos (2 a 18 anos). Adenomegalia cervical foi a principal queixa referida (68% dos pacientes) e 55% apresentavam tempo de queixa menor que seis meses. Os subtipos EN e CM foram encontrados em 43% e 41% dos casos, respectivamente. Os estádios clínicos II e III foram os mais frequentes (33% cada um). Os sítios metastáticos mais frequentes nos EC IV foram fígado (42%) e pulmão (38%). As taxas de SG e SLE em 10 anos foram de 82,4% e 82,5%, respectivamente. O estádio clínico se mostrou como fator prognóstico significativo para as SG e SLE. A análise univariada revelou a presença de sintomas B, nível de Hb £ 9,3 g/dl, leucócitos £ 6.100 mm3, plaquetas £ 274.000/mm3 e ocorrência de recaída como fatores de mau prognóstico, enquanto a análise múltipla mostrou como fatores prognósticos independentes a presença de sintomas B e contagem de plaquetas. Conclusões: A identificação de fatores prognósticos é valiosa para a adequada estratificação dos pacientes em grupos de risco, adequando-os a esquemas de tratamento que maximizem as taxas de cura e minimizem os efeitos colaterais tardios.

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

ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis.

The ADAM23 gene is frequently silenced in different types of tumors, and, in breast tumors, silencing is correlated with tumor progression, suggesting that it might be associated with the acquisition of a metastatic phenotype. ADAM23 exerts its function mainly through the disintegrin domain, because its metalloprotease domain is inactive. Analysis of ADAM23 binding to integrins has revealed a specific interaction with alpha(v)beta(3) integrin mediated by the disintegrin domain. Altered expression of alpha(v)beta(3) integrin has been observed in different types of tumors, and expression of this integrin in the activated form has been shown to promote metastasis formation. Here, we investigated the possibility that interaction between ADAM23 and alpha(v)beta(3) integrin might negatively modulate alpha(v)beta(3) activation during metastatic progression. ADAM23 expression was knocked down using short hairpin RNA in the MDA-MB-435 cell line, which has been extensively used as a model for alpha(v)beta(3) integrin activation. Ablation of ADAM23 enhanced alpha(v)beta(3) integrin activation by at least 2- to 4-fold and ADAM23 knockdown cells showed enhanced migration and adhesion to classic alpha(v)beta(3) integrin ligands. Ablation of ADAM23 expression also enhanced pulmonary tumor cell arrest in immunodeficient mice. To complement our findings with clinical evidence, we showed that silencing of ADAM23 gene by DNA promoter hypermethylation in a collection of 94 primary breast tumors was significantly associated with lower distant metastases-free and disease-specific survivals and was an independent prognostic factor for poor disease outcome. Our results strongly support a functional role of ADAM23 during metastatic progression by negatively modulating alpha(v)beta(3) integrin activation.

Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis.

Cellular Prion Protein (PrP(C)) is a cell surface protein highly expressed in the nervous system, and to a lesser extent in other tissues. PrP(C) binds to the extracellular matrix laminin and vitronectin, to mediate cell adhesion and differentiation. Herein, we investigate how PrP(C) expression modulates the aggressiveness of transformed cells. Mesenchymal embryonic cells (MEC) from wild-type (Prnp(+/+)) and PrP(C)-null (Prnp(0/0)) mice were immortalized and transformed by co-expression of ras and myc. These cells presented similar growth rates and tumor formation in vivo. When injected in the tail vein, Prnp(0/0)ras/myc cells exhibited increased lung colonization compared with Prnp(+/+)ras/myc cells. Additionally, Prnp(0/0)ras/myc cells form more aggregates with blood components than Prnp(+/+)ras/myc cells, facilitating the arrest of Prnp(0/0)ras/myc cells in the lung vasculature. Integrin alpha(v)beta(3) is more expressed and activated in MEC and in transformed Prnp(0/0) cells than in the respective Prnp(+/+) cells. The blocking of integrin alpha(v)beta(3) by RGD peptide reduces lung colonization in transformed Prnp(0/0) cells to similar levels of those presented by transformed Prnp(+/+) cells. Our data indicate that PrP(C) negatively modulates the expression and activation of integrin alpha(v)beta(3) resulting in a more aggressive phenotype. These results indicate that PrP(C) may have main implications in modulating metastasis formation.

Cisplatin and etoposide in childhood germ cell tumor: brazilian pediatric oncology society protocol GCT-91.

PURPOSE: In 1988, we formed a consortium of Brazilian institutions to develop uniform standards for the diagnostic assessment and multidisciplinary treatment of children and adolescents with germ cell tumors. We also implemented the first childhood Brazilian germ cell tumor protocol, GCT-91, evaluating two-agent chemotherapy with cisplatin and etoposide (PE). We now report on the clinical characteristics and survival of children and adolescents with germ cell tumors treated on this protocol. PATIENTS AND METHODS: From May 1991 to April 2000, 115 patients (106 assessable patients) were enrolled onto the Brazilian protocol with a diagnosis of germ cell tumor. RESULTS: Patients were treated with surgery only (n = 35) and chemotherapy (n = 71). Important prognostic factors included stage (P = .025), surgical procedure at diagnosis according to resectability (P < .032), and abnormal lactate dehydrogenase value at diagnosis (P < .001). CONCLUSION: The improvement in survival by the introduction of a standard protocol is an important achievement. This is of particular importance for smaller institutions with previous limited experience in the treatment of childhood germ cell tumors. In addition, the results of a two-agent regimen with PE were favorable (5-year overall survival rate is 83.3% for patients in the high-risk group [n = 36] who received PE v 58.8% for patients in the high-risk patients group who received PE plus ifosfamide, vinblastine, and bleomycin [n = 17; P = .017]). Thus for selected patients, complex three-agent regimens may not be necessary to achieve long-term survival, even for some patients with advanced disease.

Interaction between polymorphisms of the human leukocyte antigen and HPV-16 variants on the risk of invasive cervical cancer.

BACKGROUND: Persistent infection with oncogenic types of human papillomavirus (HPV) is the major risk factor for invasive cervical cancer (ICC), and non-European variants of HPV-16 are associated with an increased risk of persistence and ICC. HLA class II polymorphisms are also associated with genetic susceptibility to ICC. Our aim is to verify if these associations are influenced by HPV-16 variability. METHODS: We characterized HPV-16 variants by PCR in 107 ICC cases, which were typed for HLA-DQA1, DRB1 and DQB1 genes and compared to 257 controls. We measured the magnitude of associations by logistic regression analysis. RESULTS: European (E), Asian-American (AA) and African (Af) variants were identified. Here we show that inverse association between DQB1*05 (adjusted odds ratio [OR] = 0.66; 95% confidence interval [CI]: 0.39-1.12]) and HPV-16 positive ICC in our previous report was mostly attributable to AA variant carriers (OR = 0.27; 95%CI: 0.10-0.75). We observed similar proportions of HLA DRB1*1302 carriers in E-P positive cases and controls, but interestingly, this allele was not found in AA cases (p = 0.03, Fisher exact test). A positive association with DRB1*15 was observed in both groups of women harboring either E (OR = 2.99; 95% CI: 1.13-7.86) or AA variants (OR = 2.34; 95% CI: 1.00-5.46). There was an inverse association between DRB1*04 and ICC among women with HPV-16 carrying the 350T [83L] single nucleotide polymorphism in the E6 gene (OR = 0.27; 95% CI: 0.08-0.96). An inverse association between DQB1*05 and cases carrying 350G (83V) variants was also found (OR = 0.37; 95% CI: 0.15-0.89). CONCLUSION: Our results suggest that the association between HLA polymorphism and risk of ICC might be influenced by the distribution of HPV-16 variants.

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.

Trends in childhood leukemia mortality in Brazil and correlation with social inequalities.

BACKGROUND: Mortality from childhood leukemia has declined substantially in developed countries but less markedly in the developing world. This study was designed to describe mortality trends in childhood leukemia and the impact of social inequalities on these trends in Brazil from 1980 to 2002. METHODS: Cancer mortality data by cause and estimates of resident population stratified by age and sex were obtained from the Brazilian Mortality Information System (SIM) for the years 1980 to 2002. Age-standardized (ages 0-19 years) mortality rates were calculated by the direct method using the 1960 world standard population. Trends were modeled using linear regression with 3-year moving average rates as the dependent variable and with the midpoint of the calendar year interval (1991) as the independent variable. The Index of Social Exclusion was used to classify the 27 Brazilian states. Pearson correlation was used to describe the correlation between social exclusion and variations in mortality in each state. RESULTS: Age-standardized mortality rates for boys decreased from 2.05 per 100,000 habitants in 1984 to 1.44 100,000 habitants in 1995, whereas the observed corresponding decline among girls was from 1.60 per 100,000 habitants in 1986 to 1.14 per 100,000 habitants in 1995. Statistically significant declining trends in mortality rates were observed for boys (adjusted correlation coefficient [r(2)] = 0.68; P < .001) and girls (adjusted r(2) = 0.62; P < .001). Significant negative correlations between social inequality and changes in mortality were noted for boys (r = -0.66; P = .001) and for girls (r = -0.78; P < .001). CONCLUSIONS: A consistent decrease in mortality rates from childhood leukemia was noted in Brazil. Higher decreases in mortality were observed in more developed states, possibly reflecting better health care.