Retinoblastoma seeds: Impact on American Joint Committee on Cancer clinical staging

Aim To investigate whether the American Joint Committee on Cancer (AJCC) clinical category cT2b needs to be subclassified by the type and distribution of retinoblastoma (RB) seeding. Methods Multicentre, international registry-based data were collected from RB centres enrolled between January 2001 and December 2013. 1054 RB eyes with vitreous or subretinal seeds from 18 ophthalmic oncology centres, in 13 countries within six continents were analysed. Local treatment failure was defined as the use of secondary enucleation or external beam radiation therapy (EBRT) and was estimated with the Kaplan-Meier method. Results Clinical category cT2b included 1054 eyes. Median age at presentation was 16.0 months. Of these, 428 (40.6%) eyes were salvaged, and 430 (40.8%) were treated with primary and 196 (18.6%) with secondary enucleation. Of the 592 eyes that had complete data for globe salvage analysis, the distribution of seeds was focal in 143 (24.2%) and diffuse in 449 (75.8%). The 5-year Kaplan-Meier cumulative globe-salvage (without EBRT) was 78% and 49% for eyes with focal and diffuse RB seeding, respectively. Cox proportional hazards regression analysis confirmed a higher local treatment failure risk with diffuse seeds as compared with focal seeds (hazard rate: 2.8; p<0.001). There was insufficient evidence to prove or disprove an association between vitreous seed type and local treatment failure risk(p=0.06). Conclusion This international, multicentre, registry-based analysis of RB eyes affirmed that eyes with diffuse intraocular distribution of RB seeds at diagnosis had a higher risk of local treatment failure when compared with focal seeds. Subclassification of AJCC RB category cT2b into focal vs diffuse seeds will improve prognostication for eye salvage.Fil: Tomar, Ankit Singh. New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. University Of Toronto. Hospital For Sick Children; CanadáFil: Kivelä, Tero. University of Helsinki; Finlandia. Helsinki University Hospital; FinlandiaFil: Mallipatna, Ashwin. University Of Toronto. Hospital For Sick Children; Canadá. Narayana Nethralaya; IndiaFil: Zhang, Chengyue. Beijing Children's Hospital; ChinaFil: Zhao, Junyang. Beijing Children's Hospital; ChinaFil: Wilson, Matthew. University of Tennessee; Estados UnidosFil: Brennan, Rachel. St Jude Children's Research Hospital; Estados UnidosFil: Burges, Michala. University of Tennessee; Estados UnidosFil: Kim, Jonathan. Keck Medical School of the University of Southern California; Estados UnidosFil: Berry, Jesse L.. Children's Hospital Los Angeles; Estados UnidosFil: Jubran, Rima. Childrens Hospital Society of Los Angeles; Estados UnidosFil: Khetan, Vikas. Vitreo Retinal Services; IndiaFil: Ganeshan, Suganeswari. Vitreo Retinal Services; IndiaFil: Yarovoy, Andrey. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Volodin, Denis. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. University of Helsinki; Finlandia. Helsinki University Hospital; FinlandiaFil: Ushakova, Tatiana L.. N.N. Blokhin Russian Cancer Research Center; Rusia. Russian Academy of Postgraduate Medical Education; RusiaFil: Yugay, Olga V.. N.N. Blokhin Russian Cancer Research Center; RusiaFil: Polyakov, Vladimir G. N.N. Blokhin Russian Cancer Research Center; Rusia. Russian Academy of Sciences; RusiaFil: Ramirez Ortiz, Marco Antonio. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fandiño, Adriana Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. The Chinese University of Hong Kong Faculty of Medicine; Hong Kon

The role of maternal age & birth order on the development of unilateral and bilateral retinoblastoma: a multicentre study

BACKGROUND/OBJECTIVES: Retinoblastoma is a common childhood intraocular malignancy, the bilateral form of which most commonly results from a de novo germline pathogenic variant in the RB1 gene. Both advanced maternal age and decreasing birth order are known to increase the risk of de novo germline pathogenic variants, while the influence of national wealth is understudied. This cohort study aimed to retrospectively observe whether these factors influence the ratio of bilateral retinoblastoma cases compared to unilateral retinoblastoma, thereby inferring an influence on the development of de novo germline pathogenic variants in RB1. SUBJECTS/METHODS: Data from 688 patients from 11 centres in 10 countries were analysed using a series of statistical methods. RESULTS: No associations were found between advanced maternal age, birth order or GDP per capita and the ratio of bilateral to unilateral retinoblastoma cases (p values = 0.534, 0.201, 0.067, respectively), indicating that these factors do not contribute to the development of a de novo pathogenic variant. CONCLUSIONS: Despite a lack of a definitive control group and genetic testing, this study demonstrates that advanced maternal age, birth order or GDP per capita do not influence the risk of developing a bilateral retinoblastoma

Risk factors associated with abandonment of care in retinoblastoma: analysis of 692 patients from 10 countries.

BACKGROUND: Rates of care abandonment for retinoblastoma (RB) demonstrate significant geographical variation; however, other variables that place a patient at risk of abandoning care remain unclear. This study aims to identify the risk factors for care abandonment across a multinational set of patients. METHODS: A prospective, observational study of 692 patients from 11 RB centres in 10 countries was conducted from 1 January 2019 to 31 December 2019. Multivariate logistic regression was used to identify risk factors associated with higher rates of care abandonment. RESULTS: Logistic regression showed a higher risk of abandoning care based on country (high-risk countries include Bangladesh (OR=18.1), Pakistan (OR=45.5) and Peru (OR=9.23), p<0.001), female sex (OR=2.39, p=0.013) and advanced clinical stage (OR=4.22, p<0.001). Enucleation as primary treatment was not associated with a higher risk of care abandonment (OR=0.59, p=0.206). CONCLUSION: Country, advanced disease and female sex were all associated with higher rates of abandonment. In this analysis, enucleation as the primary treatment was not associated with abandonment. Further research investigating cultural barriers can enable the building of targeted retention strategies unique to each country

Lag Time between Onset of First Symptom and Treatment of Retinoblastoma: An International Collaborative Study of 692 Patients from 10 Countries.

BACKGROUND: The relationship between lag time and outcomes in retinoblastoma (RB) is unclear. In this study, we aimed to study the effect of lag time between onset of symptoms and diagnosis of retinoblastoma (RB) in countries based on their national-income and analyse its effect on the outcomes. METHODS: We performed a prospective study of 692 patients from 11 RB centres in 10 countries from 1 January 2019 to 31 December 2019. RESULTS: The following factors were significantly different among different countries based on national-income level: age at diagnosis of RB (p = 0.001), distance from home to nearest primary healthcare centre (p = 0.03) and mean lag time between detection of first symptom to visit to RB treatment centre (p = 0.0007). After adjusting for country income, increased lag time between onset of symptoms and diagnosis of RB was associated with higher chances of an advanced tumour at presentation (p < 0.001), higher chances of high-risk histopathology features (p = 0.003), regional lymph node metastasis (p < 0.001), systemic metastasis (p < 0.001) and death (p < 0.001). CONCLUSIONS: There is a significant difference in the lag time between onset of signs and symptoms and referral to an RB treatment centre among countries based on national income resulting in significant differences in the presenting features and clinical outcomes

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: 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. Objectives: 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. Design, Setting, and Participants: 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. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: 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]). Conclusions and Relevance: 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

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

BACKGROUND: The 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 to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe. METHODS: A cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries. RESULTS: Capture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI -12.4 to -5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease. CONCLUSIONS: Fewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral

The global retinoblastoma outcome study : a prospective, cluster-based analysis of 4064 patients from 149 countries

DATA SHARING : The study data will become available online once all analyses are complete.BACKGROUND : Retinoblastoma is the most common intraocular cancer worldwide. There is some evidence to suggest that major differences exist in treatment outcomes for children with retinoblastoma from different regions, but these differences have not been assessed on a global scale. We aimed to report 3-year outcomes for children with retinoblastoma globally and to investigate factors associated with survival. METHODS : We did a prospective cluster-based analysis of treatment-naive patients with retinoblastoma who were diagnosed between Jan 1, 2017, and Dec 31, 2017, then treated and followed up for 3 years. Patients were recruited from 260 specialised treatment centres worldwide. Data were obtained from participating centres on primary and additional treatments, duration of follow-up, metastasis, eye globe salvage, and survival outcome. We analysed time to death and time to enucleation with Cox regression models. FINDINGS : The cohort included 4064 children from 149 countries. The median age at diagnosis was 23·2 months (IQR 11·0–36·5). Extraocular tumour spread (cT4 of the cTNMH classification) at diagnosis was reported in five (0·8%) of 636 children from high-income countries, 55 (5·4%) of 1027 children from upper-middle-income countries, 342 (19·7%) of 1738 children from lower-middle-income countries, and 196 (42·9%) of 457 children from low-income countries. Enucleation surgery was available for all children and intravenous chemotherapy was available for 4014 (98·8%) of 4064 children. The 3-year survival rate was 99·5% (95% CI 98·8–100·0) for children from high-income countries, 91·2% (89·5–93·0) for children from upper-middle-income countries, 80·3% (78·3–82·3) for children from lower-middle-income countries, and 57·3% (52·1-63·0) for children from low-income countries. On analysis, independent factors for worse survival were residence in low-income countries compared to high-income countries (hazard ratio 16·67; 95% CI 4·76–50·00), cT4 advanced tumour compared to cT1 (8·98; 4·44–18·18), and older age at diagnosis in children up to 3 years (1·38 per year; 1·23–1·56). For children aged 3–7 years, the mortality risk decreased slightly (p=0·0104 for the change in slope). INTERPRETATION : This study, estimated to include approximately half of all new retinoblastoma cases worldwide in 2017, shows profound inequity in survival of children depending on the national income level of their country of residence. In high-income countries, death from retinoblastoma is rare, whereas in low-income countries estimated 3-year survival is just over 50%. Although essential treatments are available in nearly all countries, early diagnosis and treatment in low-income countries are key to improving survival outcomes.The Queen Elizabeth Diamond Jubilee Trust and the Wellcome Trust.https://www.thelancet.com/journals/langlo/homeam2023Paediatrics and Child Healt

Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

Abstract of the work presented at the 30th ECCMID 2020, European Congress of Clinical Microbiology and Infectious Diseases, organized by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).-- www.eccmid.org .-- www.escmid.org.-- Accepted abstract 1508.[Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis.[Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP.[Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis.[Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis.Peer reviewe

Дерматологическая токсичность высоких доз тиотепы у детей. Описание клинического случая

Hematopoietic stem cell transplantation (HSCT) is a treatment modality for a number of severe malignant and non-neoplastic diseases. Autologous hematopoietic stem cell transplantation (auto-HSCT) improves outcomes in patients with solid and hematological malignancies. Skin lesions at the auto-HSCT stage are quite common and represent an important diagnostic and therapeutic problem. The most significant causes of skin lesions in auto-HSCT are drug toxicity, infectious and viral lesions. Each of the complications can manifest itself to varying degrees as well as combine with others, having a significant negative on the patient’s condition, posing a threat to the patient’s life in severe cases.Трансплантация гемопоэтических стволовых клеток (ТГСК) является методом терапии ряда тяжелых злокачественных и неопухолевых заболеваний. Аутологичная трансплантация гемопоэтических стволовых клеток (ауто-ТГСК) улучшает исходы у пациентов со злокачественными новообразованиями солидной и гематологической природы. Поражения кожи на этапе ауто-ТГСК встречаются достаточно часто и представляют собой важную диагностическую и терапевтическую проблему. Наиболее значимыми причинами поражений кожи при ауто-ТГСК являются медикаментозная токсичность, инфекционные и вирусные поражения. Каждое из осложнений может проявляться в различной степени, а также сочетаться с другими, оказывая значимое отрицательное влияние на состояние пациента, в тяжелых случаях представляя угрозу для жизни пациента