Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine mode

Purpose: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). Methods: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. Results: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9–138.7] vs. 13.6 ng/mL [5.5–15.3], respectively; P , 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 nghour/mL [247.6–347.2] and 48.9 nghour/mL [11.8–63.4], respectively; P , 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 nghour/mL [6.8–13.4] vs. 18.7 nghour/mL [6.3–21.7]; P = 0.54). Conclusion: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.Fil: 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: Buitrago, Emiliano. Universidad de Buenos Aires; ArgentinaFil: Ceciliano, Alejandro. No especifíca;Fil: Fandino, Adriana C.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Asprea, Marcelo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Sierre, Sergio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Abramson, David H.. No especifíca;Fil: Bramuglia, Guillermo Federico. Universidad de Buenos Aires; ArgentinaFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin

The Global Retinoblastoma Outcome Study: a prospective, cluster-based analysis of 4064 patients from 149 countries

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. Enudeation 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% (524-63-0) 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. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.Queen Elizabeth Diamond Jubilee TrustQueen Elizabeth Diamond Jubilee Trust

Global Retinoblastoma Treatment Outcomes: Association with National Income Level

Purpose: To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels.Design: International, multicenter, registry-based retrospective case series.Participants: Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents.Methods: Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes.Main outcome measures: Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy).Results: Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001).Conclusions: This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe 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; CanadáFil: Kivelä, Tero T.. Helsinki University Hospital; Finlandia. University of Helsinki; FinlandiaFil: Mallipatna, Ashwin. University Of Toronto. Hospital For Sick Children; CanadáFil: Zhang, Chengyue. Beijing Children’s Hospital; ChinaFil: Zhao, Junyang. Beijing Children’s Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Brenna, Rachel C.. University of Tennessee; Estados UnidosFil: Burges, Michala. University of Tennessee; Estados UnidosFil: Kim, Jonathan. Keck Medical School of the University of Southern California; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; IndiaFil: Yarovoy, Andrey. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. The S. N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. Helsinki University Hospital; Finlandia. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; Alemania. Medical Academy of Postgraduate Education; AlemaniaFil: Yugay, Olga V.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; AlemaniaFil: Polyakov, Vladimir G.. N. N. Blokhin National Medical Research Center Oncology of Russian Federation; AlemaniaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. Chinese University Of Hong Kong; Hong KongFil: Lau, Winnie W.. Chinese University Of Hong Kong; Hong KongFil: Lam, Carol P.. Chinese University Of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; Australi

A Multicenter, International Collaborative Study for AJCC-Staging of Retinoblastoma: Metastasis-Associated Mortality

Purpose: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB). Design: International, multicenter, registry-based retrospective case series. Participants: A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods: Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. Main Outcome Measures: Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the KaplaneMeier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. Results: Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n ¼ 92) from diagnosis to metastasis was 9.50 months. The 5-year KaplaneMeier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97e99) for cT1b and cT2a, 96% (95% CI, 95e97) for cT2b, 89% (95% CI, 88e90) for cT3 tumors, and 45% (95% CI, 31e59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55e25.70; P < 0.001) and cT4 (HR, 48.55; 95% CI, 12.86e183.27; P < 0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease. Conclusions: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.Fil: Tomar, Ankit Singh. The New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. The New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. The Eye Cancer Clinic, Princess Margaret Cancer Centre; CanadáFil: Mallipatna, Ashwin. Hospital for Sick Children; CanadáFil: Kivelä, Tero T.. Helsinki University Hospital; FinlandiaFil: Zhang, Chengyue. Beijing Children's Hospital; ChinaFil: Zhao, Junyang. Beijing Children's Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Kim, Jonathan. University of Southern California; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; 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: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Yugay, Olga V.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Polyakov, Vladimir G.. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de México Federico Gómez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de México Federico Gómez; 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: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. The Chinese University of Hong Kong; Hong KongFil: Lau, Winnie W.. The Chinese University of Hong Kong; Hong KongFil: Lam, Carol P.. The Chinese University of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; AustraliaFil: Moorthy, Sonia. KK Women's and Children's Hospital; SingapurFil: Long, Quah Boon. KK Women's and Children's Hospital; Singapu

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma. Part II: Treatment Success and Globe Salvage

Purpose: To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma(RB).Design: International, multicenter, registry-based retrospective case series PARTICIPANTS: 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.Methods: Patient-specific data fields for RB were designed by participating eye cancer specialists. All RB patients with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied.Main outcome measures: Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan-Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait.Results: Of the 2190 patients, the records of 2085 patients(95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. 1260 (65.4%) had unilateral RB. Amongst the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b 168 (8.1%), cT2a 197 (9.4%), cT2b 812 (38.9%), cT3 835 (40.0%) and cT4 in 18 (0.9%) patients. Of these, 1397 eyes in 1353 patients(48.1%) were treated with enucleation. One hundred and nine patients (5.2%) developed metastases and died. The median time(n=92) from diagnosis to metastasis was 9.50 months. The 5- year Kaplan-Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval[CI], 97-99) for cT1b and cT2a, 96% (95% CI, 95-97) for cT2b, 89%(95% CI, 88-90) for cT3 tumors, and 45%(95% CI, 31-59) for cT4 tumors, respectively. Risk of metastasis increased with increasing cT (and pT) category(p < .001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55-25.70; p<0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; p< 0.001) compared to category cT1. Age, tumor laterality and presence of heritable trait did not influence the incidence of metastatic disease.Conclusion: Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real life, heterogenous RB patient population.Fil: Singh Tomar, Ankit. The New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. The New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. Princess Margaret Cancer Centre; CanadáFil: Mallipatna, Ashwin. University Of Toronto. Hospital For Sick Children; CanadáFil: Kivelä, Tero T.. University of Helsinki; FinlandiaFil: Zhang, Chengyue. Beijing Children's Hospital; ChinaFil: Zhao, Junyang. Beijing Children's Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Brenna, Rachel C.. University of Tennessee; Estados UnidosFil: Burges, Michala. University of Tennessee; Estados UnidosFil: Kim, Jonathan. The Vision Center at Children's Hospital Los Angeles; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; IndiaFil: Yarovoy, Andrey. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Yugay, Olga V.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Polyakov, Vladimir G.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de México Federico Gómez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de México Federico Gómez; 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: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. The Chinese University of Hong Kong; Hong KongFil: Lau, Winnie W.. The Chinese University of Hong Kong; Hong KongFil: Lam, Carol P.. The Chinese University of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; AustraliaFil: Moorthy, Sonia. KK Women’s and Children’s Hospital; SingapurFil: Long, Quah Boon. KK Women’s and Children’s Hospital; SingapurFil: Essuman, Vera Adobea. University of Ghana; GhanaFil: Renner, Lorna A.. University of Ghana; GhanaFil: Semenova, Ekaterina. The New York Eye Cancer Center; Estados UnidosFil: Català, Jaume. Hospital Sant Joan de Déu; EspañaFil: Correa Llano, Genoveva. Hospital Sant Joan de Déu; EspañaFil: Carreras, Elisa. Hospital Sant Joan de Déu; Españ

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

AimTo 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.MethodsMulticentre, 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.ResultsClinical 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; pConclusionThis 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