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

Memoria del I Coloquio de verano de investigación de la Escuela de Negocios de ITESO, 2022

Esta memoria recoge cinco de las ponencias presentadas en el Coloquio de investigación de verano de la ENI, 2022. Son una muestra del trabajo de investigación que hacemos en el Departamento de Economía, Administración y Mercadología (DEAM), en el Centro Universidad Empresa (CUE) y en el Centro para la Gestión de la Innovación y la Tecnología (CEGINT); una investigación con una orientación principalmente práctica y aplicada, enfocada a las micro, pequeñas y medianas empresas y a su contexto socioeconómico. Esperamos que puedan ser ocasión de diálogo y de contribución no sólo al campo académico en el que nos desenvolvemos, sino también a las realidades mismas en las que queremos colaborar para apoyar los esfuerzos hacia una economía y una sociedad más justas y más humanas.ITESO, A.C

The Latin American experience of allografting patients with severe aplastic anaemia: real-world data on the impact of stem cell source and ATG administration in HLA-identical sibling transplants

We studied 298 patients with severe aplastic anaemia (SAA) allografted in four Latin American countries. The source of cells was bone marrow (BM) in 94 patients and PBSCs in 204 patients. Engraftment failed in 8.1% of recipients with no difference between BM and PBSCs (P = 0.08). Incidence of acute GvHD (aGvHD) for BM and PBSCs was 30% vs 32% (P = 0.18), and for grades III–IV was 2.6% vs 11.6% (P = 0.01). Chronic GvHD (cGvHD) between BM and PBSCs was 37% vs 59% (P = 0.002) and extensive 5% vs 23.6% (P = 0.01). OS was 74% vs 76% for BM vs PBSCs (P = 0.95). Event-free survival was superior in patients conditioned with anti-thymocyte globulin (ATG)-based regimens compared with other regimens (79% vs 61%, P = 0.001) as excessive secondary graft failure was seen with other regimens (10% vs 26%, P = 0.005) respectively. In multivariate analysis, aGvHD II–IV (hazard ratio (HR) 2.50, confidence interval (CI) 1.1–5.6, P = 0.02) and aGvHD III–IV (HR 8.3 CI 3.4–20.2, Po0.001) proved to be independent negative predictors of survival. In conclusion, BM as a source of cells and ATG-based regimens should be standard because of higher GvHD incidence with PBSCs, although the latter combining with ATG in the conditioning regimen could be an option in selected high-risk patient

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma

Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases

Medulloblastoma (MB) is the most common malignant brain tumor in children. While aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the Sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated MBs do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated MB. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPCs). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent MB. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2/M phases of the cell cycle. Here, we show that CD15+ cells progress more rapidly through the cell cycle than CD15- cells and contain an increased proportion of cells in G2/M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora and Polo-like kinases, key regulators of G2/M, induces cell cycle arrest, apoptosis and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived MB xenografts are also sensitive to Aurora and Polo-like kinase inhibitors. Our findings suggest that targeting G2/M regulators may represent a novel approach for treatment of human MB

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