16 results on '"Ester Zapotocka"'
Search Results
2. P1630: A 2022 CROSS-NATIONAL SURVEY OF PEOPLE LIVING WITH HAEMOPHILIA DURING THE COVID-19 PANDEMIC: VIEWS ON VACCINATION- AND INFECTION-RELATED RISKS
- Author
-
Ana Boban, Atanas Banchev, Angelika Bátorová, Melen Brinza, Barbara Faganel Kotnik, Letitia Pintilie-Ancuta, and Ester Zapotocka
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
- Full Text
- View/download PDF
3. Effect of two additional doses of intrathecal methotrexate during induction therapy on serious infectious toxicity in pediatric patients with acute lymphoblastic leukemia
- Author
-
Janina Heilmann, Simon Vieth, Anja Möricke, Andishe Attarbaschi, Draga Barbaric, Nicole Bodmer, Antonella Colombini, Luciano Dalla-Pozza, Sarah Elitzur, Shai Izraeli, Georg Mann, Felix Niggli, Daniela Silvestri, Jan Stary, Carmelo Rizzari, Maria Grazia Valsecchi, Ester Zapotocka, Martin Zimmermann, Gunnar Cario, Martin Schrappe, and Valentino Conter
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P
- Published
- 2023
- Full Text
- View/download PDF
4. First experience of a hemophilia monitoring platform: florio HAEMO
- Author
-
Ester Zapotocka, Angelika Batorova, Ernest Bilic, Ana Boban, Carmen Escuriola Ettingshausen, Barbara Faganel Kotnik, Radomira Hrdlickova, Pawel Laguna, Jan Machal, Laszlo Nemes, Irena Preloznik Zupan, Gediminas Puras, and Marianna Zombori
- Subjects
hemophilia ,patient preference ,pharmacokinetics ,telemedicine ,Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Abstract Background florio HAEMO is a new hemophilia treatment monitoring application consisting of a patient smartphone application (app) and a web‐based dashboard for healthcare professionals, providing several novel features, including activity tracking, wearable connectivity, kids and caregiver mode, and real‐time pharmacokinetic factor level estimation. Objectives To assess intuitiveness, ease‐of‐use, and patient preference of florio HAEMO in Central Europe using a cross‐sectional survey. Methods This survey was conducted in six Central European countries between 9 December 2020 and 24 May 2021. The online questionnaire included 17 questions about overall satisfaction, ease‐of‐use, intuitiveness, and patient preference. Adults or children with hemophilia on regular prophylaxis and using the florio HAEMO app for a minimum of 1 week were invited to complete the online questionnaire by their treating physician. Results Sixty‐six participants took part in the survey. The median duration for all respondents using the florio HAEMO app was 3 to 4 weeks. Overall, 89.4% of users reported being very satisfied or rather satisfied after using florio HAEMO. Of the 23 respondents who had switched from another hemophilia app, 87.0% indicated that they strongly preferred or preferred using florio HAEMO. Most florio HAEMO users reported that the app was very easy or rather easy to use (97.0%) and intuitive (94.0%). florio HAEMO had a positive impact on daily living, with 78.8% of users reporting that the app was very important or rather important to them. Conclusions This survey suggests that florio HAEMO is an easy‐to‐use and intuitive app to assist self‐management of home prophylaxis.
- Published
- 2022
- Full Text
- View/download PDF
5. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
- Author
-
Benjamin O. Wolthers, Thomas L. Frandsen, Chirag J. Patel, Rachid Abaji, Andishe Attarbaschi, Shlomit Barzilai, Antonella Colombini, Gabriele Escherich, Marie Grosjean, Maja Krajinovic, Eric Larsen, Der-Cherng Liang, Anja Möricke, Kirsten K. Rasmussen, Sujith Samarasinghe, Lewis B. Silverman, Inge M. van der Sluis, Martin Stanulla, Morten Tulstrup, Rachita Yadav, Wenjian Yang, Ester Zapotocka, Ramneek Gupta, and Kjeld Schmiegelow
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10−8). Moreover, rs13228878 (OR=0.61; P=7.1×10−6) and rs10273639 (OR=0.62; P=1.1×10−5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children’s Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.
- Published
- 2019
- Full Text
- View/download PDF
6. Invasive fungal diseases impact on outcome of childhood ALL - an analysis of the international trial AIEOP-BFM ALL 2009
- Author
-
Thomas, Lehrnbecher, Andreas H, Groll, Simone, Cesaro, Julia, Alten, Andishe, Attarbaschi, Draga, Barbaric, Nicole, Bodmer, Valentino, Conter, Shai, Izraeli, Georg, Mann, Anja, Möricke, Felix, Niggli, Martin, Schrappe, Jan, Stary, Ester, Zapotocka, Martin, Zimmermann, and Sarah, Elitzur
- Abstract
In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for proven/probable IFD, defined according to the updated EORTC/MSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 proven/probable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for proven/probable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P 0.0001 each). Proven/probable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for proven/probable IFD, age ≥12 years, and insufficient response to therapy (P 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.
- Published
- 2022
7. A Cross-National Survey of People Living with Hemophilia: Impact on Daily Living and Patient Education in Central Europe
- Author
-
Gediminas Puras, Atanas Banchev, Silva Zupancic-Salek, Ester Zapotocka, Barbara Faganel Kotnik, Csongor Kiss, and Angelika Batorova
- Subjects
medicine.medical_specialty ,Activities of daily living ,cross-national survey ,Medicine (miscellaneous) ,information sources ,03 medical and health sciences ,0302 clinical medicine ,hemophilia ,hemic and lymphatic diseases ,Pandemic ,050602 political science & public administration ,medicine ,Daily living ,Social media ,030212 general & internal medicine ,Everyday life ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Original Research ,Descriptive statistics ,Central Europe ,business.industry ,Health Policy ,Cross national survey ,05 social sciences ,0506 political science ,Patient Preference and Adherence ,Family medicine ,business ,patient preference ,Social Sciences (miscellaneous) ,Patient education - Abstract
Background Information about the impact of hemophilia on daily living and information preferences for patients and their caregivers in Central Europe has been limited. Methods This cross-national survey was conducted between April 1 and October 15, 2020 and utilized a self-administered questionnaire to collect data (Typeform™) from people living with hemophilia in Bulgaria, Croatia, Czech Republic, Hungary, Slovakia and Slovenia. The questionnaire included 22 questions regarding difficulties in daily life and preferences for receiving hemophilia-related information. Respondents were stratified into two main groups, people with hemophilia (PwH) or their caregivers (CPwH). Results were analyzed using descriptive statistics. Results Of the 364 respondents, 232 were PwH (63.7%) and 132 were CPwH (36.3%). In total, 70.3% of hemophilia patients/caregivers responded that they are kept sufficiently informed about life with hemophilia, with 68.0%, 59.1% and 56.3% of respondents obtaining information from their physicians, patient associations and via digital media (internet and social media), respectively. However, 97.8% of respondents expressed an interest in additional information, particularly new hemophilia treatment options (62.1%), which in contrast to other topics was indicated most frequently by both patients and caregivers in all six countries. Most frequent difficulties in everyday life with hemophilia were identified as mobility problems (41.8%), unexpected bleeding (38.5%), pain (35.4%), and uncertainty with what they can or cannot do (25.0%). During the 2020 COVID-19 pandemic, 52.5% of respondents reported that they did not experience any major change in daily living with hemophilia. Conclusion Based on our Central European survey, hemophilia mostly affects peoples’ lives by causing mobility difficulties, unexpected bleeding, pain and uncertainty in daily activities. Although the majority of respondents reported being educated about hemophilia, most PwH and CPwH respondents sought additional information, highlighting the need for continuous personalized patient education to cope with present challenges., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/zcEDOytfELU
- Published
- 2021
8. A Practical, One-Clinic Visit Protocol for Pharmacokinetic Profile Generation with the ADVATE myPKFiT Dosing Tool in Severe Hemophilia A Subjects
- Author
-
V. Komrska, Viviane Grassmann, Jan Blatny, Shannon Jackson, Derek Stephens, Massimo Morfini, Julie Curtin, Laura Zunino, Victor S. Blanchette, Ester Zapotocka, Manuel Carcao, Liane Khoo, Margaret L. Rand, Chris Barnes, Gabriela Romanova, and David Lillicrap
- Subjects
Adult ,Male ,Canada ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Population ,030204 cardiovascular system & hematology ,Hemophilia A ,Severe hemophilia A ,Models, Biological ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Clinical Protocols ,Pharmacokinetics ,Predictive Value of Tests ,hemic and lymphatic diseases ,Ambulatory Care ,medicine ,Humans ,Prospective Studies ,Dosing ,pharmacokinetic ,Child ,education ,Blood Coagulation ,Aged ,Czech Republic ,Protocol (science) ,education.field_of_study ,Factor VIII ,Coagulants ,business.industry ,Australia ,Hematology ,Factor VIII Activity ,PK Parameters ,Middle Aged ,3. Good health ,Clinic visit ,population PK ,Child, Preschool ,observational study ,Drug Monitoring ,business ,Coagulation and Fibrinolysis ,030215 immunology - Abstract
Standard pharmacokinetic (PK) assessments are demanding for persons with hemophilia A, requiring a 72-hour washout and 5 to 11 timed blood samples. A no-washout, single-clinic visit, sparse sampling population PK (PPK) protocol is an attractive alternative. Here, we compared PK parameters obtained with a traditional washout, 6-sampling time point PPK protocol with a no-washout, single-clinic visit, reverse 2-sampling time point PPK protocol in persons with severe hemophilia A (SHA) receiving ADVATE. A total of 39 inhibitor-negative males with SHA (factor VIII activity [FVIII:C]
- Published
- 2021
9. Trypsin-encoding PRSS1-PRSS2 variations influence the risk of asparaginase-associated pancreatitis in children with acute lymphoblastic leukemia: a Ponte di Legno toxicity working group report
- Author
-
Lewis B. Silverman, Marie Grosjean, Chirag J. Patel, Wenjian Yang, Morten Tulstrup, Benjamin Ole Wolthers, Rachita Yadav, Eric Larsen, Kjeld Schmiegelow, Thomas Frandsen, Ramneek Gupta, Rachid Abaji, Inge M. van der Sluis, Anja Möricke, Sujith Samarasinghe, Maja Krajinovic, Der-Cherng Liang, Antonella Colombini, Andishe Attarbaschi, Shlomit Barzilai, Gabriele Escherich, Kirsten K. Rasmussen, Martin Stanulla, and Ester Zapotocka
- Subjects
Male ,medicine.medical_specialty ,Asparaginase ,Adolescent ,Genotype ,Trypsinogen ,Antineoplastic Agents ,Gastroenterology ,Models, Biological ,Polymorphism, Single Nucleotide ,Article ,Polyethylene Glycols ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Genetic predisposition ,PRSS2 ,Humans ,Genetic Predisposition to Disease ,Trypsin ,Trypsinogen activation ,Child ,Childhood Acute Lymphoblastic Leukemia ,Alleles ,Genetic Association Studies ,business.industry ,Genetic Variation ,Infant ,Hematology ,Odds ratio ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Acute Lymphoblastic Leukemia ,Phenotype ,chemistry ,Pancreatitis ,Child, Preschool ,Female ,business - Abstract
Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0−17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 x upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2x10 -8 ). Moreover, rs13228878 (OR=0.61; P=7.1x10 -6 ) and rs10273639 (OR=0.62; P=1.1x10 -5 ) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children’s Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r 2 =0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.
- Published
- 2019
10. Severe toxicity free survival: physician-derived definitions of unacceptable long-term toxicities following acute lymphocytic leukaemia
- Author
-
Liv Andrés-Jensen, Andishe Attarbaschi, Edit Bardi, Shlomit Barzilai-Birenboim, Deepa Bhojwani, Melanie M Hagleitner, Christina Halsey, Arja Harila-Saari, Raphaele R L van Litsenburg, Melissa M Hudson, Sima Jeha, Motohiro Kato, Leontien Kremer, Wojciech Mlynarski, Anja Möricke, Rob Pieters, Caroline Piette, Elizabeth Raetz, Leila Ronceray, Claudia Toro, Maria Grazia Valsecchi, Lynda M Vrooman, Sigal Weinreb, Naomi Winick, Kjeld Schmiegelow, Madeline R Adams, Liv Andres-Jensen, Katja Baust, Tineke Boesten, Gabriele Calaminus, Rachel Conyers, Anne-Sophie Darlington, Maëlle de Ville, Gabriele Escherich, Melanie Hagleitner, Jen-Yin Hou, Ting-Huan Huang, Melissa Hudson, Meriel Jenney, Maryna Krawczuk-Rybak, Leontine Kremer, Melchior Lautem, Hse-Che Liu, Elixabet Lopez Lopez, Marion Mateos, Katarzyna Muszynska-Roslan, Riitta Niinimaki, Toby Trahair, Inge van der Sluis, Raphaële van Litsenburg, Lynda Vrooman, Andreas Wiener, Michihiro Yano, Ting-Chi Yeh, Ester Zapotocka, Andres-Jensen, L, Attarbaschi, A, Bardi, E, Barzilai-Birenboim, S, Bhojwani, D, Hagleitner, M, Halsey, C, Harila-Saari, A, van Litsenburg, R, Hudson, M, Jeha, S, Kato, M, Kremer, L, Mlynarski, W, Moricke, A, Pieters, R, Piette, C, Raetz, E, Ronceray, L, Toro, C, Valsecchi, M, Vrooman, L, Weinreb, S, Winick, N, and Schmiegelow, K
- Subjects
medicine.medical_specialty ,Activities of daily living ,MEDLINE ,Antineoplastic Agents ,Blindness ,Antineoplastic Agent ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Physicians ,Medicine ,Humans ,Acute lymphocytic leukaemia ,Renal Insufficiency ,Intensive care medicine ,Child ,Hearing Loss ,Hearing Lo ,Severe toxicity ,MED/01 - STATISTICA MEDICA ,business.industry ,Cancer ,Hematology ,Hematologic Disease ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Hematologic Diseases ,Progression-Free Survival ,Blindne ,Clinical trial ,Transplantation ,Physician ,030220 oncology & carcinogenesis ,business ,Human ,030215 immunology - Abstract
5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.
- Published
- 2021
11. Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia
- Author
-
Ramneek Gupta, Marianne Helenius, Martin Stanulla, Thomas Frandsen, Line Katrine Harder Clemmensen, Rachita Yadav, Riitta Niinimäki, Sujith Samarasinghe, Jukka Kanerva, Benjamin Ole Wolthers, Anja Möricke, Morten Tulstrup, Birgitte Klug Albertsen, Rikke Linnemann Nielsen, Antonella Colombini, Shlomit Barzilai, Gabriele Escherich, Andishe Attarbaschi, Ester Zapotocka, Hsi-Che Liu, Inge M. van der Sluis, Kasper Nielsen, Kjeld Schmiegelow, Derya Aytan-Aktug, HUS Children and Adolescents, and Children's Hospital
- Subjects
Oncology ,medicine.medical_specialty ,Asparaginase ,3122 Cancers ,pediatric hematology/oncology ,Antineoplastic Agents ,acute lymphoblastic leukemia ,TOXICITY ,Machine Learning ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Child ,Childhood Acute Lymphoblastic Leukemia ,POLYMORPHISMS ,RISK ,business.industry ,PRSS1-PRSS2 ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,artificial intelligence ,medicine.disease ,pediatric hematology ,translational research ,treatment toxicity ,chemistry ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,business ,Genome-Wide Association Study - Abstract
Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved. Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.
- Published
- 2021
12. Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study
- Author
-
Martin Stanulla, Thomas Frandsen, Gabor G. Kovacs, Michihiro Yano, Lewis B. Silverman, Sujith Samarasinghe, Tomasz Ociepa, Anja Möricke, Ester Zapotocka, Antonella Colombini, Shlomit Barzilai, Kathrine Grell, Andishe Attarbaschi, Lynda M. Vrooman, Inge M. van der Sluis, Hiroto Inaba, Benjamin Ole Wolthers, Veerle Mondelaers, Kjeld Schmiegelow, Marion K. Mateos, Der-Cherng Liang, André Baruchel, Gabriele Escherich, and Pediatrics
- Subjects
Male ,medicine.medical_specialty ,Asparaginase ,Abdominal pain ,Adolescent ,medicine.medical_treatment ,Vital signs ,Antineoplastic Agents ,Cohort Studies ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,Child ,Mechanical ventilation ,business.industry ,Cancer ,Infant ,Odds ratio ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Surgery ,Oncology ,chemistry ,Pancreatitis ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,medicine.symptom ,business ,030215 immunology ,Cohort study - Abstract
Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study.Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark.Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p0·0001), and having one or more affected vital signs (fever, hypotension, tachycardia, or tachypnoea; 96 [44%] of 217 patients with affected vital signs vs 11 [24%] of 46 patients without affected vital signs, p=0·02). 1 year after diagnosis of asparaginase-associated pancreatitis, 31 (11%) of 275 patients still needed insulin or had recurrent abdominal pain or both. Both the risk of persisting need for insulin therapy and recurrent abdominal pain were associated with having had pseudocysts (odds ratio [OR] 9·48 [95% CI 3·01-35·49], p=0·0002 for insulin therapy; OR 11·79 [4·30-37·98], p0·0001 for recurrent abdominal pain). Within 8 years of asparaginase-associated pancreatitis, risk of abdominal symptoms dropped from 8% (26 of 312) to 0% (0 of 35) but the need for insulin therapy remained constant (9%, three of 35). 96 patients were re-exposed to asparaginase, including 59 after a severe asparaginase-associated pancreatitis (abdominal pain or pancreatic enzymes at least three times the ULN or both lasting longer than 72 h). 44 (46%) patients developed a second asparaginase-associated pancreatitis, 22 (52%) of 43 being severe. Risk of persisting need for insulin or abdominal pain after having had two versus one asparaginase-associated pancreatitis did not differ (three [7%] of 42 vs 28 [12%] of 233, p=0·51). Risk of a second asparaginase-associated pancreatitis was not associated with any baseline patient characteristics.Since the risk of a second asparaginase-associated pancreatitis was not associated with severity of the first asparaginase-associated pancreatitis and a second asparaginase-associated pancreatitis did not involve an increased risk of complications, asparaginase re-exposure should be determined mainly by the anticipated need for asparaginase for antileukaemic efficacy. A study of the genetic risk factors identifying patients in whom asparaginase exposure should be restricted is needed.The Danish Childhood Cancer Foundation and The Danish Cancer Society (R150-A10181).
- Published
- 2017
13. Managing Hemophilia in Children and Adolescents
- Author
-
Ester Zapotocka, Julie A. Curtin, and Victor S. Blanchette
- Published
- 2016
14. A Practical, One Clinic Visit, Population Pharmacokinetic (PK) Protocol for Generation of PK Profiles in Subjects with Severe Hemophilia a
- Author
-
Ester Zapotocka, Victor S. Blanchette, Laura Tiseo, David Lillicrap, Shannon Jackson, Jan Blatny, Liane Khoo, Massimo Morfini, Manuel Carcao, Vanessa Bouskill, V. Komrska, Margaret L. Rand, and Derek Stephens
- Subjects
Protocol (science) ,education.field_of_study ,medicine.medical_specialty ,business.operation ,business.industry ,Immunology ,Population ,Cell Biology ,Hematology ,PK Parameters ,Octapharma ,Severe hemophilia A ,Biochemistry ,Fixed dose ,Clinic visit ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Family medicine ,Medicine ,In patient ,business ,education ,030215 immunology - Abstract
Introduction Clearance of infused factor VIII (FVIII) varies approximately 2-fold between persons with severe hemophilia A. This results in significant interpatient differences in factor levels following an infusion of FVIII and contributes to potentially significant differences in protection against spontaneous musculoskeletal bleeding in patients on fixed dose prophylaxis regimens. Aim The aim of this study is to compare two PK protocols: 1) a 6-point PK protocol with a 72 hour washout; and 2) a 2-point, one clinic visit PK protocol with no washout using the following pharmacokinetic (PK) parameters: clearance (Cl) and time to FVIII:C of 1% above baseline (tt1%) in persons with severe hemophilia A. Methods Inhibitor negative males with severe hemophilia A (FVIII Results 28 males (median age: 12 years, range: 2-69 years) participated. The frequency distribution of clearance and the median half-life (t1/2) generated using myPKFiT is presented in Figure 1. There was a substantial to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout using the two PK programs (Table 1). There was a moderate to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout to the 2-point PK protocol with no washout using the myPKFiT program (Table 2). Conclusion The 2-point, one clinic visit, PK protocol (24 and 3 hrs) with no washout offers a convenient and practical approach to generating clinically relevant PK parameters in persons with severe hemophilia A. It can provide information relevant to selection of personalized prophylaxis regimens that aim to reduce to a minimum/eliminate spontaneous joint bleeding. Disclosures Blanchette: Shire: Other: Investigator-initiated research funding; Novo Nordisk: Other: Speaker's fees; Shire: Other: Speaker's fees; Bayer: Other: speaker's fees; Bioverativ: Other: Investigator-initiated research funding; Pfizer: Other: Speaker's fees. Jackson:Pfizer: Honoraria; Roche: Honoraria; Bayer: Honoraria; Novo Nordisk: Honoraria; Shire: Honoraria; Bioverativ: Other: Investigator initiated grant funding. Carcao:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoo:Shire: Research Funding; Biogen Idec: Research Funding. Blatny:Shire, Pfizer, Roche: Consultancy, Speakers Bureau.
- Published
- 2018
15. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus
- Author
-
Inge M. van der Sluis, Maria Caterina Putti, Caroline Piette, Torben Stamm Mikkelsen, Der Cherng Liang, Motohiro Kato, Ruta Tuckuviene, Sima Jeha, Riitta Niinimäki, Shlomit Barzilai, Kjeld Schmiegelow, Roderick Skinner, Thomas Frandsen, Rachael Hough, Anja Möricke, Christina Halsey, Elizabeth A. Raetz, Gabriele Escherich, Andishe Attarbaschi, Lewis B. Silverman, Ester Zapotocka, and Pediatrics
- Subjects
0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Asparaginase ,Consensus ,Delphi Technique ,Drug-Related Side Effects and Adverse Reactions ,MEDLINE ,Review ,Radiation Tolerance ,Nephrotoxicity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Level of consciousness ,hemic and lymphatic diseases ,medicine ,Journal Article ,Toxicity Tests, Acute ,Humans ,Intensive care medicine ,Child ,business.industry ,Incidence (epidemiology) ,Posterior reversible encephalopathy syndrome ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Combined Modality Therapy ,030104 developmental biology ,Peripheral neuropathy ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Pancreatitis ,business - Abstract
Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment.
- Published
- 2015
16. Common Genetic Variants in Trypsin Regulating Genes Are Associated with AsparAginase-Associated Pancreatitis in Children with Acute Lymphoblastic Leukemia: A Ponte Di Legno Toxicity Working Group Study
- Author
-
Kjeld Schmiegelow, Ramneek Gupta, Der-Cherng Liang, Inge M. van der Sluis, Gabriele Escherich, Sujith Samarasinghe, Anja Möricke, Antonella Colombini, Thomas Frandsen, Chirag J. Patel, Shlomit Barzilai, Kirsten K. Rasmussen, Andishe Attarbaschi, Ester Zapotocka, Marie Grosjean, Morten Tulstrup, Benjamin Ole Wolthers, and Martin Stanulla
- Subjects
medicine.medical_specialty ,Hereditary pancreatitis ,business.industry ,Trypsinogen ,Immunology ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Odds ratio ,medicine.disease ,Biochemistry ,Gastroenterology ,Minor allele frequency ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Genotype ,Medicine ,Pancreatitis ,Allele ,business - Abstract
Background: Asparaginase-associated pancreatitis (AAP) is a well-known toxicity of childhood acute lymphoblastic leukemia (ALL) therapy. Recent multi-trial group phenotyping of 465AAP caseshas documented severe complications to AAP, including 8% risk of needing assisted mechanical ventilation, 26% risk of developing pancreatic pseudocysts and 9% risk of developing persisting diabetes (Wolthers et al. Lancet Oncology, 2017) . Investigation of host genome variation associated with AAP has been limited by varying phenotype definition, inclusion criteria and small study sizes. Objectives and Methods: To investigate genetic variants associated with risk of developing AAP, this genome-wide association study reports data on 1544 children (1.0−17.9 years) from 10 ALL trial groups treated with ALL from January 2000−January 2016. The Ponte di Legno toxicity working group consensus definition (Schmiegelow et al. Lancet Oncology, 2016) was used to diagnose AAP: At least two of i) amylase, pancreatic amylase, or pancreatic lipase >3x upper normal limit (UNL), ii) abdominal pain, iii) imaging compatible with AAP. Controls included children treated for ALL with verified completion of intended asparaginase therapy, 78% of whom (1024/1320) received at least 8 injections of PEG-asparaginase without developing AAP. Germline DNA obtained after clinical remission was genotyped on Illumina Infinium Omni2.5exome-8 BeadChip arrays. Association analyses were done in PLINK and annotation in Ensembl. Results: Of 1564 patients passing genotype quality control, 244 had AAP. 205 of 244 (84%) of cases and 1185/1320 (90%) of controls were of European ancestry. Median age was 8.1 years (IQR 4.3−13.1) and 5 (IQR: 3−9) for cases and controls, respectively. After filtering, 1401908 single nucleotide polymorphisms (SNPs) with a minor allele frequency above 1% were analyzed. In logistic regression analysis, adjusting for age and ancestry, the variant rs62228256 (reference allele=C, minor allele=T (C>T)) on 20q13.2 had the strongest association to AAP (OR=3.75; 95% CI 2.33−6.04; p=5.2∙10-8). rs62228256 is located in a non-coding region without known regulatory effects. rs13228878 (A>G; OR=0.61; 95% CI 0.5−0.76; p=7.1∙10-6) and rs10273639 (C>T; OR=0.62; 95% CI 0.5−0.77; p =1.1∙10-5) were among the top 30 SNPs most significantly associated to AAP. They are in high linkage disequilibrium (R2=0.94) and located in the PRSS1-PRSS2 locus on chromosome 7. The rs13228878 A risk allele was not associated with level of amylase (p=0.1) or lipase (p=0,68) at diagnosis of AAP, age at diagnosis of AAP (p=0.63), or risk of pseudocysts (p=0.78). Using identical diagnostic criteria for pancreatitis, the major C allele in rs10273639 has been associated with pancreatitis risk in adults (Whitcomb et al. Nature Genetics, 2012; Masson et al. Gut, 2017) with identical risk allele and similar odds ratios. PRSS1 and PRSS2 encode cationic and anionic trypsinogen, respectively. rs10273639 is an expressive quantitative locus for PRSS1 and the C risk-variant is associated with elevated expression of trypsinogen in pancreatic tissue. Gain of function mutations in PRSS1, known from hereditary pancreatitis, lead to increased autoactivation, increased intra-acinar trypsin levels, and increased risk of auto-digestion leading to pancreatitis. Further investigation of previously validated SNPs known to regulate trypsin activation gave the following results for associations with AAP; rs17107315 in pancreatic secretory trypsin inhibitor (SPINK1; OR=2.87; 95% CI 1.36−5.8; p=4∙10-3), rs10436957 in chymotrypsin C (CTRC ; OR=0.69; 95% CI 0.53−0.89; p=5∙10-3) and rs4409525 in Claudin-2 (CLDN2 ; OR=1.41; 95% CI 1.08−1.83; p=1∙10-2). In total, 207 out of 244 cases were homozygous for the risk allele in rs13228878 (n=104), rs17107315 (n=1), rs10436957 (n=165) and/or rs4409525 (n=16). However, no significant additive effect of having more than one risk allele was found. Conclusion: Children who develop AAP possess the same pancreatitis risk variants as adults with non-asparaginase associated pancreatitis. This shared genetic disposition may facilitate research into pathogenesis and identification of effective interventions towards AAP. Disclosures No relevant conflicts of interest to declare.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.