Palliative care for children with central nervous system tumors: results of a Spanish multicenter study

Background Brain tumors represent the most common cause of cancer-related death in children. Few studies concerning the palliative phase in children with brain tumors are available. Objectives (i) To describe the palliative phase in children with brain tumors; (ii) to determine whether the use of palliative sedation (PS) depends on the place of death, the age of the patient, or if they received specific palliative care (PC). Methods Retrospective multicenter study between 2010 and 2021, including children from one month to 18 years, who had died of a brain tumor. Results 228 patients (59.2% male) from 10 Spanish institutions were included. Median age at diagnosis was 5 years (IQR 2–9) and median age at death was 7 years (IQR 4–11). The most frequent tumors were medulloblastoma (25.4%) and diffuse intrinsic pontine glioma (DIPG) (24.1%). Median number of antineoplastic regimens were 2 (range 0–5 regimens). During palliative phase, 52.2% of the patients were attended by PC teams, while 47.8% were cared exclusively by pediatric oncology teams. Most common concerns included motor deficit (93.4%) and asthenia (87.5%) and communication disorders (89.8%). Most frequently prescribed supportive drugs were antiemetics (83.6%), opioids (81.6%), and dexamethasone (78.5%). PS was administered to 48.7% patients. Most of them died in the hospital (85.6%), while patients who died at home required PS less frequently (14.4%) (p = .01). Conclusion Children dying from CNS tumors have specific needs during palliative phase. The optimal indication of PS depended on the center experience although, in our series, it was also influenced by the place of death (AU)

Palliative care for children with central nervous system tumors: results of a Spanish multicenter study.

BACKGROUND: Brain tumors represent the most common cause of cancer-related death in children. Few studies concerning the palliative phase in children with brain tumors are available. OBJECTIVES: (i) To describe the palliative phase in children with brain tumors; (ii) to determine whether the use of palliative sedation (PS) depends on the place of death, the age of the patient, or if they received specific palliative care (PC). METHODS: Retrospective multicenter study between 2010 and 2021, including children from one month to 18 years, who had died of a brain tumor. RESULTS: 228 patients (59.2% male) from 10 Spanish institutions were included. Median age at diagnosis was 5 years (IQR 2-9) and median age at death was 7 years (IQR 4-11). The most frequent tumors were medulloblastoma (25.4%) and diffuse intrinsic pontine glioma (DIPG) (24.1%). Median number of antineoplastic regimens were 2 (range 0-5 regimens). During palliative phase, 52.2% of the patients were attended by PC teams, while 47.8% were cared exclusively by pediatric oncology teams. Most common concerns included motor deficit (93.4%) and asthenia (87.5%) and communication disorders (89.8%). Most frequently prescribed supportive drugs were antiemetics (83.6%), opioids (81.6%), and dexamethasone (78.5%). PS was administered to 48.7% patients. Most of them died in the hospital (85.6%), while patients who died at home required PS less frequently (14.4%) (p = .01). CONCLUSION: Children dying from CNS tumors have specific needs during palliative phase. The optimal indication of PS depended on the center experience although, in our series, it was also influenced by the place of death.

Haematological and renal toxicity of radiation therapy in neuroblastoma paediatric patients

Purpose The objective of this study was to evaluate the renal and hematologic toxicity in paediatric patients with adrenal high-risk neuroblastoma who have received radiation therapy (RT) as part of radical treatment. Material and methods Pediatric patients diagnosed with high-risk adrenal neuroblastoma who received RT as part of the definitive treatment between January 2004 and May 2020 in a single institution were selected. Complete blood counts (CBC) and creatinine clearance (CrCl) pre-RT and post-RT were compared through the Wilcoxon signed-rank test and correlated with survival analysis by Cox regression. Results Forty-two children with a median age of 3 years at diagnosis and 2.8 years of follow-up were selected. A significant and acute decrease in lymphocytes was found (p = 0.002) 1 month from RT. Patients with a drop higher than 50% of the previous value experimented a significant reduction in overall survival (55 vs 10%; p = 0.031). At the end of the follow-up, a significant increase in all blood counts was observed. With respect to renal function, an acute and significant decrease in CrCl was observed tin patients younger than 4 years who received RT (p = 0.013). However, it was not clinically relevant. Conclusion Our data suggest that acute lymphopenia occurs after RT and could be associated with a poorer prognosis. Other blood counts are reduced after RT and all of them are in physiological range at the end of follow-up. Our cohort presented excellent renal outcomes without any case of chronic renal dysfunction (AU)

Generation of mesenchymal stromal cells from urine-derived iPSCs of pediatric brain tumor patients.

Human induced pluripotent stem cells (iPSCs) provide a virtually inexhaustible source of starting material for next generation cell therapies, offering new opportunities for regenerative medicine. Among different cell sources for the generation of iPSCs, urine cells are clinically relevant since these cells can be repeatedly obtained by non-invasive methods from patients of any age and health condition. These attributes encourage patients to participate in preclinical and clinical research. In particular, the use of urine-derived iPSC products is a convenient strategy for children with brain tumors, which are medically fragile patients. Here, we investigate the feasibility of using urine samples as a source of somatic cells to generate iPSC lines from pediatric patients with brain tumors (BT-iPSC). Urinary epithelial cells were isolated and reprogrammed using non-integrative Sendai virus vectors harboring the Yamanaka factors KLF4, OCT3/4, SOX2 and C-MYC. After reprogramming, BT-iPSC lines were subject to quality assessment and were compared to iPSCs obtained from urine samples of non-tumor pediatric patients (nonT-iPSC). We demonstrated that iPSCs can be successfully derived from a small volume of urine obtained from pediatric patients. Importantly, we showed that BT-iPSCs are equivalent to nonT-iPSCs in terms of morphology, pluripotency, and differentiation capacity into the three germ layers. In addition, both BT-iPSCs and nonT-iPSCs efficiently differentiated into functional mesenchymal stem/stromal cells (iMSC) with immunomodulatory properties. Therefore, this study provides an attractive approach to non-invasively generate personalized iMSC products intended for the treatment of children with brain tumors.

Recent Evidence-Based Clinical Guide for the Use of Dinutuximab Beta in Pediatric Patients with Neuroblastoma.

The anti-GD2 antibody dinutuximab beta (Qarziba®) has been added to the present standard of care for patients with high-risk neuroblastoma in Europe based on the positive results obtained in different studies. In both the first-line and relapsed/refractory settings, treatment with dinutuximab beta attains objective clinical responses in children with high-risk neuroblastoma. Its incorporation has changed the outcome for these patients and optimized management should be guaranteed to minimize possible adverse effects. Most prevalent adverse events include pain, allergic reactions, fever and capillary leak syndrome. There are still no evidence-based clinical guidelines that include the latest published evidence to optimize its use, as it depends on the experience gained in each referral center. Topics such as the mode of preparation and administration, the concomitant use of interleukin-2, the recommended pediatric age and dose for its use, or the adequate management of possible toxicities are important aspects to review. The objective of this article was to update the clinical guide to management with dinutuximab beta of children with neuroblastoma based on the most recent published evidence and our own experience in clinical practice.

Prognostic implications of systolic function in patients with cirrhosis.

INTRODUCTION: LV intrinsic systolic cardiac function in cirrhotic patients is conditioned by the degree of sympathetic activation and the use of non-selective beta-blockers (NSBBs). Systolic function can be non-invasively measured by ultrasound using Ejection Intraventricular Pressure Differences in the LV (EIVPD). We aimed to address the relationship between systolic function and long-term clinical outcomes using EIVPD. METHODS: We studied 45 Child-Pugh B or C patients (13 female, 24 on NSBBs) using echocardiography. The primary endpoint was the combination of any-cause mortality or liver transplantation. After a follow-up of 7 years (796 person-months) and a median period of 17 (10-42) months, 41 patients (91%) reached the primary endpoint: 13 (29%) died and 28 (62%) underwent transplantation. RESULTS: By univariable analysis the primary endpoint was related exclusively to MELD score. However, in a multivariable proportional-hazards analysis, adjusted for age, sex and MELD score, EIVPD was inversely related to the primary endpoint, showing interaction with NSBBs. In patients without NSBBs, EIVPD inversely predicted the primary endpoint, whereas in patients with NSBBs, EIVPD was unrelated to outcomes. These relationships were undetected by myocardial strain or conventional cardiac indices. CONCLUSIONS: LV intrinsic systolic function, as noninvasively measured by EIVPD is a predictor of long-term outcomes in patients with cirrhosis. The prognostic value of EIVPD is present along any degree of liver dysfunction but blunted by NSBBs. Because NSBBs have a deep effect on myocardial contractility, these drugs need to be considered when assessing the prognostic implications of cardiac function in these patients.

Haematological and renal toxicity of radiation therapy in neuroblastoma paediatric patients.

PURPOSE: The objective of this study was to evaluate the renal and hematologic toxicity in paediatric patients with adrenal high-risk neuroblastoma who have received radiation therapy (RT) as part of radical treatment. MATERIAL AND METHODS: Pediatric patients diagnosed with high-risk adrenal neuroblastoma who received RT as part of the definitive treatment between January 2004 and May 2020 in a single institution were selected. Complete blood counts (CBC) and creatinine clearance (CrCl) pre-RT and post-RT were compared through the Wilcoxon signed-rank test and correlated with survival analysis by Cox regression. RESULTS: Forty-two children with a median age of 3 years at diagnosis and 2.8 years of follow-up were selected. A significant and acute decrease in lymphocytes was found (p = 0.002) 1 month from RT. Patients with a drop higher than 50% of the previous value experimented a significant reduction in overall survival (55 vs 10%; p = 0.031). At the end of the follow-up, a significant increase in all blood counts was observed. With respect to renal function, an acute and significant decrease in CrCl was observed tin patients younger than 4 years who received RT (p = 0.013). However, it was not clinically relevant. CONCLUSION: Our data suggest that acute lymphopenia occurs after RT and could be associated with a poorer prognosis. Other blood counts are reduced after RT and all of them are in physiological range at the end of follow-up. Our cohort presented excellent renal outcomes without any case of chronic renal dysfunction.

Childhood cancer survivorship care during the COVID-19 pandemic: an international report of practice implications and provider concerns.

PURPOSE: Long-term follow-up (LTFU) care is essential to optimise health outcomes in childhood cancer survivors (CCS). We aimed to assess the impact of the COVID-19 pandemic on LTFU services and providers. METHODS: A COVID-19 working group within the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) distributed a questionnaire to LTFU service providers in 37 countries across Europe, Asia, North America, Central/South America, and Australia. The questionnaire assessed how care delivery methods changed during the pandemic and respondents' level of worry about the pandemic's impact on LTFU care delivery, their finances, their health, and that of their family and friends. RESULTS: Among 226 institutions, providers from 178 (79%) responded. Shortly after the initial outbreak, 42% of LTFU clinics closed. Restrictions during the pandemic resulted in fewer in-person consultations and an increased use of telemedicine, telephone, and email consultations. The use of a risk assessment to prioritise the method of LTFU consultation for individual CCS increased from 12 to 47%. While respondents anticipated in-person consultations to remain the primary method for LTFU service delivery, they expected significantly increased use of telemedicine and telephone consultations after the pandemic. On average, respondents reported highest levels of worry about psychosocial well-being of survivors. CONCLUSIONS: The pandemic necessitated changes in LTFU service delivery, including greater use of virtual LTFU care and risk-stratification to identify CCS that need in-person evaluations. IMPLICATIONS FOR CANCER SURVIVORS: Increased utilisation of virtual LTFU care and risk stratification is likely to persist post-pandemic.

Preclinical Safety Evaluation of Intranasally Delivered Human Mesenchymal Stem Cells in Juvenile Mice.

Mesenchymal stem cell (MSC)-based therapy is a promising therapeutic approach in the management of several pathologies, including central nervous system diseases. Previously, we demonstrated the therapeutic potential of human adipose-derived MSCs for neurological sequelae of oncological radiotherapy using the intranasal route as a non-invasive delivery method. However, a comprehensive investigation of the safety of intranasal MSC treatment should be performed before clinical applications. Here, we cultured human MSCs in compliance with quality control standards and administrated repeated doses of cells into the nostrils of juvenile immunodeficient mice, mimicking the design of a subsequent clinical trial. Short- and long-term effects of cell administration were evaluated by in vivo and ex vivo studies. No serious adverse events were reported on mouse welfare, behavioral performances, and blood plasma analysis. Magnetic resonance study and histological analysis did not reveal tumor formation or other abnormalities in the examined organs of mice receiving MSCs. Biodistribution study reveals a progressive disappearance of transplanted cells that was further supported by an absent expression of human GAPDH gene in the major organs of transplanted mice. Our data indicate that the intranasal application of MSCs is a safe, simple and non-invasive strategy and encourage its use in future clinical trials.

Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños / Endocrine manifestations of central nervous system germ cell tumors in children

INTRODUCCIÓN: Los tumores germinales del sistema nervioso central deben ser correctamente diagnosticados, pues su tratamiento suele ser eficaz y no siempre requieren cirugía. Los objetivos del estudio son describir las manifestaciones endocrinas de estas neoplasias y comparar su momento de aparición con el de las alteraciones neurológicas y visuales. PACIENTES Y MÉTODOS: Revisión de historias de pacientes menores de 14 años atendidos en una unidad de endocrinología pediátrica desde 2000 hasta 2018. Pruebas estadísticas: Wilcoxon y Fisher. RESULTADOS: Se estudió a 12 pacientes (10 mujeres) con una edad al diagnóstico de 9,4±1,7 años y un tiempo de seguimiento de 5,5±3,0 años; 10 presentaban tumores de la región selar, uno pineal y uno bifocal. Las alteraciones clínicas que llevaron al diagnóstico eran neurológicas o visuales en 9casos y hormonales en 3. De los que consultaron por síntomas neurológicos o visuales, 7 refirieron previamente alteraciones hormonales, luego, estas estaban presentes en 10 de los niños al diagnóstico; la más frecuente fue la diabetes insípida central (8 casos). El periodo medio de presencia de síntomas endocrinológicos previos al diagnóstico fue de 25,0±26,2 meses, mucho más largo que el de los neurooftalmológicos, de 2,0±2,1 meses (p = 0,012). CONCLUSIONES: Casi todos los tumores germinales intracraneales presentaron al diagnóstico manifestaciones endocrinas, la más frecuente de las cuales fue la diabetes insípida central. Los síntomas hormonales suelen presentarse bastante antes que los neurooftalmológicos. La correcta valoración clínica y endocrinológica puede adelantar el diagnóstico de estos tumores

INTRODUCTION: Central nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. PATIENTS AND METHODS: The medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. RESULTS: We found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p = 0.012). CONCLUSIONS: Almost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

BACKGROUND: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. PATIENTS AND METHODS: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. RESULTS: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. CONCLUSIONS: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. TRIAL REGISTRATION: NCT01962103 and EudraCT 2013-000144-26.

Endocrine manifestations of central nervous system germ cell tumors in children. / Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños.

INTRODUCTION: Central nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. PATIENTS AND METHODS: The medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. RESULTS: We found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). CONCLUSIONS: Almost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.

18F-FDG PET/TC en la estadificación inicial de pacientes con rabdomiosarcoma alveolar / 18F-FDG PET/CT as staging of alveolar rhabdomyosarcoma

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Hepatotoxicity after high-dose intravenous methylprednisolone in multiple sclerosis patients.

Hepatotoxicity is a rare adverse event of methylprednisolone that should be considered in clinical practice. In patients at risk, we propose liver function surveillance, by measuring hepatic enzymes concentration 15-30 days after methylprednisolone administration. Additionally, we propose ACTH, dexamethasone, or plasma exchange as alternate treatment options for these patients.

Caracterización del sistema físico-geográfico que influye en las multiamenazas de la subcuenca del río Caldera, Panamá / Physico-geographical characterization of the system that influences the multi-hazards in the sub-basin of Caldera River, Panama

RESUMEN La caracterización del sistema físico-geográfico constituye una herramienta que permite deter minar las multiamenazas generadas por los fenómenos naturales. El término de multiamenaza describe la presencia de más de una amenaza relevante en el geosistema con interacciones en diferente nivel. El objetivo de este trabajo fue la caracterización de los factores del sistema físico-geográfico de la subcuenca del río Caldera, Panamá, que pueden ser considerados como multiamenazas naturales y que influyen en el riesgo a desastres del área. Se estudió la geología, geomorfología, climatología, edafología e hidrografía de la zona. Se realizó un análisis sistémico, complementado con el trabajo de campo, utilizando el método directo, sobre la base del criterio experto o método heurístico. Se determinó que las principales amenazas que ocurren en el área de estudio son de origen sísmico, volcánico, la alta susceptibilidad por inestabilidad de laderas y las inundaciones. Dichas amenazas y su relación con la acción antrópica deben ser consideradas dentro de los planes de ordenamiento territorial y en la gestión del riesgo de desastres existentes en esta zona de Panamá.

ABSTRACT The characterization of the physico-geographical system is a tool used to determine the multi-hazards generated by natural phenomena. The term multi-hazard describes the presence of more than one relevant hazard in the geosystem with different levels of interaction. The aim of this work was the characterization of the physico-geographical factors that can be considered as multi-hazard, and influence the disaster risk for the sub-basin of Caldera River, Panama. A systemic analysis of the geology, geomorphology, climatology, soil science and hydrography of the zone was conducted. Such analysis was complemented by fieldwork, using the direct method on the base of the expert criterion or heuristic method. The results indicate that the main hazards occurring in the study area are related to seismic and volcanic issues and its high vulnerability due to slope instability and flooding. These hazards and their relationship with anthropic action need to be considered in land use plans and disaster risk management in this area of Panama.

Protagonismo del paciente y papel de los médicos en el seguimiento a largo plazo de los supervivientes del cáncer infantil / Empowerment of patients and physicians’ role in the long-term follow-up survivors of childhood cancer

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Glioma del quiasma óptico en niños: complicaciones endocrinológicas en 14 casos / Optic chiasm glioma in children: Endocrine disorders in 14 cases

Fundamento y objetivos: Describir la frecuencia de endocrinopatías en niños con glioma del quiasma óptico y analizar los factores relacionados. Pacientes y métodos: Revisión de historias recogiendo las variables sexo, edad, antecedente de neurofibromatosis, forma de presentación, tratamiento del tumor y presencia de endocrinopatías. Pruebas estadísticas: Wilcoxon y Fisher. Resultados: Catorce pacientes (6 mujeres) con edad al diagnóstico de 0,5 a 7,0 años (media ± desviación típica: 2,97 ± 2,32) y tiempo de seguimiento de 10,64 ± 3,30 años (rango 6,0-16,0). Doce de 14 presentaban endocrinopatía al final del seguimiento: 8 pubertad precoz, 5 hipopituitarismo y 5 obesidad. La aparición de déficits se relacionó con la clínica neurooftalmológica antes de los 5 años de edad (p = 0,02) y con el requerimiento de tratamiento de la lesión (p = 0,03). Conclusiones: Los niños con gliomas del quiasma óptico pueden presentar endocrinopatías desde el momento del diagnóstico del tumor y, sobre todo, a lo largo de su evolución. La más frecuente es la pubertad precoz. Los déficits hipofisarios se relacionan con los tumores más agresivos (aquellos que debutan con clínica neurooftalmológica antes de los 5 años de edad y que requieren tratamiento) (AU)

Background and objectives: To describe the frequency of endocrine disorders in children with optic chiasm glioma and analyze related factors. Patients and methods: Review of medical records by collecting sex, age, history of neurofibromatosis, clinical presentation, treatment of tumour, and presence of endocrine abnormalities. Statistical tests Wilcoxon and Fisher. Results: 14 patients (6 female) with age at diagnosis of 0.5 to 7.0 years (mean ± standard deviation: 2.97 ± 2.32) and follow-up of 10.64 ± 3.30 years (range 6.0 to 16.0). 12/14 presented endocrinopathy at follow-up: 8 precocious puberty, 5 hypopituitarism, and 5 obesity. The onset of deficits was related to the neuroophthalmological symptoms under the age of five (P = .02)and treatment of the tumour was required.(P = .03). Conclusions: Children with optic chiasm gliomas may present endocrine disorders from the time of diagnosis of the tumor and, in particular as they develop on. The most common of these is precocious puberty. Pituitary deficits are associated with more aggressive tumours (those presenting with neuroophthalmological signs and symptoms before the age of five and requiring treatment) (AU)