Figure - available from: Cancers
This content is subject to copyright.
Scatter plot of lesion sizes and age at diagnosis. Individual ages at diagnosis are depicted (y-axis) against lesion size values (x-axis), colored by IV-MTX dose. Lower cumulative MTX doses of 20 g/m² and 35 g/m² are presented in dark and light blue, while higher doses of 50 and 55 g/m² are presented in yellow and red, respectively. While the age range of non-lesioned patients (i.e., lesion size = 0.000) covers a wide range, the ages of lesioned patients are more densely distributed in the younger age range.
Source publication
Methotrexate (MTX) is associated with leukoencephalopathy (LE) in children treated for lymphoblastic leukemia/lymphoma (ALL/LBL). However, large-scale studies with systematic MR acquisition and quantitative volumetric lesion information remain limited. Hence, the prevalence of lesion burdens and the potential risk factors of LE in this population a...
Similar publications
Background and aim:
We present a case of a 22-year-old male diagnosed with B-cell acute lymphoblastic leukemia who received intrathecal (IT) methotrexate (MTX) in addition to his systemic chemotherapy regime. During induction treatment, he presented with a rapidly progressive bilateral paresis, anarthria, and respiratory insufficiency requiring in...
Citations
... Por otra parte, se ha relacionado la prevalencia de complicaciones neurológicas con la administración de fármacos, siendo la leucoencefalopatía la manifestación más común de neurotoxicidad por medicamentos (13,14,17,24,25). Estudios han informado que el aumento de la exposición a mayores dosis acumuladas de metotrexato intravenoso influyó en la prevalencia de leucoencefalopatía en pacientes pediátricos que recibieron tratamiento para la LLA (25,26). Entre los factores de riesgo, se ha observado que la leucoencefalopatía fue más frecuente en los casos de menor edad, presentando episodios de convulsiones focales, hemiparesia ipsilateral, parálisis del nervio facial, ataxia y estado mental alterado (14,26). ...
... Estudios han informado que el aumento de la exposición a mayores dosis acumuladas de metotrexato intravenoso influyó en la prevalencia de leucoencefalopatía en pacientes pediátricos que recibieron tratamiento para la LLA (25,26). Entre los factores de riesgo, se ha observado que la leucoencefalopatía fue más frecuente en los casos de menor edad, presentando episodios de convulsiones focales, hemiparesia ipsilateral, parálisis del nervio facial, ataxia y estado mental alterado (14,26). Se ha observado que la leucoencefalopatía es en su mayoría transitoria y su prevalencia disminuye después de la finalización del tratamiento, sin embargo, si no se diagnostica y trata rápidamente, puede provocar daño neurológico permanente (26). ...
... Entre los factores de riesgo, se ha observado que la leucoencefalopatía fue más frecuente en los casos de menor edad, presentando episodios de convulsiones focales, hemiparesia ipsilateral, parálisis del nervio facial, ataxia y estado mental alterado (14,26). Se ha observado que la leucoencefalopatía es en su mayoría transitoria y su prevalencia disminuye después de la finalización del tratamiento, sin embargo, si no se diagnostica y trata rápidamente, puede provocar daño neurológico permanente (26). ...
La leucemia linfoblástica aguda (LLA), también conocida como leucemia linfocítica aguda, es la neoplasia maligna más común y debilitante en la infancia, representando aproximadamente el 80% de los casos de leucemia en niños. A pesar de ser una de las leucemias agudas con las tasas de curación más altas, gracias a la intensificación de los protocolos de quimioterapia, sigue generando efectos adversos en los pacientes pediátricos. La quimioterapia, principal tratamiento para esta enfermedad, no solo destruye las células cancerosas, sino que también ralentiza su crecimiento. Sin embargo, su aplicación no está exenta de complicaciones, que en algunos casos superan las propias de la enfermedad. Entre las principales complicaciones que presentan mayor incidencia se encuentran las afecciones neurológicas, musculoesqueléticas, bucodentales y metabólicas, todas ellas asociadas, en su mayoría, a la toxicidad de los medicamentos administrados. Estas complicaciones afectan significativamente el desarrollo físico, psicomotor y la calidad de vida de los niños que padecen esta forma de leucemia hematológica.
... Age and dietary habitwere associated with problem-solving function. Younger children experienced more severe neurocognitive impairment during treatment, which is consistent with the study of Rijmenams et al. [28]. Sleurs et al. [29] have further confirmed through a multicenter follow-up study involving 94 children with leukemia that the younger a child is diagnosis, the lower the subsequent IQ assessments tends to be. ...
Background and aims
Cancer and its treatments may cause neurocognitive impairments in preschool children, but there is limited research on the neurocognitive outcomes of this population. This study, which assessed the neurocognitive function of preschool children with cancer and analyzed various influencing factors of neurocognitive functioning, is of significant importance. We aimed to investigate neurocognitive function and related risk factors in preschool children with cancer to inform preventive and intervention strategies.
Methods
From September 2023 to May 2024, we recruited 100 preschool children with cancer. The Chinese version of the Ages & Stages Questionnaires, the Spence Preschool Anxiety Scale Chinese Version, and the Sleep Disturbance Scale for Children were used to collected data. Binary logistic stepwise regression analysis was used to explore the influencing factors of neurocognitive function in preschool children with cancer.
Results
49% of the preschool children with cancer had abnormalities in at least one neurocognitive dimension. The majority of children had abnormalities in gross motor dimension, accounting for 30%, which was related to age and frequency of participation in neurocognitive activities. Communication dimension was related to father’s education level, dietary habit, and frequency of participation in activities. Fine motor dimension was associated with age, sex, and father’s education level. Problem-solving dimension was associated with age and dietary habit. Personal-social dimension was related to age and radiotherapy.
Conclusions
Nearly half of preschool children with cancer experienced neurocognitive impairment. The Chinese version of the Ages & Stages Questionnaires is a simple and effective tool for screening children with possible neurocognitive impairment. It was found that children’s neurocognitive function was significantly influenced by family environment, dietary habit, cognitive activities, and cancer treatment. Therefore, it is recommended to strengthen family and social support, and to formulate personalized intervention such as cognitive therapy and dietary adjustment based on children’s age and family background, which are important for promoting neurocognitive recovery.
... [3][4][5] Methotrexate-induced neurotoxicity may vary depending upon the dose, frequency, route of administration, patient age, race and ethnicity. [6][7][8] Direct toxic increase in homocysteine, decrease in S-adenosyl methionine (SAM) and increase in excitatory amino acids are some of the postulated mechanisms of this neurotoxicity. 8 Risk factors attributed to MTX-induced neurotoxicity include adolescent age, high-risk ALL therapy, elevated aspartate aminotransferase during ALL induction/consolidation cycles and high serum creatinine. ...
Methotrexate (MTX), although an indispensable part of contemporary treatment protocols for childhood acute lymphoblastic leukaemia (ALL)/lymphomas (LBL) in improving outcomes, can lead to serious neurotoxicity with long‐term consequences. The aetiopathogenesis, predisposing factors and treatment for MTX‐induced neurotoxicity are not yet well defined. The aim of our study was to detect the incidence, risk factors and to assess the overall outcomes of MTX‐induced neurotoxicity among large cohort of paediatric ALL/LBL patients treated on a uniform protocol. We conducted retrospective audit of medical records of 622 consecutive children (≤14 years) diagnosed with ALL and LBL between January 2018 and December 2022 and treated on modified BFM‐95 protocol at the Department of Pediatric Oncology, Regional Cancer Centre, Thiruvananthapuram. Risk factors predisposing to MTX‐induced neurotoxicity were identified using binary logistic regression analysis. Forty‐three children were diagnosed with MTX‐induced neurotoxicity with an incidence rate of 6.9%. More than two‐thirds of them had high‐grade MTX‐induced neurotoxicity CTCAE v5.0 with a median age of 9 years (range: 9 months to 14 years). Almost half of them developed MTX neurotoxicity during Protocol M followed by Phase‐Ib consolidation (15%). Majority of these patients (84%, 36/43) were challenged again with MTX, with 11% (4/36) developing recurrence. Fifteen per cent had persistent neurological deficits at last follow‐up. Univariate analysis found older age (age > 5 years) (p < 0.001), T‐cell phenotype (p = 0.040), tumour lysis syndrome during induction (p < 0.001), baseline renal problems prior to MTX exposure (p < 0.001) and CNS leukaemic involvement (p < 0.003) to be significantly associated with MTX neurotoxicity. On multivariate analysis, older age (>5 years), tumour lysis during induction and CNS leukaemia retained statistical significance (p < 0.05). Methotrexate‐induced neurotoxicity during paediatric acute lymphoblastic leukaemia/lymphoma therapy is a transient phenomenon in majority and re‐challenge with MTX is generally safe. Older age children who develop tumour lysis during induction and CNS leukaemic involvement are at increased risk for MTX‐induced neurotoxicity during ALL/LBL treatment.
... There are multiple pathways by which younger age at diagnosis may confer neurocognitive vulnerability. During early childhood, white matter pathways are rapidly developing and therefore disruption of the CNS during this time has been associated with leukoencephalopathy [17,18]. These white matter pathways are a crucial aspect of neurodevelopment and allow for rapid and efficient information processing. ...
To investigate the association of environmental factors, rehabilitation services during therapy and socioeconomic status (SES – insurance type), with neurocognitive outcomes at the end of therapy for survivors of childhood acute lymphoblastic leukemia (ALL).
Survivors (n = 236) treated on the St. Jude Total Therapy Study 16 completed end of therapy testing with performance measures (IQ, attention, processing speed, fine motor skills, academics) and caregiver ratings (attention, executive function, adaptive skills). Environmental factors were abstracted from the medical record.
Distribution of sex (47.3% female, p = 0.399), treatment arm (45.5% low risk, 54.5% standard/high risk p = 0.929), insurance type (47.7% private, 52.3% public/none, p = 0.117), and mean age at diagnosis (7.7 vs. 6.8 years, p = 0.143) were similar for groups with (n = 110; 46.6%) and without (n = 126; 53.6%) rehabilitation services during therapy. Compared to those without rehabilitation, the rehabilitation group (n = 110; 46.4%) had more caregiver reported problems with attention (Z = -0.28 vs. 0.43, p = 0.022), executive function (Z = -0.50 vs. -0.08, p = 0.003), and adaptive skills (Z = -0.41 vs.—0.13, p = 0.031). Among the rehabilitation group, there was no difference in outcomes by insurance status. Among those without rehabilitation, those with public insurance had worse neurocognitive outcomes than those with private insurance in IQ (Z = -0.04 vs. -0.45, p = 0.0115), processing speed (Z = -0.10 vs. -0.75, p = 0.0030), reading (Z = 0.18 vs. -0.59, p < 0.0001), and math (Z = -0.04 vs. -0.50, p = 0.0021).
Participation in rehabilitation services during early intensive therapy is associated with end of therapy caregiver-reported neurocognitive outcomes in daily life.
... Methotrexate (MTX) is one of the most routinely employed chemotherapeutic agents in acute lymphoblastic leukemia (ALL) and other cancers; however, its use has been linked to an increased incidence of neurotoxicity in about 9-53% of patients [1,2]. This is evident as cognitive impairment, memory problems, and motor dysfunction which appear in 30-60% of pediatric cancer survivors who have undergone chemotherapy [2,3]. The severity of MTX-induced neurotoxicity is multifactorial, with many predisposing factors influencing its severity, including age, dose, route of administration, and exposure to radiation [3]. ...
... This is evident as cognitive impairment, memory problems, and motor dysfunction which appear in 30-60% of pediatric cancer survivors who have undergone chemotherapy [2,3]. The severity of MTX-induced neurotoxicity is multifactorial, with many predisposing factors influencing its severity, including age, dose, route of administration, and exposure to radiation [3]. Although several theories have been proposed to contemplate the neurotoxic actions of MTX, the exact mechanism is still unknown. ...
Microglial activation underpins the methotrexate (MTX)-induced neurotoxicity; however, the precise mechanism remains unclear. This study appraised the potential impact of apigenin (Api), a neuroprotective flavonoid, in MTX-induced neurotoxicity in rats in terms of microglial activation through targeting the miR-15a/Rho-associated protein kinase-1 (ROCK-1)/extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Male Sprague Dawley rats were randomly divided into 4 groups: Normal control (saline i.p. daily and i.v. on days 8 and 15); Api control (20 mg/kg, p.o.) daily for 30 days; MTX-alone (75 mg/kg, i.v.) on days 8 and 15, then four i.p. injections of leucovorin (LCV): 6 mg/kg after 18 h, then three doses (3 mg/kg) every 8 h post-MTX; and Api co-treated (20 mg/kg/day, p.o.) throughout the model for 30 days, with administration of MTX and LCV as in group 3. MTX administration elevated hippocampal ionized calcium-binding adaptor protein-1 (Iba-1) immunostaining, indicating microglial activation. This was accompanied by neuroinflammation, oxidative stress, and enhanced apoptosis manifested by elevated hippocampal interleukin-1β, malondialdehyde, and caspase-3, and decreased reduced glutathione levels. Concurrently, abated miR-15a expression, overexpression of its target ROCK-1, diminished downstream ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation, and decreased hippocampal brain-derived neurotrophic factor (BDNF) levels were observed. Api mitigated the MTX-induced neurotoxicity by reversing the biochemical, histopathological, and behavioral derangements tested by novel object recognition and Morris water maze tests. Conclusively, Api lessens MTX-induced neuroinflammation, oxidative stress, and apoptosis and boosts cognitive function through inhibiting microglial activation via modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway.
Graphical Abstract
Graphical abstract showing the effects of methotrexate and apigenin co-treatment in MTX-induced neurotoxicity model.
On the left, methotrexate (MTX) administration to rats resulted in hippocampal miR-15a downregulation, which triggered an enhanced expression of its target ROCK-1, consequently inhibiting the downstream ERK1/2/CREB/BDNF pathway, instigating a state of microglial activation, neuroinflammation, oxidative stress, and apoptosis. On the other hand, apigenin (Api) co-treatment restored miR-15a, inhibited ROCK-1 expression, and activated the ERK1/2/CREB/BDNF pathway, leading to diminished hippocampal microglial activation, neuroinflammation, and apoptosis, and restoration of the redox balance, along with improvement in memory and cognitive function of the MTX-treated rats.
... The main cause is treatment with potential neurotoxic drugs during the vulnerable phase of brain maturation [38][39][40]. The literature can be divided into two groups, firstly about morphologic changes of the brain in children treated for acute leukemias alone [15][16][17][18][19][20][21][22][23][24][25][26][27][28]41,42] and secondly about the association between cMRI alterations and neurocognitive sequelae [2][3][4][5][6][7][8][9][10][11][12][13]22,34,[43][44][45][46]. ...
... Age as a risk factor is not a common finding in the literature [2,7,41]. Like us, Rijmenams et al. [42] identified young age as a risk factor for leukoencephalopathy. ...
... Our results showed white-matter changes less often than Rijmenams et al. [42], Duffner et al. [5], and Iuvone et al. [34], who detected this pathology in 41-67%. Nevertheless, some of these cohorts more often received cranial radiotherapy. ...
Due to high survival rates, long-term sequelae, especially neurotoxicity, need to be considered in childhood acute leukemias. In this retrospective analysis of morphologic changes of the brain in children treated for acute leukemias, we included 94 patients (77 ALL, 17 AML; 51 male, 43 female; median age: 5 years) from a single center. We analyzed 170 cranial MRI scans (T2, FLAIR axial) for morphologic alterations of the brain and variations of the ventricular width (GDAH). In addition, the corresponding literature was reviewed. More than 50% of all patients showed cerebral pathomorphologies (CP). They were seen more often in children with ALL (55.8%), ≤
6 years of age (60.8%), in relapse (58.8%) or after CNS irradiation (75.0%) and included white matter changes, brain atrophy, sinus vein thrombosis and ischemic events. GDAH significantly enlarged mainly in children up to 6 years, with relapse, high-risk leukemias or ALL patients. However, GDAH can normalize again. The number of intrathecal Methotrexate applications (≤12 vs. >12) showed no correlation to morphologic alterations besides a significant increase in GDAH (−0.3 vs. 0.9 mm) between the first and last follow-up MRI in ALL patients receiving >12 ith. MTX applications. The role of ith. MTX on CP needs to be further investigated and correlated to the neurocognitive outcome of children with acute leukemias.
... 13 This is an important mechanistic distinction, 1,6,14 as ASMs may not be needed if chemotherapy-related seizures occur from a direct transient toxic effect on neurons, but long-term treatment is required for a toxic leukoencephalopathy that may be potentially persistent, especially in the pediatric age group with incomplete brain myelination. 15 Of note, the exact seizure etiology could not be determined in six patients, possibly due to the lack of advanced MRI. 14,16 Confirming the presence of a possibly persistent structural brain insult with high-resolution MRI or even more advanced technologies 14,16 is essential to devise the optimal ASM regimen given the diverse seizure etiologies and their level of chronicity in this population. Abbreviations: ASM ¼ Anti-seizure medication CNS ¼ Central nervous system HSV ¼ Herpes simplex virus PRES ¼ Posterior reversible encephalopathy syndrome * These nine patients were considered to have provoked seizures (immediate reversible cause). ...
Background
Seizures occur in up to 13% of children with non-central nervous system (CNS) malignancies, but little is known about their causes and optimal diagnostic and therapeutic approaches. Here we sought to determine etiologies and clinical trajectories of new-onset seizures in this patient population.
Methods
A retrospective chart review over a 10-year period was conducted at the American University of Beirut Medical Center to identify children with non-CNS malignancies and at least one new-onset seizure. Data was collected on the underlying malignancy, seizure etiology, clinical course, treatments, electroencephalograms, and brain imaging.
Results
New-onset seizures occurred in 56 children (2-year median follow up), most commonly in the context of acute lymphoblastic leukemia, lymphomas, and sarcomas. In 19 children, the first seizure consisted of status epilepticus. The most common etiologies were cerebrovascular accidents, posterior reversible encephalopathy syndrome (PRES), and metastasis. Fourty-nine patients received anti-seizure medications (ASMs). Withdrawal of ASMs was successful in 19 children with normal initial or follow-up brain imaging but failed in three patients with persistent brain lesions. The remaining children, all of whom except two had structural brain abnormalities, received chronic ASMs and remained seizure-free for a median period of 2 years at the last follow up in survivors.
Conclusions
Not only are seizures in children with non-CNS cancers often indicative of a serious brain insult, but they can also be challenging in the form of status epilepticus. An urgent diagnostic workup is therefore needed to expedite treatment, which should be tailored to the chronicity of the underlying cause.
... In contrast to findings in other oncological populations, e.g. leukaemia patients [45], these results suggest no (acute) changes in lesion burden in early-stage breast cancer patients (compared to controls) after the currently applied chemotherapeutic regimens (i.e. often a combination of 5-fluorouracil, epirubicin and/or cyclophosphamide). ...
Background
Although chemotherapy-induced leukoencephalopathy has been described in case and cohort studies, literature remains inconclusive about its prevalence and mechanisms. Therefore, we investigated the presence of leukoencephalopathy after multiagent chemotherapy in women treated for breast cancer and potential underlying neuroinflammatory processes.
Methods
In this exploratory study, 15 chemotherapy-treated and 15 age-matched chemotherapy-naïve patients with early-stage breast cancer, as well as 15 healthy controls underwent simultaneous PET-MR neuroimaging, including T1-weighted MPRAGE, T2-weighted FLAIR and dynamic PET with the 18-kDA translocator protein (TSPO) radioligand [¹⁸F]DPA-714. Total and regional (juxtacortical, periventricular, deep white matter and infratentorial) lesion burden were compared between the groups with one-way ANOVA. With paired t-tests, [¹⁸F]DPA-714 volume of distribution [VT, including partial volume correction (PVC)] lesioned and normal appearing white matter (NAWM) were compared within subjects, to investigate inflammation. Finally, two general linear models were used to examine the predictive values of neurofilament light-chain (NfL) serum levels on (1) total lesion burden or (2) [¹⁸F]DPA-714 VT of lesions showing elevated inflammation.
Results
No significant differences were found in total or localized lesion burden. However, significantly higher (20–45%) TSPO uptake was observed in juxtacortical lesions (p ≤ 0.008, t ≥ 3.90) compared to NAWM in both cancer groups, but only persisted for chemotherapy-treated patients after PVC (p = 0.005, t = 4.30). NfL serum levels were not associated with total lesion volume or tracer uptake in juxtacortical lesions.
Conclusion
This multimodal neuroimaging study suggests that neuroinflammatory processes could be involved in the development of juxtacortical, but not periventricular or deep white matter, leukoencephalopathy shortly after chemotherapy for early-stage breast cancer.
Methotrexate (MTX) is a widely used neurotoxic drug with broad antineoplastic and immunosuppressant spectra. However, the exact molecular mechanisms by which MTX inhibits hippocampal neurogenesis are yet unclear. Dexmedetomidine (Dex), an α2-adrenergic receptor agonist, has recently shown neuroprotective effects; however, its full mechanism is unexplored. This study investigated the potential of Dex to mitigate MTX-induced neurotoxicity and memory impairment in rats and the possible role of the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway. Notably, no former studies have linked this pathway to MTX-induced neurotoxicity. Male Sprague Dawley rats were placed into four groups. Group 1 received saline i.p. daily and i.v. on days 8 and 15. Group 2 received Dex at 10 μg/kg/day i.p. for 30 days. Group 3 received MTX at 75 mg/kg i.v. on days 8 and 15, followed by four i.p. doses of leucovorin at 6 mg/kg after 18 h and 3 mg/kg after 26, 42, and 50 h. Group 4 received MTX and leucovorin as in group 3 and Dex daily dosages as in group 2. Bioinformatic analysis identified the association of miR-15a with ROCK-1/ERK1/2/CREB/BDNF and neurogenesis. MTX lowered hippocampal doublecortin and Ki-67, two markers of neurogenesis. This was associated with the downregulation of miR-15a, upregulation of its target ROCK-1, and reduction in the downstream ERK1/2/CREB/BDNF pathway, along with disturbed hippocampal redox state. Novel object recognition and Morris water maze tests demonstrated the MTX-induced memory deficiencies. Dex co-treatment reversed the MTX-induced behavioral, biochemical, and histological alterations in the rats. These neuroprotective actions could be partly mediated through modulating the miR-15a/ROCK-1/ERK1/2/CREB/BDNF pathway, which enhances hippocampal neurogenesis.
