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BACKGROUND: Craniopharyngiomas (CP) are histologically benign (WHO grade 1), embryonal malformations which are related to remnants of the Rathke's pouch and are located in the (peri)sellar region. Already before CP diagnosis, many patients show a reduced growth velocity and tend to present with weight gain. However, it is unknown whether patients with CP develop an increased head circumference (HC) before CP diagnosis, which could be a useful early diagnostic indicator. PATIENTS AND METHODS: For a cohort of 83 patients recruited in the multicenter studies KRANIOPHARYNGEOM 2000 and HIT-ENDO data on HC could be analyzed, based on medical records assessed in developmental monitoring visits performed at defined time points before CP diagnosis. RESULTS: When comparing HC standard deviation scores (SDS) before CP diagnosis in 83 patients at defined time points between birth and 4 years of age, all HC were in the upper normal range. However, CP patients diagnosed at an age ≤4 years with initial hypothalamic involvement presented with a tendency towards an increased HC SDS early before CP diagnosis at routine medical examinations during the first 7 months of life. CONCLUSIONS: We conclude that monitoring of growth and weight development including HC can lead to early CP diagnosis and treatment. This might prevent higher grades of hypothalamic involvement and lead to an improvement of quality of life after CP. Further studies on the specific value of HC as a diagnostic marker are warranted.
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Craneofaringioma , Neoplasias Hipofisarias , Humanos , Craneofaringioma/diagnóstico , Craneofaringioma/patología , Masculino , Femenino , Preescolar , Lactante , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/patología , Cabeza , Niño , Recién Nacido , Edad de Inicio , AdolescenteRESUMEN
Objective: It is well known that both genetic background and lifestyle influence the development of 'general' obesity. However, the role of parental body mass index (BMI) on the development of obesity in long-term survivors of childhood-onset craniopharyngioma (CP) is not well understood. This study analyzed the correlation of patients' BMI at diagnosis and last visit and parental BMI at CP diagnosis and further explored potential risk factors for obesity in CP patients. Design: This is a registry-based retrospective cohort study. Methods: In total,291 CP patients and their parents recruited in the German KRANIOPHARYNGEOM studies were included. Correlations between patient's BMI SDS at CP diagnosis and last visit and parental BMI at CP diagnosis were analyzed. The associations between hypothalamic damage, maternal/paternal BMI and CP patients' obesity at last visit were analyzed by multivariable logistic regression. Results: At follow-up, 52% of CP patients developed obesity (BMI > 3SDS). Patient's BMI SDS at last visit was moderately correlated with BMI-SDS at CP diagnosis (r = 0.48, 95% CI: 0.38-0.58, P < 0.001), and also with maternal BMI at diagnosis (r = 0.28, 95% CI: 0.17-0.38, P < 0.001) and paternal BMI at diagnosis (r = 0.3, 95% CI: 0.19-0.41, P < 0.001). However, the contributing role of parental BMI to the pathogenesis of obesity was small compared to the impact of hypothalamic damage. Conclusion: We conclude that besides hypothalamic damage, parental disposition for obesity is associated with the development of obesity in patients after CP. Our results indicate that also the family situation could have an influence on the development of obesity after CP and might be a therapeutic target. Significance statement: Survivors of childhood-onset craniopharyngioma are at risk of developing morbid obesity. So far, patients with posterior hypothalamic involvement and lesion were identified as a high risk group. With this study, the influence of parental body mass index on the risk of obesity was investigated. Patient's body-mass-index at last visit was correlated with maternal and paternal body mass index at diagnosis. With increasing maternal or paternal body mass index, the likelihood of obesity in individuals with CP increased. Nevertheless, the parents' weight had only a small effect on the development of patients' obesity compared to hypothalamic damage.
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BACKGROUND: Neurocognition can be severely affected in pediatric brain tumor survivors. We analyzed the association of cognitive functioning with radiotherapy dose, postoperative cerebellar mutism syndrome (pCMS), hydrocephalus, intraventricular methotrexate (MTX) application, tumor localization and biology in pediatric survivors of a posterior fossa tumor. METHODS: Subdomain-specific neurocognitive outcome data from 279 relapse-free survivors of the HIT-2000 trial (241 medulloblastoma and 38 infratentorial ependymoma) using the Neuropsychological Basic Diagnostic (NBD) tool based on Cattell-Horn-Carroll's model for intelligence were analyzed. RESULTS: Cognitive performance 5.14 years (mean; range=1.52-13.02) after diagnosis was significantly below normal for all subtests. Processing speed and psychomotor abilities were most affected. Influencing factors were domain-specific: CSI-dose had strong impact on most subtests. pCMS was associated with psychomotor abilities (ß=-0.25 to -0.16) and processing speed (ß=-0.32). Postoperative hydrocephalus correlated with crystallized intelligence (ß=-0.20) and short-term memory (ß=-0.15), age with crystallized intelligence (ß=0.15) and psychomotor abilities (ß=-0.16 and ß=-0.17). Scores for fluid intelligence (ß=-0.23), short-term memory (ß=-0.17) and visual processing (ß=-0.25) declined, and scores for selective attention improved (ß=0.29) with time after diagnosis. CONCLUSION: Dose of CSI was strongly associated with neurocognitive outcome. Low psychomotor abilities and processing speed both in patients treated with and without CSI suggest a strong contribution of the tumor and its surgery on these functions. Future research therefore should analyze strategies to both reduce CSI-dose and toxicity caused by other treatment modalities.
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PURPOSE: Craniopharyngiomas (CPs) are rare tumors of the sellar region often leading to significant comorbidities due to their close proximity to critical structures. The aim of this study was to analyze survival outcome and late toxicities after surgery and proton beam therapy (PBT) in childhood CPs. METHODS AND MATERIALS: Within the prospective registry study "KiProReg" (DRKS0000536), data of 74 childhood patients with CP, receiving PBT between August 2013 to June 2022 were eligible. Late toxicities were analyzed according to the grading system of the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Median follow-up since first diagnosis was 4.3 years (range, 0.8-14.7). In addition, 75.7% of patients received PBT at time of disease progression or recurrence, whereas 24.3% as part of their primary therapy (definitive or adjuvant). Predominantly (85.1%), pencil beam scanning technique was used. The median total dose and initial tumor volume were 5400 cGy relative biologic effectiveness (RBE) and 17.64 cm³ (range, 3.07-300.59), respectively. The estimated (±SE) 3-year overall survival, progression-free, and cystic failure-free survival rate after PBT were 98.2% (±1.7), 94.7% (±3.0), and 76.8% (±5.4), respectively. All local failures (n = 3) were in-field relapses necessitating intervention and occurred exclusively in patients receiving PBT at progression or recurrence. Early cystic enlargements after PBT were typically asymptomatic and self-limiting. Fatigue, headaches, vision disorders, obesity, and endocrinopathies were the predominant late toxicities. No high-grade (≥3) new-onset visual impairment or cognitive deterioration occurred compared with baseline. The presence of cognitive impairments at the end of follow-up correlated with size of the planning target volume (P = .034), Dmean dose to the temporal lobes (P = .032, P = .045) and the number of surgical interventions before PBT (P = .029). CONCLUSIONS: Our findings demonstrate favorable local control rates using modern PBT with acceptable late toxicities. Cyst growth within 12 months after radiation therapy is typically not associated with tumor progression. Longer follow-up must be awaited to confirm results.
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Craneofaringioma , Neoplasias Hipofisarias , Terapia de Protones , Sistema de Registros , Humanos , Craneofaringioma/radioterapia , Craneofaringioma/mortalidad , Terapia de Protones/efectos adversos , Niño , Masculino , Femenino , Estudios Prospectivos , Preescolar , Adolescente , Neoplasias Hipofisarias/radioterapia , Neoplasias Hipofisarias/mortalidad , Resultado del Tratamiento , Carga Tumoral , Recurrencia Local de Neoplasia , Dosificación Radioterapéutica , Lactante , Efectividad Biológica RelativaRESUMEN
Craniopharyngioma (CP) treatment, including surgery and radiotherapy, can have short- and long-term vascular side effects. Hypothalamic damage is related to morbid obesity and may increase the lifelong risk of experiencing vascular events in CP patients. This review summarized the available evidence regarding vascular complications in adamantinomatous or papillary CP patients, whatever their age at diagnosis. Three databases (Medline, CINAHL, Web of Science) were searched (06/2023) to retrieve eligible articles. The search was limited to peer-reviewed articles. Titles, abstracts, and full texts were screened by two independent reviewers, and data were extracted using a self-developed grid. Seventy-two studies were included in this review; the majority were case reports. Reported vascular sequela that occurred due to surgery were fusiform dilation of the carotid artery, stroke, vasospasm, hemorrhage, and aneurysm. Related conditions that emerged due to radiotherapy included Moyamoya syndrome and cavernoma. Cardiovascular morbidity and mortality often lead to hypothalamic obesity and metabolic syndrome in CP patients. Vascular damage is a rare complication of CP treatment. Surgical strategies should protect the surrounding hypothalamic and vascular structures. Patients receiving radiotherapy, particularly at a young age, should undergo magnetic resonance angiography monitoring to identify possible neurovascular sequela during post-treatment care.
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Background: Proton beam therapy (PBT) is being increas16ingly used to treat residual craniopharyngioma (CP) after hypothalamus-sparing surgery. Compared to photon-based radiation therapy (XRT) with PBT, less irradiation in the penumbra reduces the scattered dose to critical organs neighboring but outside the area of treatment, minimizing the risk of sequelae. Patients and methods: Between 2007 and 2019, 99 of 290 (34%) childhood-onset CP patients recruited in KRANIOPHARYNGEOM 2007 received external radiation therapy (RT) (65% PBT, 35% XRT). Outcome was analyzed in terms of survival, endocrinological and anthropometric parameters (BMI and height SDS), quality of life (QoL using PEDQOL), and functional capacity (FMH) with special regard to irradiation technique. Results: PBT became predominant (used in 43% and 72% of all irradiated patients registered within the first and second halves of the recruitment period, between 2008 and 2013 and 2013 and 2018, respectively). Five-year event-free survival rates after PBT or XRT were comparable (92% ± 4% vs. 91% ± 4%, p = 0.42) and higher than for the whole cohort since diagnosis, including non-RT patients (37% ± 4%). Radiation doses to the hypothalamus and pituitary did not differ between PBT and XRT. Endocrine deficits due to disturbances of the hypothalamic-pituitary axis (HPA) were already common before irradiation. During the first 5 years after CP diagnosis/RT, no differences between PBT, XRT, and non-RT CP patients concerning functional capacity and anthropometric parameters have been obtained. Only for the PEDQOL domain "physical function", parental-assessed QoL was lower 12 months after PBT versus XRT or non-RT patients. Conclusion: QoL, functional capacity, degree of obesity, and endocrinopathy varied over time from diagnosis, but by 5 years, there was no significant difference between PBT and XRT upfront or delayed, nor was there any compromise in historic survival rates, which remained high >90%. RT of any type is extremely effective at stabilizing disease after hypothalamic-sparing surgery. The purported specific benefits of PBT-reducing sequelae are not proven in this study where the organ of critical interest is itself diseased, increasing an urgent need to better address and treat the tumor-induced endocrine harm from diagnosis in dedicated pituitary services. Other hypothesized benefits of PBT versus XRT on vascular events and secondary cancers await longer comparison. Clinical trial registration number: https://clinicaltrials.gov/study/, identifier NCT01272622.
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Quality of life (QoL) is a critical component of aftercare in survivors of childhood-onset craniopharyngioma (CP). Visual impairment adversely affects QoL after CP. This study assessed the frequency of visual impairment in patients with CP and its association with QoL. This study analyzed vision-related QoL in patients recruited 2000-2019 in the prospective cohort studies KRANIOPHARYNGEOM 2000/2007. Ophthalmologic examinations were performed at diagnosis, three, 12, and 36 months, respectively after the diagnosis. The QoL (PEDQOL) scores, were also evaluated at three, 12, and 36 months, respectively after the CP diagnosis. Multivariable logistic regression was used to analyze factors associated with visual impairment during follow-up. One-hundred twenty patients were included in this study. On ophthalmological examination, visual impairment was observed in the majority of the patients (n = 84, 70%) at CP diagnosis. After surgery, vision was restored in 27 patients (32%) with visual impairment at diagnosis. In the first (p = 0.017) and third (p = 0.011) year after diagnosis, parents of patients with visual impairment reported lower social functioning (family). Reduced autonomy was found three years after diagnosis in self- (p = 0.029) and parental (p = 0.048) assessments. Next to visual impairment at diagnosis, no additional risk factors for visual impairment during follow-up could be identified. Visual impairment has a clinically relevant impact on QoL after CP. The visual status at CP diagnosis determines the visual outcome during follow-up. Early detection of visual impairment, regular QoL assessments, and risk-appropriate aftercare are recommended.Clinical Trial Registration KRANIOPHARYNGEOM 2000 (Clinical trial registration number: NCT00258453) and KRANIOPHARYNGEOM 2007 (Clinical trial registration number: NCT01272622).
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Craneofaringioma , Neoplasias Hipofisarias , Humanos , Craneofaringioma/complicaciones , Craneofaringioma/cirugía , Calidad de Vida , Estudios Prospectivos , Neoplasias Hipofisarias/cirugía , Trastornos de la Visión/complicacionesRESUMEN
Background: Craniopharyngiomas (CPs) are rare embryonic tumors. Clinical presentation and outcome of patients perinatally diagnosed with congenital CP (cCP) are not clear and refer mainly to a few case reports in the literature. The aim of this study was to analyze clinical presentation and outcome in patients with cCP. Study design: Three hundred and sixty-one patients diagnosed with adamantinomatous CP were recruited 2007-2022 in KRANIOPHARYNGEOM 2007/Registry 2019 and prospectively observed. In two cases, cCP was diagnosed prenatally and in one case on the second day of life. Pre- and perinatal diagnostic findings, postnatal evaluation, and therapeutic interventions and outcome in these three cases of cCP were analyzed. Results: All patients survived. One patient developed psychomotor retardation and a mild hemiparesis. Prenatal routine ultrasound examination led to the diagnosis of cCP. Tumor resection was performed during the early postnatal period (range: 11-51 days of age). Functional capacity, measured by Fertigkeitenskala-Münster-Heidelberg (FMH) was reduced in three and behavioral parameters, measured by the Strength and Difficulties Questionnaire (SDQ) were abnormal in two cases. Conclusion: cCP is a rare diagnosis with a prevalence of 0.83% in our study group. Compared to cases reported in the literature, the presented cases were treated immediately and had a better prognosis. Based on improvements of diagnostic and therapeutic techniques, prenatal diagnosis of cCP should lead to transfer prior to delivery of cCP patients to a specialized center for delivery and postnatal treatment of newborns with sellar masses by a multidisciplinary team to secure the improved prognosis of these patients. Significance statement: We previously reported that lower event-free survival rates after craniopharyngioma are associated with younger age at diagnosis. Perinatally diagnosed congenital craniopharyngiomas are very rare. This article presents three unique cases with congenital craniopharyngioma, comparing their diagnostics, therapy, and development. All three cases had surgery during the early postnatal period with sparing of the posterior hypothalamus. In each case, endocrinopathy was present at follow-up. Low functional capacity was reported in all cases and an abnormal total difficulties score in two cases. Compared to the literature, the presented cases had better prognosis in morbidity and mortality. This report and the review of the literature confirm the importance of a multidisciplinary approach in the diagnostic and treatment of the very rare condition of congenital craniopharyngioma.
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PURPOSE: Pediatric meningioma differs not only in its rare incidence from the adult meningioma, but also in its clinical characteristics. Many treatment approaches of pediatric meningioma are based on the study results of adult meningioma studies. The aim of this study was to explore the clinical and epidemiological characteristics of pediatric meningioma. METHODS: Data on pediatric patients diagnosed between 1982 and 2021 with NF2-associated or sporadic meningioma and recruited in the trials/registries HIT-ENDO, KRANIOPHARYNGEOM 2000/2007 and KRANIOPHARYNGEOM Registry 2019 were retrospectively analyzed for clinical characteristics, etiology, histology, therapy, and outcome. RESULTS: One hundred fifteen study participants were diagnosed with sporadic or NF2-associated meningioma at a median age of 10.6 years. There was a 1:1 sex ratio, with 14% of study participants suffering from NF2. 46% of the meningiomas were located hemispherically, 17% at the optic nerve/ intraorbital and 10% ventricularly. Multiple meningiomas were detected in 69% of NF2 patients and in 9% of sporadic meningiomas. 50% of the meningiomas were WHO grade I, 37% WHO grade II and 6% WHO grade III. Progressions or recurrences occurred after a median interval of 1.9 years. Eight patients (7%) died, 3 of them due to disease. The event-free survival was higher for WHO grade I than for WHO grade II meningioma patients (p = 0.008). CONCLUSIONS: The major difference to the preceding literature could be found in the distribution of different WHO grades and their influence on event-free survival. Prospective studies are warranted to assess the impact of different therapeutic regimens. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00258453; NCT01272622; NCT04158284.
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Neoplasias Meníngeas , Meningioma , Neurofibromatosis 2 , Adulto , Humanos , Niño , Adolescente , Meningioma/epidemiología , Meningioma/terapia , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/epidemiología , Neurofibromatosis 2/terapia , Neoplasias Meníngeas/epidemiología , Neoplasias Meníngeas/terapia , Estudios Retrospectivos , Progresión de la EnfermedadRESUMEN
OBJECTIVE: Craniopharyngiomas (CP) are rare malformational tumors. Clinical presentation and outcome of pediatric patients with CP with specific regard to age at diagnosis is not clear. The aim of this cohort study was to determine clinical presentation and outcome in these patients diagnosed at different ages at diagnosis. DESIGN: Seven hundred and nine patients diagnosed with CP were recruited from 1999 to 2021 in HIT-Endo and KRANIOPHARYNGEOM 2000/2007/Registry 2019 and prospectively observed. METHODS: Age at diagnosis was categorized as infants and toddlers (<2 years), early childhood (2-6 years), middle childhood (6-12 years), and early adolescence (12-18 years). Overall and event-free survival (EFS), functional capacity (FMH), and quality of life (QoL) (PEDQOL) were assessed. RESULTS: Severe obesity (body mass index [BMI] >3 standard deviation score [SDS]) was prevalent in 45.4% at last visit. A lower EFS but better QoL was observed in children with age at diagnosis <6 years compared with ≥6 years. Reduced functional capacity percentiles were associated with increased BMI-SDS at last visit (rho = -0.125, 95% confidence interval [CI; -0.21; -0.04]) and age at diagnosis <2 years. Posterior hypothalamic involvement and hypothalamic lesion (HL) were independent risk factors for reduced EFS (hazard ratio = 1.59, 95% CI [1.12-2.26]) and obesity at last visit (odds ratio = 2.94, 95% CI [1.73-5.08]). Age at diagnosis did not contribute to severe obesity and reduced QoL. CONCLUSIONS: Diagnosis of CP at age <6 years may help patients to adapt early to disabilities but may lead to a higher probability of CP relapse. Not age at diagnosis but posterior HL may be the contributing factor to severe obesity and a reduced QoL. CLINICAL TRIAL REGISTRATION NUMBERS: NCT00258453; NCT01272622; NCT04158284.
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Craneofaringioma , Obesidad Mórbida , Neoplasias Hipofisarias , Adolescente , Niño , Preescolar , Humanos , Lactante , Estudios de Cohortes , Craneofaringioma/complicaciones , Craneofaringioma/diagnóstico , Recurrencia Local de Neoplasia , Obesidad/complicaciones , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/complicaciones , Calidad de VidaRESUMEN
BACKGROUND: The prognostic impact of clinical risk factors and DNA methylation patterns in sonic hedgehog (SHH)-activated early childhood desmoplastic/nodular medulloblastoma (DMB) or medulloblastoma with extensive nodularity (MBEN) were evaluated to better identify patients at risk for relapse. METHODS: One hundred and forty-four patients with DMB (n = 99) or MBEN (n = 45) aged <5 years and treated with radiation-sparing approaches, including intraventricular methotrexate in 132 patients were evaluated. RESULTS: Patients with DMB had less favorable 5-year progression-free survival than MBEN (5y-PFS, 71% [DMB] vs. 93% [MBEN]). Patients aged >3 years were associated with more unfavorable 5y-PFS (47% [>3 years] vs. 85% [<1 year] vs. 84% [1-3 years]). DNA methylation profiles available (n = 78) were reclassified according to the 2021 WHO classification into SHH-1 (n = 39), SHH-2 (n = 38), and SHH-3 (n = 1). Hierarchical clustering delineated 2 subgroups among SHH-2: SHH-2a (n = 19) and SHH-2b (n = 19). Patients with SHH-2b medulloblastoma were older, predominantly displayed DMB histology, and were more often located in the cerebellar hemispheres. Chromosome 9q losses were more frequent in SHH-2b, while few chromosomal alterations were observed in SHH-2a. SHH-2b medulloblastoma carried a significantly increased relapse risk (5y-PFS: 58% [SHH-2b] vs. 83% [SHH-1] vs. 95% [SHH-2a]). Subclassification of SHH-2 with key clinical and cytogenetic characteristics was confirmed using 2 independent cohorts (total n = 188). Gene mutation analysis revealed a correlation of SHH-2a with SMO mutations. CONCLUSIONS: These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with a higher risk of relapse.
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Neoplasias Cerebelosas , Meduloblastoma , Humanos , Preescolar , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/genética , Proteínas Hedgehog/genética , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/radioterapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Cranioparyngiomas are rare low-grade embryonic malformational tumors of the sellar/parasellar region. The prognosis after diagnosis during childood and adolescence is influenced by (neuro)endocrine long-term sequelae. A legal status of the degree of disability (GdB), according to the German Social Code Book V that is worthy of support provides financial means for psychosocial integration and participation of craniopharyngioma survivors. PATIENTS AND METHODS: HIT-Endo is a German registry study on craniopharyngioma patients aged≤18 years at diagnosis . In a sample of 108 patients, the degree of disability and the association with endocrine, ophthalmological, neuropsychological (QLQ-C30; MFI-20; FMH-scale) and psychosocial parameters was analyzed after a mean follow-up period of 16 years. RESULTS: 47 patients (43%) did not receive a GdB or received a GdB of 30-40, 43 patients (40%) a GdB of 50-90 and 18 patients (17%) the maximal GdB of 100. Higher GdB were associated with lower education, higher body mass index standard deviation and a higher degree of visual impairment and hypothalamic involvement of the craniopharyngioma. Patients with a GdB of 100 reported loss in physical and cognitive function, dyspnea, and pain (QLQ-C30), as well as fatigue (MFI-20), and limitations in social and occupational contexts. They further had a lower functional capacity (German daily life ability scale (FMH)) compared to those with a smaller GdB. CONCLUSION: The GdB is associated with psychosocial and physical impairments and reflects the long-term consequences of craniopharyngioma. A low functional capacity may indicate a high GdB in later life of craniopharyngioma survivors.
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Craneofaringioma , Neoplasias Hipofisarias , Adolescente , Humanos , Craneofaringioma/complicaciones , Craneofaringioma/psicología , Estudios de Seguimiento , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/complicaciones , Pronóstico , Sobrevivientes , Calidad de VidaRESUMEN
BACKGROUND: Medulloblastoma is the most common malignant paediatric brain tumour, and cerebrospinal fluid (CSF) dissemination (M1 stage) is a high-risk prognostic factor. Criteria for CSF evaluation and for differentiating M0 from M1 stage are not clearly defined, and the prognostic significance of M1 stage in this context is unknown. PATIENTS AND METHODS: CSF investigations from 405 patients with medulloblastoma of the prospective multicenter trial HIT-2000 (HIirnTumor-2000) were reviewed. Data from 213 patients aged ≥4 years were related to 5-year progression-free (5y-PFS) and overall survival. RESULTS: Patients with cytological tumour dissemination only (M1 stage only) aged ≥4 years (n = 18) and patients with radiologically detected metastases (M2/3, n = 85) showed a worse 5y-PFS than M0 patients (n = 110) without signs of metastatic disease (5y-PFS 61.1% and 59.6% vs 80.7%; p < 0.02 and p < 0.01, log rank). Patients with positive samples drawn early after surgery who turned negative within 14 days postoperatively (n = 9) and patients with atypical cells (n = 6) showed a 5y-PFS similar to M0 patients. No tumour cells were detected in samples containing <10 nucleated cells. Analysis of cytological criteria showed a better predictive value for tumour cell clusters than ≥2 individual tumour cells. CONCLUSION: Based on our results, we suggest that CSF medulloblastoma staging should be performed 14 days postoperatively by lumbar puncture, and specimens should contain at least 10 nucleated cells. Cytological tumour dissemination alone (M1 stage only) appears a high-risk prognostic factor associated with an outcome comparable to M2/M3 stage. Tumour cell clusters seem to have a greater impact on prognosis than single tumour cells. This should be validated further.
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Neoplasias Encefálicas , Neoplasias Cerebelosas , Meduloblastoma , Líquido Cefalorraquídeo , Niño , Humanos , Pronóstico , Estudios Prospectivos , Medición de RiesgoRESUMEN
PURPOSE: To evaluate the clinical impact of isolated spread of medulloblastoma cells into cerebrospinal fluid without additional macroscopic metastases (M1-only). METHODS: The HIT-MED database was searched for pediatric patients with M1-only medulloblastoma diagnosed from 2000 to 2019. Corresponding clinical and molecular data was evaluated. Treatment was stratified by age and changed over time for older patients. RESULTS: 70 patients with centrally reviewed M1-only disease were identified. Clinical data was available for all and molecular data for 45/70 cases. 91% were non-WNT/non-SHH medulloblastoma (Grp3/4). 5-year PFS for 52 patients ≥ 4 years was 59.4 (± 7.1) %, receiving either upfront craniospinal irradiation (CSI) or SKK-sandwich chemotherapy (CT). Outcomes did not differ between these strategies (5-year PFS: CSI 61.7 ± 9.9%, SKK-CT 56.7 ± 6.1%). For patients < 4 years (n = 18), 5-year PFS was 50.0 (± 13.2) %. M1-persistence occurred exclusively using postoperative CT and was a strong negative predictive factor (pPFS/OS < 0.01). Patients with additional clinical or molecular high-risk (HR) characteristics had worse outcomes (5-year PFS 42.7 ± 10.6% vs. 64.0 ± 7.0%, p = 0.03). In n = 22 patients ≥ 4 years with full molecular information and without additional HR characteristics, risk classification by molecular subtyping had an effect on 5-year PFS (HR 16.7 ± 15.2%, SR 77.8 ± 13.9%; p = 0.01). CONCLUSIONS: Our results confirm that M1-only is a high-risk condition, and further underline the importance of CSF staging. Specific risk stratification of affected patients needs attention in future discussions for trials and treatment recommendations. Future patients without contraindications may benefit from upfront CSI by sparing risks related to higher cumulative CT applied in sandwich regimen.
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Neoplasias Cerebelosas , Irradiación Craneoespinal , Meduloblastoma , Neoplasias Cerebelosas/tratamiento farmacológico , Neoplasias Cerebelosas/terapia , Niño , Humanos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/terapia , Factores de RiesgoRESUMEN
BACKGROUND: Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive tumors occurring in early childhood. Published clinical data refer to retrospective, heterogeneously treated cohorts. Here, we describe the outcome of patients treated according to the prospective P-HIT trial and subsequent HIT2000-interim-registry. PATIENTS AND METHODS: Age-stratified treatment included carboplatin/etoposide induction, tandem high-dose chemotherapy ("CARBO/ETO + HDCT"), and response-stratified radiotherapy. Patients with centrally reviewed neuropathological and molecularly confirmed diagnosis of ETMR recruited within the P-HIT trial (2001-2011; n = 19), the HIT2000-interim-registry (2012-2014; n = 12), and earlier HIT trials (n = 4) were selected for analysis. RESULTS: Age-adjusted incidence rate was 1.35 per 1 million children (aged 1-4 years) in the years 2012-2014. Median age at diagnosis for 35 patients was 2.9 years. Metastases at diagnosis were detected in 9 patients. One patient died due to postoperative complications. For 30 patients with non-brainstem tumor location, 5-year progression-free survival (PFS) and overall survival (OS) were 35% and 47% after treatment with CARBO/ETO + HDCT (n = 17), compared to 0% and 8% with other treatments (n = 13, P[OS] = .011). All 4 patients with brainstem tumor died within 10 months after diagnosis. By multivariable analysis, supratentorial location: (HR [PFS]: 0.07 [95%CI: 0.01-0.38], P = .003), localized disease (M0): (HR [OS] M0, no residual tumor: 0.30 [95%CI: 0.009-1.09], P = .068; M0, residual tumor: 0.18 [95%CI: 0.04-0.76], P = .020), and CARBO/ETO + HDCT treatment (HR [OS]: 0.16 [95%CI: 0.05-054], P = .003) were identified as independent prognostic factors. Of 9 survivors, 6 were treated with radiotherapy (craniospinal 4; local 2). CONCLUSIONS: Our data indicate improved survival with intensified chemotherapy (CARBO/ETO + HDCT). However, despite intensive treatment, the outcome was poor. Thus, innovative therapies need to be evaluated urgently in an upfront setting.
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Neoplasias Encefálicas , Neoplasias de Células Germinales y Embrionarias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/uso terapéutico , Niño , Preescolar , Etopósido , Humanos , Quimioterapia de Inducción , Lactante , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Cerebral infarction (CI) is a known vascular complication following treatment of suprasellar tumors. Risk factors for CI, incidence rate, and long-term prognosis are unknown for patients with childhood-onset craniopharyngioma (CP). METHODS: MRI of 244 CP patients, recruited between 2007 and 2019 in KRANIOPHARYNGEOM 2007, were reviewed for CI. Risk factors for CI and outcome after CI were analyzed. RESULTS: Twenty-eight of 244 patients (11%) presented with CI based on reference assessment of MRI. One CI occurred before initial surgery and one case of CI occurred after release of intracystic pressure by a cyst catheter. 26 of 28 CI were detected after surgical tumor resection at a median postoperative interval of one day (range: 0.5-53 days). Vascular lesions during surgical procedures were documented in 7 cases with CI. No relevant differences with regard to surgical approaches were found. In all 12 irradiated patients, CI occurred before irradiation. Multivariable analyses showed that hydrocephalus and gross-total resection at the time of primary diagnosis/surgery both were risk factors for CI. After CI, quality of life (PEDQOL) and functional capacity (FMH) were impaired. CONCLUSIONS: CI occurs in 11% of surgically-treated CP cases. Degree of resection and increased intracranial pressure are risk factors, which should be considered in the planning of surgical procedures for prevention of CI.
RESUMEN
Adult medulloblastomas (MB) are rare. We investigated the genetic landscape and prognostic impact of genetic aberrations in a cohort of 117 adult medulloblastomas. Histological features and pathway activation were evaluated at the protein level; 14.5% showed wingless-type activation, 63.3% SHH activation, and 22.2% were classified as non-WNT/non-SHH-MB. Genome-wide copy number analysis was performed by molecular inversion probe array technology. MB-related genes were sequenced in WNT- and SHH-activated MBs. 79.7% of SHH-MBs showed desmoplastic/nodular histology; all other MBs had classic histology. WNT-MBs carried oncogenic CTNNB1 mutations in 88.2% and had monosomy 6 in 52.9%. In SHH-MBs, TERT promoter mutations occurred in 97%, mutations in PTCH1 in 38.2%, SMO in 15.5%, SUFU in 7.4%, and TP53-mutations in 4.1%. In all, 84.6% of non-WNT/non-SHH-MBs had an isochromosome 17q. A whole chromosomal aberration (WCA) signature was present in 45.1% of SHH-TP53-wild type (wt)-MBs and 65.4% of non-WNT/non-SHH-MBs. In 98 cases with survival data, WNT-MBs had a 5-year overall survival (OS) of 68.6%. SHH-MBs TP53wt type and non-WNT/non-SHH-MBs showed 5-year OS of 80.4% and 70.8%, respectively. TP53-mutant SHH-MBs represented a prognostically unfavorable entity; all patients died within 5 years. Patients with a WCA signature showed significantly increased OS (p = 0.011 for SHH-TP53wt-MBs and p = 0.048 for non-WNT/non-SHH-MBs).
Asunto(s)
Neoplasias Cerebelosas/genética , Citogenética , Meduloblastoma/genética , Mutación/genética , Adolescente , Adulto , Carcinogénesis/genética , Carcinogénesis/metabolismo , Neoplasias Cerebelosas/diagnóstico , Análisis Citogenético/métodos , Citogenética/métodos , Femenino , Humanos , Masculino , Meduloblastoma/diagnóstico , Persona de Mediana Edad , Fenotipo , Pronóstico , Adulto JovenRESUMEN
Background: Severe obesity and tumor relapse/progression have impact on long-term prognosis in pediatric brain tumor patients. Methods: In a cross-sectional study, we analyzed nuchal skinfold thickness (NST) on magnetic-resonance imaging (MRI) follow-up monitoring as a parameter for assessment of nuchal adipose tissue in 177 brain tumor patients (40 World Health Organization (WHO) grade 1-2 brain tumor; 31 grade 3-4 brain tumor; 106 craniopharyngioma), and 53 healthy controls. Furthermore, body mass index (BMI), waist-to-height ratio, caliper-measured skinfold thickness, and blood pressure were analyzed for association with NST. Results: Craniopharyngioma patients showed higher NST, BMI, waist-to-height ratio, and caliper-measured skinfold thickness when compared to other brain tumors and healthy controls. WHO grade 1-2 brain tumor patients were observed with higher BMI, waist circumference and triceps caliper-measured skinfold thickness when compared to WHO grade 3-4 brain tumor patients. NST correlated with BMI, waist-to-height ratio, and caliper-measured skinfold thickness. NST, BMI and waist-to-height ratio were associated with increased blood pressure. In craniopharyngioma patients with hypothalamic involvement/lesion or gross-total resection, rate and degree of obesity were increased. Conclusions: NST could serve as a novel useful marker for regional nuchal adipose tissue. NST is highly associated with body mass and waist-to-height ratio, and easily measurable in routine MRI monitoring of brain tumor patients.