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JOURNAL ONKOLOGIE – STUDIE

Cerebellar Mutism Syndrome Study

Rekrutierend

NCT-Nummer:
NCT02300766

Studienbeginn:
Oktober 2014

Letztes Update:
18.01.2024

Wirkstoff:
-

Indikation (Clinical Trials):
Infratentorial Neoplasms, Mutism

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Rigshospitalet, Denmark

Collaborator:
Odense University Hospital, Aarhus University Hospital, Aalborg University Hospital, Technical University of Denmark, Karolinska University Hospital, Skane University Hospital, University Hospital, Linkoeping, Uppsala University Hospital, Sahlgrenska University H

Studienleiter

Kjeld Schmiegelow, MD, Dr. med
Study Chair
Rigshospitalet, Denmark
Marianne Juhler, MD, Dr. med
Principal Investigator
Rigshospitalet, Denmark
Karsten Nysom, MD
Study Chair
Rigshospitalet, Denmark

Kontakt

Aske F Laustsen, MD, PhD stud
Kontakt:
Phone: +45 40218998
E-Mail: aske.foldbjerg.laustsen@regionh.dk» Kontaktdaten anzeigen

Studienlocations
(3 von 30)

Aarhus University Hospital
8000 Aarhus
DenmarkRekrutierend» Google-Maps
Ansprechpartner:
Niels Clausen, MD
Phone: +45 78451700
E-Mail: nc@dadlnet.dk

Karen O Møller, Nurse
Phone: +45 78451719
E-Mail: karemoel@rm.dk» Ansprechpartner anzeigen
Rigshospitalet
2100 Copenhagen
DenmarkRekrutierend» Google-Maps
Ansprechpartner:
Aske F Laustsen, MD, PhD stud
Phone: +45 40218998
E-Mail: aske.foldbjerg.laustsen@regionh.dk

Marianne Juhler, MD, Dr. med
Phone: +45 35452088
E-Mail: marianne.juhler@gmail.com» Ansprechpartner anzeigen
Turku University Hospital
Turku
FinlandNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Päivi Lähteenmäki
E-Mail: paivi.maria.lahteenmaki@tyks.fi

Marika Gronroos
E-Mail: marika.gronroos@tyks.fi» Ansprechpartner anzeigen
Hospital of Lithuanian University of Health Sciences Kauno klinikos
Kaunas
LithuaniaRekrutierend» Google-Maps
Ansprechpartner:
Rosita Kiudeline
E-Mail: rosikiud@gmail.com

Giedre Rutkauskiene
E-Mail: giedre.rutkauskiene@gmail.com» Ansprechpartner anzeigen
Uppsala University Hospital
Uppsala
SwedenRekrutierend» Google-Maps
Ansprechpartner:
Christoffer Ehrstedt
E-Mail: christoffer.ehrstedt@akademiska.se

Pelle Nilsson
E-Mail: pelle.nilsson@akademiska.se» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

Background:

Cancer accounts for 22 % of all deaths among children in Europe and is thus the leading

non-traumatic pediatric cause of death. Central nervous system (CNS) tumours constitute 25%

of all childhood cancers, and the majority of these are located in the posterior fossa. One

of the most troublesome late effects after neurosurgery for such a tumour is the cerebellar

mutism syndrome which is seen in up to 25% of the patients. It is characterized by mutism,

hypotonia, ataxia and irritability. The exact aetiology, risk factors, clinical course and

treatment have yet to be identified. The aim of this study is to accomplish that.

Method:

This is an observational prospective multicentre study that will include a minimum of 500

paediatric patients with posterior fossa CNS tumours from the Nordic countries. Additional

countries might be added later once the study is running. The study has started in fall 2014

in 20 centres from 5 Nordic countries. Prior to this a pilot study was performed on 43 Danish

adult patients to validate and fine-tune registration procedure. All patients will be treated

according to local standards, but clinical data will be collected and imaging will be

reviewed centrally.

To calculate the participation rate the annual number of included patients from each country

will be compared to the number of registered patients in the cancer registers of the

respective country and year.

A blood sample for genetic analysis will be collected from all patients. The patients'

neurology and speech functions will be examined both pre-operatively and repeatedly

post-operatively, including recording of standardised speech samples. All data will be

collected trough a, for the purpose developed, online database.

Registration of data

The following data will be registered at the following 5 time points:

1. Preoperatively Hospital and country, and patient related variables (date of birth,

handedness, bilingualism, sex and date of diagnosis). Medical history (Previous

neurological/neuropsychological/ psychiatric problems, comorbidities, previous

operations or other treatment for the tumour, previous regular use of any kind of

medication). Preoperative neurological status will be examined and a language and speech

test will be performed and recorded. If the patient is younger than 2 years a bedside

assessment of the speech will be performed instead of a test. A blood sample for genetic

analysis will be drawn together with the standard blood samples. Alternatively this can

be done at any time during follow-up.

2. Postoperatively within 72 hours of surgery Operation related variables (date, duration

and course of operation, surgical position, surgical approach, and tumour removal

method), complications, technology employed, preoperative hydrocephalus and estimated

completeness of tumour resection.

3. Postoperatively within 1-4 weeks from surgery Approximately 1-2 weeks post-op:

Postoperative language and speech status and for those older than 2 years, a recording

of a speech sample. Neurological examination. Glucocorticoid administration pre-, intra-

or postoperatively plus other medications used to treat the CMS postoperatively and

their effects. Kind(s) of imaging performed on the tumour pre- and postoperatively.

Approximately 4 weeks post-op: Development and treatment of postoperative intracranial

haematoma and hydrocephalus, leakage of cerebrospinal fluid and need for ventilator.

4. Postoperatively at about 2 months from surgery Postoperative development of CMS,

detailed survey of the status of CMS in those affected including recording of speech

sample and neurological examination. Medications used to treat the CMS since last

registration and their effects.

5. Postoperatively at about 12 months from surgery Language and neurological status

including a speech sample for those older than 2 years. Medications used to treat the

CMS since last registration and their effects. Other anti-cancer treatment given

(chemotherapy and/or radiotherapy). Results from the pathology department regarding the

kind of tumour histology and genetics. Registration of whether neuropsychological

assessment(s) have been performed. Kind(s) of imaging performed on the tumour since 1st

follow-up. Copies of the MRIs and descriptions performed pre-op, right after the

operation and approximately. 12 months post-op are obtained.

All registered data will be examined by a third party who will check for missing data or

misentries in order to ensure a high quality of the data. In case of missing data or

misentries the third party will contact the person who made the registration.

The database is administered by the children's cancer epidemiology group (CCEG) at Karolinska

Hospital in Stockholm, which is also responsible for the Swedish children's brain tumour

registry and the leukaemia database for the Nordic Society of Pediatric Hematology and

Oncology (NOPHO)

Other courses:

In case of acute surgery, coma etc. information about the study and the offer to participate

can be given within 7 days from the operation. In these cases preoperative data about the

patient can be obtained from the patient's medical record and/or from the parents, but a

preoperative speech sample cannot be performed. These patients will not be included in the

analysis of whether and how preoperative speech and language status affects the risk of

developing CMS, but will be included in all the other study analyses. Speech samples will be

performed postoperatively in exactly the same manner as in patients that were included before

operation to able to monitor the patient's speech postoperatively and register signs of the

CMS.

Should the patient have posterior fossa tumour surgery performed again during the 12 months

follow-up period, the patient will re-start the follow-up programme from that date. A

separate pre-op and all the post-op registrations will be performed again, and used in the

analysis of risk of first versus second or further surgery. New genetic blood samples will

not be necessary in these cases. Should the patient have posterior fossa tumour surgery

performed after the last 12 months follow-up, the patient will be offered to participate in

the study again and a new consent will have to be obtained. New genetic blood samples will

not be necessary in these cases.

If the patient leaves the study for any reason before the follow-up 12 months post-op, a

separate form will be filled out explaining why the patient left.

If the patient turns 18 while included in the study, a new consent to participate will have

to be given by the patient him- /herself.

Blood samples and analyses:

As soon as a patient has been registered, the study centre will request a 2 ml anticoagulated

blood sample for genetic profiling (Single-Nucleotide Polymorphism (SNP) analysis).

The investigators will use a newly developed single nucleotide polymorphism (SNP) sequencing

strategy that allows cost-effective mapping of 25-30.000 genetic polymorphisms within

biological domains that could potentially be linked to the development of CMS (e.g.

inflammation, vascularization, blood-brain-barrier markers, and apolipoprotein E and other

lipoprotein pathway genes). The genetic data will be linked to the clinical data to identify

genetic variants associated with the risk of CMS or the course of CMS. Specifically the

investigators will map all SNPs in all genes that are known or are likely to be linked to

these pathways, including mRNA binding sites and first order protein-protein interactions.

Rather than expecting large effects of single SNPs, the strategy of this approach is to use

front-line bioinformatics and pathway analyses to explore the additive effect of numerous

SNPs involved in the same biological pathway. This will identify high-impact pathways,

although with individual low-impact SNPs. The results obtained could guide future therapeutic

approaches to CMS.

If the custodial parents do not consent to their child contributing a blood sample to the

study, the child may still participate in the study, albeit not in the part involving genetic

analysis. The samples as well as the rest of the study data will be protected under the Act

on Processing of Personal Data and the Act on the Health Act.

All MRIs are analyzed by neuroradiologists with respect to tumour resection and

neuroradiographic signs associated with CMS.

All speech recording are analyzed by speech therapists with respect to signs associated with

CMS. The results of neuropsychological tests that may have been performed routinely will be

separately obtained and analyzed.

Power calculations:

For the surgical hypothesis, assuming that 35% of patients are operated with an approach that

has a lower risk of CMS (assumed to be 10%) and the remaining 65% of patients are operated

using other approaches that carries a 20% risk of CMS, the investigators will with 80% power

be able to identify a difference at a 5% significance level if the investigators include a

total of 450 patients.

For the genetic analysis, several pathways and SNP-profiles will be explored with appropriate

adjustments for multiple comparisons. Multiple SNPs will due to randomness be found to be

related with the risk of CMS. Their true biological significance will subsequently be

validated through internal validation, as the investigators will explore if other SNPs in the

same biological pathway, e.g. SNPs in the same genes but not the same haplotype or SNPs that

affect coding or regulatory regions in the identified risk-related genes are more

significantly associated with risk of CMS than randomly selected SNPs. Furthermore, the

genes/SNPs will be explored by bioinformatic predictions of the impact of the SNPs on

protein-folding, binding affinity etc. Once such high-risk SNPs/genes/pathways have been

identified and published, the investigators will attempt to have them confirmed in

independent patient cohorts from Europe or the US. Based on a projected overall risk of CMS

of 20%, a frequency of a specific SNP (or SNP-profile) of 30%, and a projected doubled risk

of CMS in the group that harbour the SNP (or SNP-profile), the investigators will with 90%

power be able to identify such a genetic predisposition at a 5% significance level, if a

total of 343 patients are included in the study. Thus, the study has sufficient power.

To analyze the effect of the above mentioned variables (surgical method, administration of

corticosteroid, handedness etc.) on the risk of developing CMS the investigators will perform

univariate and multivariate regression analyses as well as standard descriptive analyses.

These analyses will be performed using R.

Discussion:

The study will be the largest prospective multicenter study on cerebellar mutism syndrome to

date, and the first one of its kind to systematically gather detailed information about 1)

the surgical approaches least likely to cause the syndrome, 2) how the syndrome is best

treated, 3) the role of genetics and 4) differences in incidence and clinical course of the

syndrome for different patients.

The ultimate aim of the study is to reduce the incidence and improve the treatment of

cerebellar mutism syndrome and lead to harmonization of the treatment of CNS tumour patients

across the Nordic countries.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Age < 18 years at the date of first imaging showing this tumour

- Tumour in the cerebellum/4th ventricle/brainstem with intention to treat with surgical

resection or open biopsy. Second and further surgeries are also included.

- Informed consent from custodial parent(s)

Exclusion Criteria:

- None

Studien-Rationale

Primary outcome:

1. Development and progress of Cerebellar Mutism Syndrome (Time Frame - 1 year after surgery):
The development of CMS is determined by a survey developed Robertson et al. The correlation between the risk of developing CMS and different neurosurgical techniques, genomic variants, treatments, tumor types, comorbidities, neuroradiologic findings, handedness and preoperative language status will be explored.



Secondary outcome:

1. Development and progress of reduced speech output (Time Frame - 1 year after surgery):
Speech production that is severely reduced and limited to single words or short sentences which can only be elicited after vigorous stimulation

Quelle: ClinicalTrials.gov


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