Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Pain

Infratentorial Neoplasms

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Central Nervous System Depressants

All Drugs and Chemicals

Adjuvants, Anesthesia

Analgesics

Bupivacaine

Fentanyl

Patient in this group will receive 2 ml of bupivacaine 0.5% (up to a maximum of 2 mg/kg) subcutaneous under ultrasound guidance in the greater occipital nerve region bilaterally.

Patient in this group will receive the intraoperative standard of care(intraoperative intravenous fentanyl and paracetamol)

ultrasound guided Greater occipital nerve block with 2 ml of bupivacaine 0.5% (up to a maximum of 2 mg/kg) subcutaneous under ultrasound guidance in the greater occipital nerve region bilaterally.

ultrasound guided Greater occipital nerve block

control group C

Surgery within the posterior fossa is associated with the highest incidence and greatest severity of acute postoperative pain that may persist beyond the immediate postoperative period.

The utilization of local nerve blocks of the scalp in children may provide analgesia with stable hemodynamics while reducing the need for other anesthetics such as inhaled anesthetics and opioids. This could in turn result in less side effects, higher patient and family satisfaction, and better outcomes.

The use of ultrasound-guided greater occipital nerve block (GONB) for perioperative pain management of posterior fossa surgery in pediatrics is not previously reported.

Surgery within the posterior fossa is associated with the highest incidence and greatest severity of acute postoperative pain that may persist beyond the immediate postoperative period.

Despite a greater awareness of pain after all types of intracranial surgery, clinicians remain reluctant to administer opioids to patients undergoing intracranial surgery because the opioid side effects that may mask signs of neurologic decompensation.

Furthermore, opioids can depress minute ventilation, leading to hypercapnia and increased intracranial pressures. These concerns may be of greater relevance for surgery of the posteriorfossa. However, untreated, pain can also be detrimental. Patients in pain may appear agitated, uncooperative, and experience longer-term pain-related sequelae.

The utilization of local nerve blocks of the scalp in children may thus provide analgesia with stable hemodynamics while reducing the need for other anesthetics such as inhaled anesthetics and opioids: this could in turn result in less side effects, higher patient and family satisfaction, and better outcomes.

The use of ultrasound-guided greater occipital nerve block (GONB) for perioperative pain management of posterior fossa surgery in pediatrics is not previously reported.

The authors hypothesize that ultrasound-guided greater occipital nerve block (GONB) for perioperative pain management of posterior fossa is feasible and superior to conventional methods for perioperative pain management.

After institutional research ethics committee approval, 40 children aged (2-10 years), ASA physical status I or II, Glasgow Coma Scale (GCS) 15, scheduled for craniotomy for posterior fossa tumors will be recruited and a written informed consent will be obtained from the patient guardians.

Anesthetic management:

Patients will not receive any premedication. Upon arrival to the operating room heart rate, noninvasive blood pressure NBP and oxygen saturation SPO2 will be monitored using standard monitor (drȁger infinity vista XL) before inhalational induction of anesthesia using sevoflurane titration (2-8%). 20 or 22 G canula will be inserted after the patient is put to sleep. Anesthesia will be completed by fentanyl (2µg/kg) and atracurium 0.5mg/kg. if IV canula is present anesthesia will be induced by propofol (1-2 mg/kg), fentanyl (2µg/kg) and atracurium 0.5mg/kg After tracheal intubation anesthesia will be maintained using isoflurane 1% in oxygen and air (FIO2 0.6), atracurium infusion at a rate of 0.5 mg/kg/h. Controlled ventilation will be adjusted to maintain moderate hyperventilation (end tidal CO2 30-35 mmHg). A core temperature will be measured using nasopharyngeal probe and a Foley's catheter will be inserted in the urinary bladder. 22G radial arterial canula will be inserted for invasive blood pressure monitoring and blood sampling and central venous line (CVP) will be inserted under complete aseptic condition with ultrasound guidance and wide bore peripheral canula for fluid management.

Greater occipital nerve block:

After the patient is positioned in the prone position with mild neck flexion and after disinfection of the skin; the GON will be located in the short axis plane using the (M-Turbo TM) ultrasound system with a 6-13 MHz high-resolution linear ultrasound transducer (Sonosite, USA).

The ultrasound probe will be placed in a transverse plane over the classical block site, at the level of the superior nuchal line, with the center of the probe at about 2-3 cm lateral to the external occipital protuberance. The GON will be identified in the short axis plane, Then, under real-time scanning, A 22 G canula will be advanced guided with ultrasound using an in-plane (IP) technique from lateral to medial to position the tip of the canula exactly at the center of the nerve. Thereafter, 2 ml of bupivacaine 0.5% will be injected to block the nerve. This technique will then be repeated on the other side.

Vital signs (heart rate, arterial blood pressure, and SpO2) will be monitored continuously And recorded every 30 minutes intraoperatively, and at 2, 4, 6, 8, 12, 16, and 24 hours postoperatively. Bradycardia (heart rate less than 60 beats/minute) will be treated with atropine (0.02mg/kg IV). Fentanyl 0.5 µg /kg as rescue analgesia will be given if HR and systolic BP increased \>20% of base line up to maximum 5 µg/ kg. 15 mg/kg of IV paracetamol will be given at the beginning of dural closure at the end of the procedure for both groups.

Postoperative assessment and analgesic regimen:

Objective Pain Scale (OPS) will be assessed at 2, 4, 6, 8, 12, 16, and 24 hours postoperatively. The time to the first request of rescue postoperative analgesic will be: "the time interval between the onset of GONB and the first request to postoperative analgesia and or OPS score ˃2-3". When patients first complain of pain (OPS score ˃2-3) an intravenous paracetamol 15mg/kg will be given and will be repeated every 6 hours. Persistent or breakthrough pain will be managed with incremental intravenous morphine at a dose of 0.05mg/kg to maintain resting OPS at \< 2-3. Cumulative 24 hours analgesic consumption will be recorded.

An online randomization program (http://www.randomizer.org) will be used to generate random list and to allocate patients into two study groups. Random allocation numbers will be concealed in opaque closed envelops. The patient and investigator performing the block and assessing study outcomes will all be blinded to the study group allocation. The intraoperative study outcomes will be assessed by an anesthetist who is not involved in the block performance and postoperative data will be collected by PICU trained nurses who are blinded to the study groups.

Ultrasound-guided Greater Occipital Nerve Block in Children Undergoing Posterior Fossa Craniotomy

Ultrasound-guided Greater Occipital Nerve Block in Children Undergoing Posterior Fossa Craniotomy: Randomized, Controlled Study

the score has five items(systolic blood pressure, crying, movement,agitation and complain of pain) with a minimum of zero and a maximum of 2 for each item.

total score = SUM of all points for all parameters

* Minimum score: 0
* Maximum score: 10
* Maximum score if too young to complain of pain: 8 if the score is used with 5 items, a score exceeding the number 3 requires therapeutically effective analgesic. if the score is used with its 4 items, a score exceeding the number 2 requires therapeutic effective analgesic.

the time interval between the onset of GONB and the first request to postoperative analgesia and or OPS score ˃2- 3".

number of patients who develop scalp hematoma in the GONB group

number of patients who develop postoperative nausea and vomiting

systolic and diastolic arterial blood pressure.

Kasr El Aini Hospital

lecturer of anesthesia, SICU and pain management

Rare Diseases

Disease Progression

Genetic Predisposition to Disease

Medulloblastoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Disease Susceptibility

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Tumor, Childhood

Neuroepithelioma

Antineoplastic Agents

Antirheumatic Agents

Micronutrients

Cyclophosphamide

Carboplatin

Doxorubicin

Liposomal doxorubicin

Leucovorin

Vincristine

Cisplatin

Lomustine

Vinblastine

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Tubulin Modulators

Antimitotic Agents

Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.

Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy.

Total treatment duration is 48 weeks.

Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age.

Total treatment duration is 39 to 48 weeks.

Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to

* presence of metastasis
* germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year

Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks

LR Arm after Amendment (Protocol version 11- 17 Nov 2014):

Brain - 18.0 Gy in 10 daily fractions of 1.80 Gy Spine - 18.0 Gy in 10 daily fractions of 1.80 Gy Primary tumour boost - 36.0 Gy in 20 daily fractions of 1.80 Gy Total dose - 54 Gy Duration of radiotherapy 6 weeks

Radiotherapy without Carboplatin

Starts 6 weeks after radiotherapy. 6 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15, Regimen B: (cycles 2, 4, 6): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1.

Interval after cycle A: 6 weeks, after cycle B: 3 weeks, for a total duration of 27 weeks.

Cumulative doses of chemotherapy drugs: cisplatin 210 mg/m2, lomustine (CCNU) 225 mg/m2, vincristine 18 mg/m2, cyclophosphamide 6 g/m2.

Reduced-intensity maintenance chemotherapy

Brain - 23.40 Gy in 13 daily fractions of 1.80 Gy Spine - 23.40 Gy in 13 daily fractions of 1.80 Gy Primary tumour boost - 30.60 Gy in 17 daily fractions of 1.80 Gy Total dose - 54 G Carboplatin 35 mg/m2 5 times/week.

Radiotherapy with Carboplatin

Starts 6 weeks after radiotherapy. 8 cycles alternating Regimen A and Regimen B. Regimen A (cycles 1, 3, 5, 7): cisplatin 70 mg/m2 day 1, CCNU 75 mg/m2 day 1, vincristine 1.5 mg/m2 days 1, 8 and 15 Regimen B: (cycles 2, 4, 6, 8): cyclophosphamide 1 x 1000 mg/m2 days 1-2, vincristine 1.5 mg/m2 day 1.

Interval after cycle A: 6 weeks, after cycle B: 3 weeks. Duration 36 weeks. Cumulative doses of chemotherapy drugs: cisplatin 280 mg/m2, lomustine (CCNU) 300 mg/m2, vincristine 24 mg/m2, cyclophosphamide 8 g/m2, carboplatin 1050 mg/m2 (in randomized patients).

Maintenance chemotherapy

Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Boost to macroscopic metastases - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

WNT-HR < 16 years

Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 14.4 Gy in 8 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 50.4 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

WNT-HR >= 16 years

Doxorubicin 37,5mg/m² in 24h-infusion, days 1 and 2 (If administration of doxorubicin is not deemed appropriate, doxorubicin can be substituted by carboplatin 200mg/m²) VCR 1,5mg/m² (max. dose 2mg) in short infusion, days 1, 15, 29, 43 HD-MTX 5g/m²in two doses (0.5g/m² in 0.5h and 4.5g/m² in 23.5h), days 15 and 29 (+ Leucovorin) Carboplatin 200mg/m² in 1h-infusion, days 43, 44, and 45 MTX 2mg intraventricularly, days 1-4, 15, 16, 29, 30, 43-46

Induction Chemotherapy

* with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks
* clinical target volume (CTV): safety margin along typical spread 10 mm: 23.4.Gy in 13 fractions to CTV.
* focal RT boost to tumour bed and residual tumour (GTV) (boost: 30.6 Gy in 17 daily fractions of 1.8 Gy)

SHH-TP53 M0

craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 23.4 Gy in 13 daily fractions of 1.8 Gy Spine - 23.4 Gy in 13 daily fractions of 1.8 Gy Primary tumour boost - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (cranial) - 30.6 Gy in 17 daily fractions of 1.8 Gy Metastases boost (spinal) - 21.6 Gy in 12 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45.0 Gy in 25 daily fractions of 1.8 Gy

SHH-TP53 M+ (germline)

craniospinal radiotherapy with boost to tumour bed, residual tumour and metastatic deposits with VCR 1,5 mg/m2 (max. 2mg), once weekly during radiotherapy, for a maximum of 6 weeks Brain - 36.0 Gy in 20 daily fractions of 1.8 Gy Spine - 36.0 Gy in 20 daily fractions of 1.8 Gy Primary tumour boost - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (cranial) - 18.0 Gy in 10 daily fractions of 1.8 Gy Metastases boost (spinal) - 9.0 Gy in 5 daily fractions of 1.8 Gy Total dose to primary tumour - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to cranial metastases - 54.0 Gy in 30 daily fractions of 1.8 Gy Total dose to spinal metastases - 45 Gy in 25 daily fractions of 1.80 Gy

SHH-TP53 (somatic)

Weekly VBL (5mg/m², max. 10mg/dose) for 24 weeks

Vinblastin Maintenance

Francois Doz, Prof. Dr.

Till Milde, Dr. med.

The study PNET 5 MB has been designed for children with medulloblastoma of standard risk (according to the risk-group definitions which have been used so far; e.g. in PNET 4). With the advent of biological parameters for stratification into clinical medulloblastoma trials, the ß-catenin status will be the only criterion according to which study patients will be assigned to either treatment arm PNET 5 MB - LR or to PNET 5 MB - SR, respectively. The initial diagnostic assessments (imaging, staging, histology, and tumor biology) required for study entry are the same for both treatment arms. With the amendment for version 12 of the protocol, patients who have a WNT-activated medulloblastoma with clinically high-risk features can be included in the PNET 5 MB WNT-HR study, and patients with a high-risk SHH medulloblastoma with TP53 mutation (both somatic or germline including mosaicism) can be included in the PNET5 MB SHH-TP53 study.

Data on patients with pathogenic germline alteration or cancer predisposition syndrome, who cannot be included in any prospective trial due to unavailability or due to physician or family decision, can be documented within the observational PNET 5 MB registry.

The aim of the LR-study is to confirm the high rate of event-free survival in patients between the ages of 3 to 5 years and less than 22, with 'standard risk' medulloblastoma with a low-risk biological profile. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and low-risk biological profile, defined as ß-catenin nuclear immuno-positivity by immuno-histochemistry (IHC). Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 18.0 Gy to the craniospinal axis. Following radiotherapy, patients will receive a reduced-intensity chemotherapy with a total of 6 cycles of chemotherapy consisting of 3 courses of cisplatin, CCNU and vincristine alternating with 3 courses of cyclophosphamide and vincristine.

The aim of the SR-study is to test whether concurrent carboplatin during radiotherapy followed by 8 cycles of maintenance chemotherapy in patients with 'standard risk' medulloblastoma with an average-risk biological profile may improve outcome. Patients eligible for the study will be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI imaging) at diagnosis and average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC. Patients will have undergone total or near-total tumour resection and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the primary tumor and 23.4 Gy to the craniospinal axis. Following radiotherapy, patients will receive a modified-intensity chemotherapy with a total of 8 cycles of chemotherapy consisting of 4 courses of cisplatin, CCNU and vincristine alternating with 4 courses of cyclophosphamide and vincristine.

The primary aim of the WNT-HR study is to maintain a 3-year EFS over 80 %. The small number of patients does not allow neither conventional methods of test size and power, nor strict stopping rules. The 3-year EFS will be estimated by the Kaplan-Meier method at the end of the trial and its two-sided 95 % confidence interval will be calculated.

The primary endpoint of the SHH-TP53 study is event-free survival (EFS). The aim of the study is the comparison of EFS between patients receiving a dose reduced induction chemotherapy, radiotherapy and maintenance chemotherapy and a historic population from unpublished data.

International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

AN INTERNATIONAL PROSPECTIVE TRIAL ON MEDULLOBLASTOMA (MB) IN CHILDREN OLDER THAN 3 TO 5 YEARS WITH WNT BIOLOGICAL PROFILE (PNET 5 MB - LR and PNET 5 MB - WNT-HR), AVERAGE-RISK BIOLOGICAL PROFILE (PNET 5 MB -SR), OR TP53 MUTATION, AND REGISTRY FOR MB OCCURRING IN THE CONTEXT OF GENETIC PREDISPOSITION

Defined in 5 categorical variables:

no relapse, local relapse, distant relapse, local and distant relapse, death

measured as

1. subfertility (FSH \> 15 IU/L)
2. endocrine deficits (hormone supplementation necessary)
3. growth retardation (calculated as the difference in height standard deviation score from diagnose) 2 and 5 years after diagnosis and age of 18 years

measured on audiogram performed 2 years after diagnosis, grading according to Chang ototoxicity grading (Chang and Chinosornvatana 2010)

Measured as

1. presence, duration, and therapy of hydrocephalus symptoms (pre- and post-operatively)
2. presence of posterior fossa syndrome (cerebellar mutism survey after surgery, before radiotherapy)
3. cerebellar symptoms (brief ataxia rating scales 2 and 5 years after diagnosis and age of 18 years)
4. presence of symptoms for brain nerve dysfunction (2 and 5 years after diagnosis and age of 18 years)

measured with standardized questionnaires/ scores:

1. HUI3 (health status)
2. BRIEF (executive functions)
3. SDQ (behavioural outcome)
4. PedsQL (quality of life)
5. QLQ-C30 (quality of life)
6. MEES (neurological function, educational provision)
7. MFI (fatigue) 2 and 5 years after diagnosis and age of 18 years

measured as timely delivery of chemotherapy number of interruptions days during radiotherapy toxicities within 8 weeks after end of radiotherapy

measured by central MRI review postoperatively

measured 2 years after diagnosis grades 0, 1, 2, 3, 4

Deutsche Kinderkrebsstiftung

Universitätsklinikum Hamburg-Eppendorf

Surgical position

Sergio Bergese, MD

The main objectives of this study are comparison of the incidence of intraoperative air embolism and the extent of blood loss in patients undergoing posterior cranial fossa (PCF) and pineal region (PR) surgeries in sitting and horizontal position. Additionally, the overall treatment outcome, neurological functional outcome, degree of tumor removal, clinical course in the postoperative period, and the patient satisfaction will be compared between the groups.

This was a prospective observational study to assess the effects of patient positioning during craniotomies on surgical outcomes. Patients were distributed into 2 major groups based on the surgical position: sitting and horizontal. Each group was further divided into subgroups based on the type and location of the lesion. To achieve the study goals, comparison of the 2 approaches in equivalent patient groups was performed, including comparable demographics, diagnoses, topographic location of the lesions, anesthetic approaches, and surgical experience.

The operating surgeons decided patient positioning based on clinical judgment. Type of anesthesia was defined by the anesthesiologist in charge of the patient however, it was maximally standardized for both sites. All the surgeries were performed by neurosurgeons with sufficient experience of sitting craniotomies.

Sitting Versus Horizontal Position on Craniotomies

The Effects of Sitting Position on the Outcome During Surgery on Posterior Cranial Fossa and Pineal Region

All individual participant data that underlie results in a publication

Measured intraoperatively with transesophageal echocardiogram and/or PETCO2 levels

Indicated by surgeon description and/or postoperative imaging

Compared sensory-motor function, cranial nerve function and Glasgow scale before and after surgery.

Collected on phone script during follow-up phone call

Burdenko Neurosurgery Institute

Ohio State University

Carcinoma

Spinal Cord Neoplasms

Pinealoma

Brain Stem Neoplasms

Spinal Cord Diseases

Pineocytoma

Choroid Plexus Carcinoma

Pineoblastoma

Anti-Infective Agents

Pharmaceutical Solutions

Other Dietary Supplements

Ethanol

Perillyl alcohol

Glycerol

Enzyme Inhibitors

Perillyl Alcohol

Patients will receive IN NEO100 that will follow a dose titration design, followed by a standard dose escalation design to establish safety. Brain tumor delivery of NEO100 will be confirmed in each disease sub-type by surgical resection/needle biopsy only if clinically indicated and scheduled for clinical purposes and testing with residual tissue for NEO100 and the major metabolite of NEO100 (Perillic Acid).

The study will use a modified Fibonacci dose titration design, followed by a standard dose escalation design.

* Cohort 1: 192 mg NEO100, QID on a 28-day cycle
* Cohort 2: 288 mg NEO100, QID on a 28-day cycle
* Cohort 3: 384 mg NEO100, TID on a 28-day cycle;
* Cohort 4 (ceiling dose): 576 mg NEO100, BID on a 28-day cycle.

Patients undergoing surgical or needle biopsy (only when clinically indicated) will receive a minimum of four days IN NEO100 treatment prior to the procedure.

NEO100 is a purified form (\>98.5%) of the naturally occurring monoterpene perillyl alcohol.

NEO100 drug product is a non-sterile solution for intranasal administration. It is compounded as a 10% solution in a 50:50 mixture of ethanol:glycerol.

NEO100

Chris Beardmore

Chloe Richmond

This is an open label, Phase 1b safety, dose-finding, brain tumor delivery, and pharmacokinetics study of intranasal NEO100 in patients with pediatric-type diffuse high grade gliomas. Patients will receive IN NEO100 that will follow a dose titration design, followed by a standard dose escalation design to establish safety. Brain tumor delivery of NEO100 will be confirmed in each disease sub-type by surgical resection/needle biopsy only if clinically indicated and scheduled for clinical purposes and testing with residual tissue for NEO100 and the major metabolite of NEO100 (Perillic Acid).

NEO100 drug product is a non-sterile solution for intranasal administration.

A feature of the clinical trials of NEO100 is to investigate the efficacy of this drug when it is delivered intranasally. Based on the general body of data on intranasal drug delivery, as well as the promising results from clinical studies in which perillyl alcohol was delivered intranasally, NeOnc expects that intranasal administration of NEO100 will allow rapid and more selective delivery of therapeutic levels of the drug to the brain, while minimizing systemic toxicity and first pass metabolism.

The study is a dose titration 1+1 design with a modified Fibonacci dose escalation, followed by a expansion design, used to determine the maximum tolerated dose and to select a recommended Phase 2 dose (RP2D). The starting dose of 192 mg mg/dose administered QID, on a 28-day cycle, is one dose below the safe dose administered to adults in a Phase 1/2a study. Dosing will increase using a modified Fibonacci dose escalation. The daily dose will start at 768 mg/day, and rise to 1,152 mg/day, which is also the safe dose administered to adults in a Phase 1/2a study.

The study is open to patient with Pediatric-type high grade glioma: Newly diagnosed and recurrent Diffuse Midline Glioma, H3 K27-altered; Diffuse hemispheric glioma, H3 G34-mutant, grade III and IV diffuse pediatric-type HGG, H3-wildtype and IDH-wildtype (including spinal cord tumors); Recurrent malignant tumors involving the brainstem or posterior fossa (choroid plexus carcinoma, CNS embryonal tumors, and pineoblastoma).

A Study of the Safety, Dosing, and Delivery of NEO100 in Patients With Pediatric Brain Tumors

An Open Label, Phase 1b Safety, Dose-finding, Brain Tumor Delivery, and Pharmacokinetics Study of Intranasal NEO100 in Patients With Pediatric-type Select Brain Tumors

Assess the safety and tolerability of increasing dose levels of intranasally administered NEO100 using the NCI CTCAE (version 5.0) for reporting of non-hematologic AEs

Assess the maximum tolerated dose (MTD) of intranasally administered NEO100 using the NCI CTCAE (version 5.0) for reporting of non-hematologic AEs

Confirm brain tumor delivery by measuring levels of NEO100 (POH) and its metabolite perillic acid (PA) in postsurgical tumor tissue in patients with pediatric-type brain tumors (measured in ng/mg).

To confirm blood brain barrier (BBB) penetration of NEO100 by measuring the concentration of NEO100 and its metabolite in resected tumor tissue.

Pharmacokinetic parameters of NEO100 metabolite perillic acid in the resected tumor tissue as measured by peak plasma concentration (Cmax).

Pharmacokinetic parameters of NEO100 metabolite perillic acid in the resected tumor tissue as measured by the time to peak plasma concentration (Tmax).

Pharmacokinetic parameters of NEO100 metabolite perillic acid in the resected tumor tissue as measured by the area under the plasma concentration vs time curve (AUC).

Objective CNS tumor response to NEO100 as determined by RANO 2.0 criteria.

Neonc Technologies, Inc.

Respiratory Tract (Lung and Bronchial) Diseases

Hyperventilation

Respiration Disorders

Respiratory Tract Diseases

Signs and Symptoms, Respiratory

Oculocerebral Syndrome With Hypopigmentation

• Group 1: hyperventilation (ETco2 25-30 mm Hg) for 20 minutes that will start immediately after skin incision followed by normoventilation (ETco2 31-35 mm Hg) for another 20 minutes.

• Group 2: normoventilation (ETco2 31-35 mm Hg) for 20 minutes immediately after skin incision followed by hyperventilation (ETco2 25-30 mm Hg) for another 20 minutes.

evaluation of the changes of cerebral oxygen saturation during hyperventilation and normo-ventilation (using near-infrared spectroscopy) in pediatrics undergoing posterior fossa tumor resection.

cerebral oximetry

The aim of this study is to evaluate the changes of cerebral oxygen saturation during hyperventilation and normo-ventilation (using near-infrared spectroscopy) in pediatrics undergoing posterior fossa tumor resection.

Introduction:

Hyperventilation has been used for intraoperative brain relaxation for decades, Interestingly, this common practice is not based on robust evidence .

The mechanism of brain relaxation secondary to hyperventilation is attributed to the hypocapnia induced cerebral vasoconstriction and the subsequent reduction of cerebral blood volume (CBV) and intracranial volume. The CBV reduction is accompanied by the reduction in cerebral blood flow that could render the brain at ischemic risk, if the cerebral metabolic activity remains the same before and after hyperventilation. So, it is possible that inadvertent cerebral ischemia may outweigh the benefits of hyperventilation and should be subjected for further investigation.

Cerebral near-infrared spectroscopy (NIRS) is a useful non-invasive tool for regional cerebral oxygen saturation (rScO2) monitoring, which provides continuous, real time information on the balance between cerebral oxygen delivery and consumption.

Cerebral oximetry monitoring had the ability to detect clinically silent episodes of cerebral ischemia in a variety of clinical settings which could be an important safeguard for cerebral function.

Hyperventilation had been shown to significantly reduce cerebral oxygenation using near-infrared spectroscopy in patients undergoing elective abdominal surgery.

Multiple studies have shown that prolonged hyperventilation correlated with poor outcome especially in brain injured patients. 5,6 However, there is still a lack of evidence on the relationship between hyperventilation and neurological outcome in patients having craniotomy.

However, to the best of the investigator's knowledge no previous randomized controlled trials had studied the effect of hyperventilation versus normo-ventilation on cerebral oximetry in pediatrics undergoing posterior fossa tumor surgeries.

V. Study procedure:

This is a prospective, randomized controlled trial with a two-period crossover design so that the patient can act as a control to himself. Enrolled patients are children (1-6 years old) undergoing posterior fossa tumor resection. Prior to anesthetic induction, the two sensors (SAFB-SM, Covidien, Dublin, Ireland) for near-infrared spectroscopy (INVOS 5100C, Covidien, Dublin, Ireland) will be applied on the left and right sides of the forehead with the caudal border approximately 1 cm above the eyebrows to measure regional oxygen saturation (rSO2). A bispectral index (BIS) sensor will also be fixed on the left forehead (Model QUATRO, Covidien, Dublin, Ireland) to monitor the depth of anesthesia. Both sensors will be fixed to their positions using adhesive pads to avoid removal during positioning and soaking with betadine solution. Baseline values for cerebral oxygen saturation will be obtained using NIRS monitor, Standard monitors (electrocardiogram, non-invasive blood pressure, pulse oximeter) will be applied to all patients. The anesthetic management will be standardized for all patients as follows:

General anesthesia will be induced by inhalational agent 'sevoflurane' until intravenous line is secured then Fentanyl (1-2 µg/kg), Propofol (1-2 mg/Kg) will be given intravenously. Intubation will be facilitated by Atracurium (0.5 mg/kg) and confirmed by capnography. Nasopharyngeal temperature probe will be inserted for monitoring of core body temperature which will be kept between 36.5-37 C using warming blankets. A 22 G arterial cannula will be placed in the left radial artery and baseline ABG will be obtained to correlate value of Etco2 and Paco2. Anesthesia will be maintained with isoflurane in oxygen 40% and will be adjusted to maintain BIS between 40 and 60 and Atracurium infusion (0.5 mg/kg/hr). Central venous line will be inserted in the right internal jugular vein under complete aseptic condition under ultrasound guidance, wide bore peripheral cannula will be inserted for fluid management and a Foley's catheter will be inserted in the urinary bladder for urine output monitoring. Patients will be positioned in the prone position with the arms positioned and secured at the patient's side and after careful padding of the pressure points; the patient head will be supported on the forehead using a horseshoe adapter. Slight neck flection will be permitted till the anesthetist can pass two fingers easily between the chin and the chest to allow for optimum surgical exposure. Patients will be randomly assigned using concealed envelopes, according to a computer-generated random number to one of the following two treatment sequences:

* Group 1: hyperventilation (ETco2 25-30 mm Hg) for 20 minutes that will start immediately after skin incision followed by normoventilation (ETco2 31-35 mm Hg) for another 20 minutes.
* Group 2: normoventilation (ETco2 31-35 mm Hg) for 20 minutes immediately after skin incision followed by hyperventilation (ETco2 25-30 mm Hg) for another 20 minutes. The ventilation strategies will be achieved using volume-controlled mode with a tidal volume of 8 ml/kg, I/E ratio:1/2 and ETco2 will be maintained at the desired range by adjusting the respiratory rate. Positive end-expiratory pressure (PEEP) will not be applied. After removal of the bone flap and exposure of the dura matter, a 20-gauge plastic cannula will be inserted into the subdural space along the surface of the brain. This will be connected to a calibrated pressure transducer via a length of polyethylene high pressure tubing filled with normal saline. The transducer will be zeroed at ear level. During the study period, the mean subdural pressure will be recorded at 2 minutes intervals at the end expiratory phase.

Assessment phase 1: An arterial blood sample will be obtained immediately after skin incision for blood gas analysis to determine the difference between arterial and end-tidal carbon dioxide tension (Pa-ETCO2). Ventilation and ETCO2 will be kept constant for at least 20 min, which is long enough for stabilization of any vascular responses to the change in Paco2. At the end of the equilibration period (20 minutes), another arterial blood sample will be obtained to confirm that the targeted Paco2 (was achieved. The neurosurgeon, unaware of the anesthetic and ventilatory management provided, will be then asked to score the brain bulk according to a four-point scale as follows:

1. Excellent with no swelling
2. Minimal swelling, acceptable
3. Swollen but no treatment required
4. Swollen, needing treatment. After this assessment, ventilation will be changed immediately according to group assignment.

Assessment phase 2: Another 20 min of equilibration will be allowed and measurements will be repeated as previously described. During the whole period of study (40 minutes), the cerebral oximetry will be recorded at 5 minutes intervals. During this period factors that may affect cerebral oximeter will be controlled by maintaining position of the patient head, (normothermia with temperature at 36.5-37 C), within 20% of the base line blood pressure using increments of ringer solution and ephedrine boluses as appropriate, maintain PH 7.35-7.45, Hb level around 10 gm/dl guided by blood loss and repeated measurements of Hb in ABG and blood glucose level between 80-180 mg/dl. The study will be ended at this point, the subdural cannula will be removed, and surgery will proceed as normal. Specific or routine interventions for brain swelling such as a change in body position or diuretic therapy with mannitol or furosemide will not be administered until the study had ended. However, for ethical reasons, interventions will be made if requested by the surgeon and the patient will be then withdrawn from the study. Data will be collected by an independent blinded anesthesiologist using a data collection form.

• Measurement tools:

* Demographic and categorical characteristics including patient's age in years, weight in Kg, gender, type of the procedure( 4th ventricular, medulloblastoma,... )
* Both NIRS values at baseline and every 5 minutes during each phase of the study
* Subdural intracranial pressure (ICP) every 2 minutes during each phase of the study
* End tidal co2 every 5 minutes during each phase of the study
* Paco2 baseline and at the end of each phase of ventilation (20 minutes following start of phase 1 assessment and 20 minutes after start of phase 2 assessment)
* Heart rate and mean arterial blood pressure every 10 minutes.
* Brain relaxation score

The Effect of Different Ventilation Strategies on Cerebral Oxygenation Using Near Infrared Spectroscopy (NIRS) in Pediatrics Undergoing Posterior Fossa Tumor Surgery

The Effect of Different Ventilation Strategies on Cerebral Oxygenation Using Near Infrared Spectroscopy (NIRS) in Pediatrics Undergoing Posterior Fossa Tumor Surgery: Randomized Controlled Cross Over Study

NIRS value at the end of phase 1 assessment in each group

Brain relaxation score: four-point scale as follows:

1. Excellent with no swelling
2. Minimal swelling, acceptable
3. Swollen but no treatment required
4. Swollen, needing treatment. the higher the score the higher the intracranial pressure

lecturer of anesthesia

Neoplasm Metastasis

Neoplastic Processes

Posterior Fossa Irradiation 37.5 Gy in 2.5 Gy fractions+Radiosurgical boost; Follow up:Contrast enhanced MRI \& Mini Mental Status Examination

Posterior Fossa Irradiation-total dose of 37.5 Gy in 2.5 Gy fractions administered via conformal beams.

Radiosurgical boost-total dose administered to each lesion will be titrated to the size of the metastatic focus as follows:

Maximum Tumor Diameter:\<2.0 cm; Assigned Dose:24 Gy. Maximum Tumor Diameter:2.1-3.0 cm;Assigned Dose:18 Gy. Maximum Tumor Diameter:3.1-4.0 cm;Assigned Dose:15 Gy.

Irradiation plus Stereotactic Radiosurgery

Ben Corn, Prof.

Marina Gurman

Vika Gurevich

Andrew Kanner, M.D.

Deborah Blumenthal, M.D.

Felix Bokstein, M.D.

The aggregate of data pertaining to brain metastases suggests that optimal results are achievable with a 2-pronged approach that addresses both the specific focus (with surgery or radiosurgery) and the surrounding brain parenchymal tissue that may harbor micrometastases. Patterns of failure following treatment of metastases that arise in the posterior fossa have not been reliably defined. Although most would agree that radiosurgery alone is not sufficient treatment for focal metastases in the cerebellum, it may be possible to deliver less than WBI as an "expanded port" beyond the SRS volume.

The current study acknowledges that at least two therapeutic modalities are requisite for patients with cerebellar metastases but hypothesizes that it is unnecessary to extend the treatment of ostensibly uninvolved brain tissue beyond the limits of the posterior fossa. In so doing, it is hoped that the putative advantage derived from foregoing whole brain irradiation (e.g., reduction in neurocognitive impairment) will not be at the expense of excessive surpratentorial failure.

SCHEMA:

* Posterior Fossa Irradiation as defined by diagnostic MRI and CT simulation.
* 37.5 Gy in 2.5 Gy fractions administered via conformal beams.
* Radiosurgical boost (with dose titrated to parameters of RTOG 9005).
* Contrast enhanced MRI will be obtained at baseline and then at 3, 6, and 12 months following completion of posterior fossa irradiation.
* The Mini Mental Status Examination will be used to evaluate global cognitive function at baseline and then at 3, 6, and 12 months following completion of posterior fossa irradiation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Ultrasound-guided Greater Occipital Nerve Block in Children Undergoing Posterior Fossa Craniotomy	NCT03762343	Posterior Fossa...	ultrasound guid... control group C	2 Years - 10 Years	Kasr El Aini Hospital
International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma	NCT02066220	Brain Tumors	Radiotherapy wi... Reduced-intensi... Radiotherapy wi... Maintenance che... WNT-HR < 16 yea... WNT-HR >= 16 ye... Induction Chemo... SHH-TP53 M0 SHH-TP53 M+ (ge... SHH-TP53 (somat... Vinblastin Main...	3 Years - 21 Years	Universitätsklinikum Hamburg-Eppendorf
Sitting Versus Horizontal Position on Craniotomies	NCT03364283	Craniotomy Brain Tumor	Surgical positi...	18 Years - 75 Years	Ohio State University
A Study of the Safety, Dosing, and Delivery of NEO100 in Patients With Pediatric Brain Tumors	NCT06357377	Pediatric Tumor... Pediatric Tumor... Diffuse Midline... Pediatric Tumor... Pineocytoma Choroid Plexus ... Spinal Cord Tum... High Grade Glio...	NEO100	5 Years - 18 Years	Neonc Technologies, Inc.
Ultrasound-guided Greater Occipital Nerve Block in Children Undergoing Posterior Fossa Craniotomy	NCT03762343	Posterior Fossa...	ultrasound guid... control group C	2 Years - 10 Years	Kasr El Aini Hospital
The Effect of Different Ventilation Strategies on Cerebral Oxygenation Using Near Infrared Spectroscopy (NIRS) in Pediatrics Undergoing Posterior Fossa Tumor Surgery	NCT04232059	Infratentorial ... Hyperventilatio... Craniotomy	cerebral oximet...	1 Year - 6 Years	Kasr El Aini Hospital
The Role of Posterior Fossa Irradiation (PFI) Plus Stereotactic Radiosurgery (SRS) for Cerebellar Metastases	NCT00781209	Neoplasm Metast...	Irradiation plu...	18 Years -	Tel-Aviv Sourasky Medical Center
The Effect of Different Ventilation Strategies on Cerebral Oxygenation Using Near Infrared Spectroscopy (NIRS) in Pediatrics Undergoing Posterior Fossa Tumor Surgery	NCT04232059	Infratentorial ... Hyperventilatio... Craniotomy	cerebral oximet...	1 Year - 6 Years	Kasr El Aini Hospital
Sitting Versus Horizontal Position on Craniotomies	NCT03364283	Craniotomy Brain Tumor	Surgical positi...	18 Years - 75 Years	Ohio State University

Spots Global Cancer Trial Database for posterior fossa