Neuroblastoma in children aged =1 to =21 years
Cancer
Malignant neoplasm of adrenal gland

Current intervention as of 25/03/2019:
Investigational medicinal products: bevacizumab, irinotecan, temozolomide, topotecan, dinutuximab beta, cyclophosphamide

Arm T:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks

Arm BT:
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks

Arm IT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Duration of intervention: 18 weeks

Arm BIT:
Temozolomide 100 mg/m2 per day oral on days 1-5 every 3 weeks
Irinotecan 50 mg/m2 per day intravenous on days 1-5 every 3 weeks
Bevacizumab 15 mg/kg intravenous on day 1 every 3 weeks
Duration of intervention: 18 weeks

Arm TTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks

Arm BTTo:
Topotecan 0.75 mg/m2/day intravenous on days 1-5 every 4 weeks
Temozolomide 200 mg/m2 per day oral on days 1-5 every 4 weeks
Bevacizumab 10mg/kg intravenous on days 1 and 15 every 4 weeks
Duration of intervention: 24 weeks

Arm dBT
Dinutuximab beta 10 mg/m2/day 24-h infusion on days 1-7 every 4 weeks
Temozolomide 200 mg/m2/day oral on days 1-5 every 4 weeks
Duration of intervention: 24 weeks

Arm dBTTo
Dinutuximab beta 10 mg/m2/day 24-h infusion on da

Kriterien zur Teilnahme an der Studie

Inclusion criteria:
Disease specific
1. Histologically proven neuroblastoma as per International Neuroblastoma Staging System (INSS) [1] definition
2. Relapsed or refractory neuroblastoma
2.1. Relapsed: any relapsed or progressed high-risk neuroblastoma
2.2. Refractory high risk disease: Lack of adequate response to frontline therapy that precludes the patient from proceeding to consolidation therapies (e.g myeloablative chemotherapy)
3. Measurable disease by cross sectional imaging (RECIST) or evaluable disease (uptake on MIBG scan with or without bone marrow histology). Patients with only bone marrow detectable disease (bone marrow aspirate or trephine) are NOT eligible for the study

General
1. Age =1 to =21 years
2. Informed consent from patient, parent or guardian

Performance and organ function
1. Performance Status:
1.1. Lansky = 50%, Karnofsky = 50% or ECOG =3
(Patients who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score)
2. Life expectancy of =12 weeks
3. Bone marrow function (within 72 hours of eligibility assessment):
No bone marrow disease:
1. Platelets = 75 x 109/L (unsupported for 72 hours)
2. ANC = 0.75 x 109/L (no G-CSF support for 72 hours)
3. Haemoglobin > 7.5 g/dL (transfusions allowed)
Bone marrow disease:
1. Platelets = 50 x109/L (unsupported for 72 hours)
2. ANC =0.5 x 109/L (no G-CSF for 72 hours)
3. Haemoglobin > 7.5 g/dL (transfusions allowed)
4. Renal function (within 72 hours of eligibility assessment):
4.1. Absence of clinically significant proteinuria (early morning urine dipstick =2+). When the dipstick urinalysis shows a proteinuria > 2+, a protein:creatinine (Pr/Cr) ratio must be < 0.5 or a 24 hour protein excretion must be < 0.5g
4.2. Serum creatinine =1.5 ULN for age, if higher, a calculated GFR (radioisotope) must be = 60 ml/min/1.73 m2
5. Liver function (within 72 hours of eligibility assessment): AST and ALT =2.5 ULN and total bilirubin =1.5 ULN. In case of liver metastases, AST and ALT =5 ULN and total bilirubin =2.5 ULN
6. Cardiac function, shortening fraction =29% on echocardiogram
7. Coagulation, patients not on anticoagulation must have an INR =1.5 and APTT =1.5 ULN for age. Anticoagulation is permitted as long as the INR or APTT is within therapeutic limits (according to the medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least two weeks at the time of study enrolment. Blood pressure below 95th centile for age and sex. Use of antihypertensive medication is permitted
8. Males or females of reproductive potential may not participate unless they agree to use an effective contraceptive method, for the duration of study therapy and for up to 6 months after the last dose of trial drugs. A negative urine pregnancy test must be obtained within 72 hours prior to dosing in females who are post-menarche

Ausschlusskriterien

Exclusion criteria:
1. Previous treatment with bevacizumab, temozolomide, irinotecan or any combination of these drugs
2. Known hypersensitivity to:
2.1. Any study drug or component of the formulation
2.2. Chinese hamster ovary products or other recombinant human or humanised antibodies
3. Prior severe arterial thrombo-embolic events (e.g. cardiac ischemia, cerebral vascular accident, peripheral arterial thrombosis)
4. Any ongoing arterial thrombo-embolic events
5. Patient less than (at point of eligibility assessment):
5.1. 48 hours post bone marrow aspirate/trephine
5.2. 48 hours post central line insertion
5.3. Four weeks post major surgery
5.4. One week post core biopsy
5.5. Two weeks from prior chemotherapy
5.6. Six weeks from prior craniospinal or MIBG therapy and two weeks from radiotherapy to the tumour bed
5.7. Eight weeks from prior myeloablative therapy with haematopoeitic stem cell rescue (autologous stem cell transplant)
5.8. Three months from prior allogeneic stem cell transplant
5.9. Two weeks from last administration of an IMP in an IMP-trial
6. Bleeding metastases (patients with CNS metastases can be enrolled as long as the metastases are not bleeding)
7. Invasion of major blood vessels
8. Use of enzyme inducing anticonvulsants within 72 hours of eligibility assessment
9. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e. in the absence of therapeutic anticoagulation)
10. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to study enrolment
11. Pregnant or lactating patient
12. Any uncontrolled medical condition that poses an additional risk to the patient (i.e. haemoptysis, non-healing, bone fracture, wound/ulcer)
13. Low probability of treatment compliance
14. Planned immunisation with live vaccine

Coronary artery disease
Circulatory System
Chronic ischaemic heart disease

Ivabradine/placebo tablets for up to 48 months.

Kriterien zur Teilnahme an der Studie

Inclusion criteria:
1. Aged 55 years or older
2. Male or female
3. Patients with stable coronary artery disease without clinical heart failure
4. Sinus rhythm and resting heart rate equal or higher than 70 bpm

Ausschlusskriterien

Exclusion criteria:
1. Unstable cardiovascular condition
2. Contra-indication to ivabradine

Pediatric palliative and intensive care, pediatric and neonatal diseases
Neonatal Diseases
Pediatric palliative and intensive care

This cross-sectional prospective study included a convenience sample of 34 (updated 02/09/2019, previously: 33) participating PICUs/NICUs representing 18 countries from the Americas, Europe, Asia, and Africa.
Two questionnaires with multiple choice and open-ended questions were applied to all centers to develop detailed descriptions of the participating units.
Questionnaire 1 focused exclusively on unit infrastructure, technology availability, and personnel ratios. Questionnaire 2 gathered further data on personnel, policies, and limited clinical and demographic data on a small sample of currently admitted patients.
Based on the IPPC recommendations, Questionnaire 2 inquired about practices related to the IPPC (The Initiative for Pediatric Palliative Care (IPPC): Quality domains, goals and indicators for family-centered care of children living with life-threatening conditions) domains:
1. Holistic care
2. Family support
3. Child-family unit involvement in care
4. Control of pain and other symptoms
5. Continuity of care
6. Support for grief and bereavement
The sum of these data reflects important aspects of the models of care employed in participating PICUs

Kriterien zur Teilnahme an der Studie

Inclusion criteria:
1. PICUs/NICUs
2. Local IRB approval to take part in the study

Ausschlusskriterien

Exclusion criteria: ICUs that are not solely for pediatric/neonatal patients.

Breast cancer
Cancer
Malignant neoplasm of breast

Arm A - Continuous letrozole 2.5 mg daily for 5 years
Arm B - Intermittent letrozole 2.5 mg daily for first 9 months of years 1 through 4, followed by 12 months in year 5

Kriterien zur Teilnahme an der Studie

Inclusion criteria:
1. Patients must be post-menopausal; definitive confirmation of post-menopausal status is required
2. Patients must be accessible for follow-up
3. At diagnosis, patients must have had operable, non-inflammatory breast cancer
4. Patients must be clinically disease-free at randomisation
5. Patients must have had steroid hormone receptor positive tumours (oestrogen receptor [ER] and/or progesterone receptor [PgR]), determined by immunohistochemistry, after primary surgery and before commencement of prior endocrine therapy
6. Following primary surgery, eligible patients must have had evidence of lymph node involvement either in the axillary or internal mammary nodes, but not supraclavicular nodes
7. There must have been no evidence of recurrent disease or distant metastatic disease at any time prior to randomisation
8. Patients must have had proper local treatment including surgery with or without radiotherapy for primary breast cancer with no known clinical residual loco-regional disease
9. Patients must have clinically adequate hepatic function
10. Patients must have completed 4 to 6 years of prior adjuvant endocrine therapy with SERMs, AI or a sequential combination of both. When calculating 4 - 6 years, neoadjuvant endocrine therapy should not be included.
11. Patients must have stopped prior endocrine SERM/AI therapy, and must be randomized within 12 months (1 year) of the last dose of prior endocrine SERM/AI therapy
12. Patients may have received any type of prior adjuvant therapy, including but not limited to neoadjuvant chemotherapy, neoadjuvant endocrine therapy, adjuvant chemotherapy, trastuzumab, ovarian ablation, GnRH analogues, lapatinib
13. Patients must have stopped hormone replacement therapy (HRT), bisphosphonates (except for treatment of bone loss), or any investigational agent at randomisation
14. Pathology material from the primary tumour must be available for submission for central review as part of the quality control measures for this protocol
15. Written informed consent (IC) must be signed and dated by the patient and the investigator prior to randomisation
16. Written consent to pathology material submission, indicating the patient has been informed of and agrees to tissue material use, transfer and handling, must be signed and dated by the patient and the investigator prior to randomisation
17. Females, no defined age limits

Ausschlusskriterien

Exclusion criteria:
1. Patients who have had bilateral breast cancer
2. Patients who have had a bone fracture due to osteoporosis at any time during the 4-6 years of prior endocrine SERM/AI therapy
3. Patients who have had any previous or concomitant malignancy EXCEPT adequately treated: basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, contra- or ipsilateral in situ breast carcinoma
4. Patients who have had any other non-malignant systemic diseases (cardiovascular, renal, lung, etc.) that would prevent prolonged follow-up
5. Patients with psychiatric, addictive, or any disorder which compromises compliance with protocol requirements

Severe traumatic brain injury;
Severe traumatic brain injury;Neurological - Other neurological disorders;Injuries and Accidents - Other injuries and accidents

Early and sustained hypothermia. Hypothermia will initially be induced by infusion of up to 2L ice cold saline. Following a safety assessment the patient will be rapidly cooled to 33C using surface temperature control equipment. They will be maintained at 33C for 72hours. Slow rewarming will occur at a rate of 1C/4hrs and will be titrated to intracranial pressure (ICP) control and blood pressure.

Kriterien zur Teilnahme an der Studie

Inclusion criteria: Pre-hospital Inclusion Criteria
*Blunt trauma with clinical diagnosis of severe Traumatic Brain Injury (TBI) and Glasgow Coma Scale <9
*Estimated age = 18 and < 60 years of age
*The patient is intubated or intubation is imminent
Emergency Dept Inclusion Criteria
*Blunt trauma with clinical diagnosis of severe TBI and GCS <9
*Estimated age > or = 18 and < 60 years of age
*The patient is intubated or intubation is imminent

Ausschlusskriterien

Exclusion criteria: ***********Pre-hospital Exclusion Criteria
Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma
Randomisation unable to be performed within 3 hrs of estimated time of injury
Estimated transport time to study hospital >2.5hrs
Able to be intubated without drugs
Systolic BP <90mmHg
Heart rate > 120bpm
Cardiac arrest at the scene or in transit
GCS=3 and un-reactive pupils
Penetrating neck/torso injury
Known or obvious pregnancy
Receiving hospital is not a study site
Evidence of current anti-coagulant treatment
Known to be carer dependent due to a pre-existing neurological condition

***********Emergency Dept Exclusion Criteria
Clinical diagnosis of drug or alcohol intoxication as predominant cause of coma
Randomisation unable to be performed within 3 hrs of estimated time of injury
Able to be intubated without drugs
Persistent Systolic BP <90mmHg
GCS=3 + un-reactive pupils
Cardiac arrest at the scene or in transit
Clinically significant bleeding likely to require haemostatic intervention, for example:
Bleeding into the chest, abdomen or retro-peritoneum likely to require surgery +/- embolisation
**Pelvic fracture likely to require surgery +/- embolisation
**More than two long bone fractures requiring operative fixation
**Penetrating neck/torso injury
Positive urine or blood pregnancy test
Evidence of current anti-coagulant treatment
Known to be carer dependent due to a pre-existing neurological condition
In the treating clinician’s opinion, cooling” is not in the patient’s best interest

Germ Cell Tumor;Teratoma;Choriocarcinoma;Germinoma;Mixed Germ Cell Tumor;Yolk Sac Tumor;Childhood Teratoma;Malignant Germ Cell Neoplasm;Extragonadal Seminoma;Non-seminomatous Germ Cell Tumor;Seminoma;Cancer;
Germ Cell Tumor
Teratoma
Choriocarcinoma
Germinoma
Mixed Germ Cell Tumor
Yolk Sac Tumor
Childhood Teratoma
Malignant Germ Cell Neoplasm
Extragonadal Seminoma
Non-seminomatous Germ Cell Tumor
Seminoma
Cancer;Cancer - Testicular;Cancer - Other cancer types

Arm A: TIP

Arm A therapy will consist of 4 cycles of Paclitaxel, Ifosfamide, Cisplatin and Pegylated G-CSF administered every 21 days (+/- 4 days) as follows:

- Paclitaxel: 250 mg/m^2 IV over 24 hours on Day 1
*Premedication (refers to the minimum allowed but institutional protocols administering
additional or more intensive prophylaxis are allowed)
*Dexamethasone: 20 mg orally approximately 14 (12-24) hours and 7 (6-9) hours before
paclitaxel (taken by the patient at home the night before and morning of day 1 or 20 mg
IV 30-60 minutes prior to the initiation of the paclitaxel infusion.
*Diphenhydramine: 25 to 50 mg IVPB 30-60 minutes prior to paclitaxel. Oral can be
substituted but must be given 60 minutes prior to paclitaxel. An equivalent H1 blocker
(e.g., hydroxyzine) can be substituted for diphenhydramine.
*H2 blocker: Ranitidine, Cimetidine, and Famotidine are acceptable, given orally 60
minutes prior or by IVPB 30-60 minutes prior to paclitaxel.

- Ifosfamide: 1500 mg/m^2 IV daily on Days 2-5 with mesna protection
*Mesna: 1500 mg/^2 should be given to match the ifosfamide dose, either mixed 1:1 with
ifosfamide or simultaneous in a separate bag or pre- or post- ifosfamide and hydration.

- Cisplatin 25 mg/m^2 IV daily on Days 2-5

- Pegylated Granulocyte Colony Stimulating Factor (G-CSF) 6 mg subcutaneous on Day 6, 7
or 8 (as determined by the investigator).

- Hydration guidelines: At least one liter of normal saline prior to the initiation of cisplatin.
Hydration should consist of normal saline infused at 100 mL/hr and continue throughout the 5 days of chemotherapy. At least one liter of normal saline should be given post the last dose of cisplatin. Hydration can be modified per institutional guidelines.

- Prophylactic fluoroquinolone antibiotics: Levofloxacin 500mg once daily by mouth or
Ciprofloxacin 500mg twice daily by

Kriterien zur Teilnahme an der Studie

Inclusion criteria: 1. Documentation of Disease

- Histologic Documentation: Confirmation of GCT histology (both seminoma and nonseminoma) on pathologic review at the center of enrollment.
- Tumor may have originated in any primary site. NOTE: In rare circumstances, patients will be allowed to enroll even if a pathological diagnosis may not have been established.
- This would require a clinical situation consistent with the diagnosis of GCT (testicular, peritoneal, retroperitoneal or mediastinal mass, elevated tumor marker levels {HCG greater than or equal to 500; AFP greater than or equal to 500} and typical pattern of metastases)

2. Evidence of Disease

- Must have evidence of progressive or recurrent GCT (measurable or non-measurable) following one line of cisplatin-based chemotherapy, defined as meeting at least one of the following criteria:

* Tumor biopsy of new or growing or unresectable lesions demonstrating viable non-teratomatous GCT (enrollment on this study for adjuvant treatment after macroscopically complete resection of viable GCT is not allowed). In the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for the study.
* Consecutive elevated serum tumor markers (HCG or AFP) that are increasing. Increase of an elevated LDH alone does not constitute progressive disease.
* Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to increase.

3. Prior Treatment

- Must have received 3-6 cycles of cisplatin-based chemotherapy as part of first-line (initial) chemotherapy.

* Prior POMBACE, CBOP-BEP, or GAMEC are allowed.
* Note: For patients requiring immediate treatment, 1 cycle of conventional-dose salvage chemotherapy is allowed. Therefore, these patients may have received 7 prior cycles of chemotherapy. 6 cycles as part of first-line chemotherapy and 1 cycle of salvage conventional chemotherapy.

- No more than one prior line of chemotherapy for GCT (other than the 1 cycle of salvage chemotherapy)

* Definition of one line of chemotherapy: One line of therapy can in some cases consist of 2 different cisplatin-based treatment combinations, provided there is no disease progression between these two regimens.
* Prior treatment with carboplatin as adjuvant therapy is allowed, provided patients meet other eligibility criteria (e.g., the patient has also received 3-4 cycles of cisplatin-based chemotherapy).
* Prior treatment with 1-2 cycles of BEP or EP as adjuvant chemotherapy for early stage GCT is allowed, provided the patient also received 3-4 cycles of BEP or EP again at relapse. Patients treated with 3-4 cycles of VIP at relapse following 1-2 cycles of BEP/EP are not eligible as this would be considered more than 1 line of prior therapy.

- No prior treatment with high-dose chemotherapy (defined as treatment utilizing stem cell rescue)
- No prior treatment with TIP with the exception when given as a bridge to treatment on protocol for patients with rapidly progressive disease who cannot wait to complete the eligibility screening process. Only one cycle is allowed.
- No concurrent treatment with other cytotoxic drugs or targeted therapies.
No radiation therapy (other than to the brain) within 14 days of day 1 of protocol chemotherapy except radiation to brain metastases, which must be completed 7 days prior to start of chemotherapy.
- No previous chemotherapy within 17 days prior to

Ausschlusskriterien

Exclusion criteria: 1. Prior treatment with high-dose chemotherapy
2. Prior treatment with TIP
*1 cycle of Prior TIP is allowed as bridge to the protocol
3. Prior radiation within 14 days
4. Prior chemotherapy within 16 days (bleomycin within 5 days)
5. Inadequate recovery from prior surgery
6. Concurrent malignancy
7. Large hemorrhagic or symptomatic brain metastases
*Become eligible 7 days or more after local treatment (surgery or RT)
8. Fully resectable late relapse (2 years or more before relapse)
9. Concurrent malignancy