Neoplasms

All Conditions

Rare Diseases

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Patients will be treated with the standard surgical therapy - glioma resection.

Glioma resection

Blood samples used for measuring studied parameters will be taken within 10 days before surgery, one day after surgery and once more within 10 days following the operative procedure.

Blood sampling

Tamara Lah Turnšek, PhD

Primož Rožman, MD, PhD

Matija Veber, dipl. biotech.

Marjan Koršič, MD, PhD

Kristina Gruden, PhD

Study on glioma patients treated with brain surgery is focusing on the analysis of their transcriptome expression profile measured in two immune cell populations, CD4+ T cells and CD56+ NK cells. The results of analysis will be compared to the reference data of healthy population. Furthermore, the metabolomic and immunological status will also be monitored and compared to healthy group reference data, before and after the surgery\*. With comparative crossomics analysis the investigators intend to possibly identify new diagnostic and prognostic biological markers for the relapse of the disease. The results are expected to convey a deeper insight into pathophysiology of the glioma as well as into the mechanisms of the current surgical therapy.

\* The healthy reference data have been published in collaborative efforts of BTC, UMC and NIB (Gruden et al. 2012).

Whole blood, blood plasma, peripheral blood mononuclear cells, CD4+ T cells, CD56+ NK cells

Gene Expression, Immunological Status and Metabolome in Glioma Patients

Monitoring and Analysis of Gene Expression, Immunological Status and Metabolome in Peripheral Blood Mononuclear Cells and Their Specific Subpopulations (CD4+ T Cells and CD56+ NK Cells) in Surgically Treated Glioma Patients

Blood Transfusion Centre of Slovenia

University Medical Centre Ljubljana

National Institute of Biology, Slovenia

Director of the National Institute of Biology, Slovenia

Symptoms and General Pathology

Wounds and Injuries

Hyperthermia

Glioblastoma

Fever

Astrocytoma

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Temozolomide

Iron

Antineoplastic Agents, Alkylating

Alkylating Agents

Recurrent glioblastoma multiforme patients treated with NanoTherm therapy.

Glioblastoma multiforme patients treated according to Stupp protocol including surgery, chemotherapy and radiotherapy.

Cyclic hyperthermia in patients with recurrent glioblastoma multiforme, who underwent implantation of iron oxide nanoparticles.

NanoTherm therapy

Removal of brain tumor - gross total ressection

Glioma Resection

The total dose according to the Stupp protocol is 60 Gy and is administered in fractions of 2 Gy per day for 5 days (Monday to Friday) for 6 weeks.

radiotherapy according to Stupp protocol

Temozolomide is used during radiotherapy: 75 mg/m2 of body surface area per day for 7 days a week. After the completion of radiotherapy, temozolomide is used as adjuvant therapy - 6 cycles of 150-200 mg/m2 of body surface area for 5 days every 28 days.

chemotherapy according to Stupp protocol

Slawomir Michalak, Prof.

Jakub Moskal, MD, PhD

Glioblastoma multiforme (GBM), the most common and malignant primary brain tumor in adults is classified as a World Health Organisation (WHO) grade 4. Surgical removal of the tumor is the primary method of treatment. Unfortunately, because GBM is a disease of the entire brain, total resection is not possible. Therefore, the use of radiotherapy and/or chemotherapy is considered as Stupp protocol. Patients with recurrent GBM will be included in the ANCHIALE study.

The goal of the trial is to evaluate the efficacy and tolerance of using the NanoTherm therapy system in recurrent GBM.

The main questions it aims to answer are:

1. how NanoTherm therapy influences overall survival, and progression free survival;
2. what is the tolerance of NanoTherm therapy in terms of side effects (allergies, intracranial bleeding, infections, brain edema, increased intracranial pressure) and quality of life.

Participants will undergo:

* initial visit, considering the inclusion/exclusion criteria, neurological examination, and surveys regarding daily functioning and quality of life;
* standard neurosurgical operation aimed, if possible, complete removal of the recurrent GBM and administration of NanoTherm ASI - a sterile suspension of iron oxide nanoparticles. A catheter will be implanted allowing for measurement of temperature during the first activation in the magnetic field;
* between the 6th and 10th day after tumor resection, a standard computerized tomography (CT) scan of the head will be performed for routine postoperative evaluation;
* after the first activation (10th day), the catheter will be removed;
* subsequently, for 6 times, the patient will be subjected to the variable magnetic field of the NanoActivator® to induce hyperthermia - activations will be conducted on the 10th, 14th, 17th, 21st, 24th, and 28th day;
* for up to 2 years post-procedure, a CT scan with an evaluation of treatment efficacy will be performed;
* during follow-up visits for up to 2 years after the surgical procedure, a neurological examination, assessment of adverse symptoms, number of hospitalizations, number of medical visits, clinimetric assessment regarding quality of life, neurological deficit and degree of disability will be conducted.

Researchers will compare NanoTherm group with patients undergoing Stupp protocol treatment for the abovementioned effects.

Glioblastoma multiforme (GBM) is the most frequent glial tumor (glioma). The epidemiology of brain gliomas depends on many factors such as age, gender, genetics, environment, and lifestyle.

According to statistics, in developed countries, brain gliomas account for about 2% of all tumors. In the USA, there are approximately 12,000 new cases of brain gliomas annually, and in Europe, there are about 25,000. The average age of individuals diagnosed with brain gliomas is 64 years, although they can occur in all age groups. However, the majority of cases are diagnosed in individuals between 45 and 70 years of age. The global incidence rate is 3.7/100,000 for men and 2.6/100,000 for women. A higher incidence rate is observed in highly industrialized countries. It is estimated that gliomas account for 30 to 40% of all intracranial tumors. Approximately 50% of adult gliomas are the most malignant form - Glioblastoma multiforme G4.

In 2009, 1444 new cases of malignant brain tumors were recorded in men and 1362 in women in Poland. Men have a slightly higher risk of developing brain gliomas than women. The presence of genetic and hereditary factors, including mutations in genes related to DNA repair and cell cycle control, increases the risk of developing gliomas. Risk factors for the development of gliomas include exposure to ionizing radiation and viral infections (cytomegalovirus), smoking, alcohol abuse, overweight, lack of physical activity, as well as exposure to certain chemicals such as pesticides and solvents.

Recommendations for the treatment of Glioblastoma multiforme include:

Surgical removal of the tumor as the primary method of treatment. Unfortunately, considering the fact that Glioblastoma multiforme is a disease of the entire brain, complete tumor resection is not possible. Therefore, the use of radiotherapy and/or chemotherapy is considered. This treatment is used according to the protocol published by Stupp in 2005.

Radiotherapy: Radiotherapy is used to destroy the remaining tumor cells after the tumor removal. It can be used after surgery or as a standalone treatment, especially in cases where the tumor cannot be surgically removed. The total dose according to the Stupp protocol is 60 Gy and is administered in fractions of 2 Gy per day for 5 days (Monday to Friday) for 6 weeks.

Chemotherapy: In the Stupp protocol, temozolomide is used during radiotherapy: 75 mg/m2 of body surface area per day for 7 days a week. After the completion of radiotherapy, temozolomide is used as adjuvant therapy - 6 cycles of 150-200 mg/m2 of body surface area for 5 days every 28 days.

However, the clinical effects of using the Stupp protocol are not fully satisfactory. The two-year survival rate after the full Stupp protocol (radio- and chemotherapy) is 26.5% of patients, and after using only radiotherapy, it is 10.4% of patients.

Supportive treatment methods used in the treatment of Glioblastoma multiforme so far include thermotherapy - hyperthermia and nanotherapy.

Hyperthermia involves:

* the use of elevated temperature to increase the effectiveness of radio- and chemotherapy
* thermoablation, in which the use of high temperatures - above 45°C - causes direct damage to tumor cells,
* magnetic hyperthermia (MHT), e.g. NanoTherm® Therapy (NTT), which has been registered in Europe as a method of treating Glioblastoma multiforme in cases of tumor recurrence Nanotherapy uses magnetic nanoparticles (MNP), which are used in diagnostic and therapeutic procedures.

Hyperthermia and thermotherapy have been treatment methods studied in cancer patients and magnetic hyperthermia induced using nanoparticles is becoming the subject of increasingly advanced research.

In a phase III study, the use of tumor-treating fields (TTF) was evaluated as a first-line therapy in patients with Glioblastoma multiforme. Low-power electromagnetic fields using long waves are directed at the tumor area using external electrodes. According to the report from the Institute for Quality and Efficiency in Health Care (IQWiG), this method resulted in a 5-month extension of the overall survival of patients with Glioblastoma multiforme compared to patients treated with temozolomide, and the tolerance of the treatment was acceptable.

On the other hand, NanoTherm therapy represents a promising form of thermotherapy leading to an extension of survival, especially in cases of Glioblastoma multiforme recurrence. In the study by Maier-Hauff et al., it was shown that the average overall survival of patients undergoing NanoTherm therapy after recurrence was 13.4 months, which was longer (P\<0.01) than in patients treated according to the Stupp protocol (6.2 months). The overall survival after the initial diagnosis of Glioblastoma multiforme was also longer (23.2 versus 14.6 months; P\<0.01). The benefit observed in both groups of patients was attributed to the use of NanoTherm therapy.

Therefore, among the sought-after new methods of treating Glioblastoma multiforme that could increase the effectiveness of the current treatment, NanoTherm therapy is a procedure that significantly increases the survival and quality of life of patients. For this reason, it is planned to conduct this study, the aim of which is to determine the effectiveness and tolerance of using nanoparticles in cyclic hyperthermia as adjuvant therapy in patients with Glioblastoma multiforme.

The main goal of the treatment for each patient with Glioblastoma multiforme is to prolong survival time and improve the quality of life. According to the literature, the median overall survival of these patients is 9 - 12 months.

Patients with recurrent glioblastoma multiforme WHO G4 will be included in the ANCHIALE study.

Study Objective:

The aim of the ANCHIALE study is to prepare a registry that allows for the evaluation of the efficacy and tolerance of using the NanoTherm therapy system in cases of recurrent glioblastoma multiforme.

Study Principles:

During the initial visit, a qualification for treatment will be conducted, taking into account the inclusion and exclusion criteria, i.e., indications and contraindications for the NanoTherm therapy system. Additionally, an interview, neurological examination, and surveys regarding daily functioning and quality of life will be conducted.

After qualifying a patient for the study, he or she will undergo standard neurosurgical operation aimed at partial or, if possible, complete removal of the recurrent brain tumor. Then, in the place of the removed tumor, NanoTherm ASI will be administered in a quantity of either 112 or 335 mg/ml of iron particles. This is a sterile suspension of iron oxide nanoparticles in sterile water, characterized by a high specific ability to absorb heat associated with its superparamagnetic properties. At the site where the thickest layer of nanoparticles (NanoTherm® ASI) is applied, a catheter will be implanted allowing for measurement and control of temperature during the first activation in the magnetic field of the NanoActivator®.

Between the 6th and 10th day after the neurosurgical procedure, a standard computerized tomography (CT) scan of the head will be performed for routine postoperative evaluation.

After the first activation (10th day post-implantation of NanoTherm® ASI), the catheter will be removed. Subsequently, cyclically, for 6 times, the patient will be subjected to the variable magnetic field of the NanoActivator® to induce hyperthermia, i.e., increase the temperature of the site after the removed tumor and the surrounding tissues. Activations will be conducted on the 10th, 14th, 17th, 21st, 24th, and 28th day. The heat released by the nanoparticles (NanoTherm® ASI) into the surrounding tissue causes destruction or damage to the cells of the glioblastoma multiforme (hyperthermia effect), increasing their susceptibility to radiotherapy and chemotherapy.

The patient will then be subjected to detailed observation for 2 years. Observation will include visits conducted on the 60th, 90th, 150th, 210th, 270th, and 360th day after surgery, and then every 3 months up to 2 years post-procedure.

On the 6th - 10th, 90th, 150th, 210th, 270th, and 360th day after surgery, and then every 3 months up to 2 years post-procedure, a CT scan with an evaluation of treatment efficacy will be performed. The treatment effects on CT will be analyzed using RANO (Response Assessment in Neuro-oncology) scale.

During follow-up visits on the 60th, 90th, 150th, 210th, 270th, and 360th day, and then every 3 months up to 2 years after the surgical procedure, a neurological examination, assessment of adverse symptoms, number of potential hospitalizations, number of medical visits, clinimetric assessment regarding quality of life (EuroQuality of Life-5 dimensions 5- levels \[EQ-5D-5L\], Neurologic Assessment in Neuro-Oncology \[NanoScale 2\]), and clinimetric assessment regarding neurological deficit and degree of disability will be conducted (modified Rankin scale, Barthel index).

The results from NanoTherm group will be compared to patients undergoing standard neurosurgical treatment for the abovementioned effects.

A prospective longitudinal study will be performed recurrent glioblastoma multiforme patients who:

1. are included for NanoTherm therapy (group A),
2. are included for standard Stupp protocol (surgery/chemo-radiotherapy) (group B)

NanoTherm In Adjuvant Therapy of Glioblastoma Multiforme

Application of Nanoparticles for Cyclic Hyperthermia In Adjuvant Therapy of gLioblastoma Multiforme (ANCHIALE)

Response Assessment in Neuro-oncology - the scale describes the response to the treatment basing on neuroimaging.

quality of life - This scale is numbered from 0 to 100; 100 means the best health you can imagine; 0 means the worst health you can imagine.

functional assessment of the nervous system: 0 - no deficit, 23 - severe neurological deficit

measure of performance in activities of daily living

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Gene Expression, Immunological Status and Metabolome in Glioma Patients	NCT01525459	Glioma	Glioma resectio... Blood sampling	20 Years - 80 Years	National Institute of Biology, Slovenia
NanoTherm In Adjuvant Therapy of Glioblastoma Multiforme	NCT06271421	Glioblastoma Mu...	NanoTherm thera... Glioma Resectio... radiotherapy ac... chemotherapy ac...	18 Years -	Poznan University of Medical Sciences
Gene Expression, Immunological Status and Metabolome in Glioma Patients	NCT01525459	Glioma	Glioma resectio... Blood sampling	20 Years - 80 Years	National Institute of Biology, Slovenia

Spots Global Cancer Trial Database for glioma resection