RU2138991C1 - Method for diagnosing voluminous formations in brain - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves intravenously injecting sodium ¹¹C- butirate at a dose of 250-400 MBq and carrying out 15 long tomographic examination of the brain in 5-6 min. At least 50% local pathologic increase of sodium ¹¹C-butirate contents accumulated in a focus relative to its normal level in the white substance being observed, malignant tumor is to be diagnosed. Accumulation increase of equal to or less than 20% being observed, benign formation is to be diagnosed. EFFECT: low radiation loading; low cost. 3 dwg

Description

 The invention relates to medicine, more specifically to oncology, and may find application in the diagnosis and treatment of diseases of the brain (GM).

 Volumetric formations of GM - tumors (benign and malignant), aneurysms and other types are most often found at the working age of 30-40 years, often leading to disability and death of patients.

 Particularly severe consequences are malignant tumors. Therefore, the issues of timely differential diagnosis of volumetric masses of GM, determining the continued growth of malignant tumors, as well as evaluating the effectiveness of their treatment are extremely relevant.

 Currently, the criteria for assessing the nature of volumetric masses of GM are the clinical picture, the presence of congestion in the fundus, x-ray changes in the bones of the skull associated with increased intracranial pressure, EEG data on pathological activity of the brain. These data provide only indirect non-specific information about the presence of volumetric education.

 To clarify the diagnosis, contrast x-ray angiography is used, with the help of which it is possible to localize and verify the formation of a vascular nature, such as aneurysms, tumors with high vascularization, for example, meningiomas. However, the use of angiography is associated with invasive vascular intervention, the introduction of contrast agents, a high risk of complications, and in some cases is not effective enough.

 New methods of radiation diagnostics, such as CT, MRI, have found widespread use in the diagnosis of volume formations. These methods allow the differential diagnosis of volumetric formations of the brain, however, due to the low contrast of GM tissue as an organ, the diagnosis is based on indirect signs associated with morphological changes in the tissue. So, CT provides anatomical information only about the morphological features of the studied object, and at the same time has a relatively high radiation dose. Difficulties in CT and MR imaging arise due to the presence of morphological changes or metal objects (tantalum clips necessary for surgical treatment) in the postoperative area, which complicate the diagnosis of continued growth, relapse of tumors.

 None of the above methods makes it possible to assess the biological nature of volumetric formations, and a biopsy of GM is always difficult due to the high risk of complications and the severity of the procedure.

Recently, for the differential diagnosis of malignant and benign tumors of GM, methods of radionuclide diagnostics, including positron emission tomography (PET) with ¹¹ CL-methionine, have begun to be used [1]. This method makes it possible to identify and differential diagnosis of tumors and non-tumor formations, however, it does not allow to determine their nature, since ¹¹ CL-methionine is also actively accumulated in inflammatory foci and glandular organs, which greatly complicates the interpretation of data and reduces the diagnostic accuracy of PET with this radiopharmaceutical.

Closest to the proposed and widely used at present is the PET method with ¹⁸ F-fluorodeoxyglucose ( ¹⁸ F-FDG), taken as a prototype [2]. The method consists in conducting PET in 30-40 minutes after intravenous administration of 180-370 MBq of ¹⁸ F-FDG. In the presence of pathological increased focal accumulation of the radiopharmaceutical (RFP), the authors conclude that the formation is malignant, and in the presence of a pathological focal decrease in radiopharmaceutical accumulation, the benign nature of the formation of GM. The criterion for malignancy is the ratio of radioactivity accumulated in the same zones of interest, selected in the volumetric formation and in the white matter of the brain. The excess accumulation of the radiopharmaceutical in the tumor by 50% (1.5 times), compared with the white matter of GM, indicates the malignant nature of the formation, and the excess accumulation of the drug in the tumor by less than 50%, compared with the white matter - of its benign nature.

Thus, using this method, it is possible to conduct differential diagnosis of malignant and benign brain formations. However, the use of this method is associated with a sufficiently large radiation load on the patient due to the long half-life of ¹⁸ F-FDG (109 min). The radiation load is especially high when it is necessary to conduct repeated PET studies.

 The technical result of the present invention is to reduce the radiation dose to the patient while maintaining diagnostic accuracy.

This result is achieved by the fact that ¹¹ C-butyrate of sodium in an amount of 250-499 MBq is intravenously administered to the patient and after 5-6 minutes a 15-minute tomographic study of GM is performed. If there is a pathological focal increase in the accumulation of ¹¹ C sodium butyrate by not less than 50% compared with its content in the white matter, a malignant tumor is diagnosed, and with an increase in accumulation by no more than 20%, or a decrease, a benign formation of GM.

RFP ¹¹ C sodium butyrate was developed at TsNIRRI and was first proposed for positron emission tomography as a diagnostic tool [3]. This drug refers to fatty acids, which are mainly used for myocardial research. On the basis of experimental studies of ¹¹ C sodium butyrate in TsNIRRI, it was previously found that the drug penetrates the blood-brain barrier and accumulates in the tissue of rat GM [3].

This fact interested us, we continued research and made an attempt to use ¹¹ C sodium butyrate for the diagnosis of volumetric formations of GM. Based on PET studies of patients with verified malignant and benign formations of GM (benign tumors, cysts), we found that the presence of a malignant process is unambiguously associated with a focal increase in accumulation of ¹¹ C sodium butyrate by more than 50% compared with its content in white matter and the presence of benign - with a focal increase in accumulation by no more than 20%, or a decrease in it, and in the presence of a cyst, there was a pronounced decrease in the accumulation of radiopharmaceuticals (usually not less than 200% )

The results of these studies allowed us to use ¹¹ C-sodium butyrate for the differential diagnosis of GM diseases, namely, malignant tumors, benign tumors. Moreover, the use of ¹¹ C sodium butyrate reduces the radiation load on the patient by at least 5 times compared with the widely used radiopharmaceuticals ¹⁸ F-FDG, due to the shorter half-life of carbon-11 ( ¹¹ C), equal to 20 minutes.

The necessity of performing positron tomography 5-6 minutes after intravenous administration of ¹¹ C sodium butyrate is explained by the fact that, as we have shown, it was at this time that its accumulation in the GM tissue reached its maximum and was sufficient for the study, and at a later date the study is impossible from - due to the short physical half-life of carbon-11 and the minimum duration of the study of 15 minutes, necessary to collect statistically reliable information.

The diagnostic dose of ¹¹ C sodium butyrate, equal to 250-400 MBq, was found by us empirically.

 The essence of the method is illustrated by the following examples.

 Example 1. Patient C., born in 1949, medical history N 8586-C, was admitted to the TsNIRRI clinic on 09.04.98 with a diagnosis of volumetric formation of the cerebellar angle on the left.

 From the anamnesis: I was sick for about 1 year, worried about growing headaches, dizziness, impaired coordination, hearing loss in the left ear, numbness of the left half of the face, facial asymmetry, hoarseness.

 At CT on February 13, 1998, performed on an outpatient basis, a volumetric formation of the left cerebellar angle of an unknown etiology was revealed.

 On March 12, 1998, the patient underwent MRI: volumetric formation of the left cerebellar bridge of an unclear etiology with compression of the brain stem.

 04/06/98 was hospitalized in the neurosurgical department of hospital No. 2, where the examination of the patient was continued.

 Optometrist: congestive discs on the fundus on both sides.

 EEG from 04/08/98: signs of gross dysfunction of brain stem structures, meso-diencephalic level with secondary inclusion in the process of mediobasal temporal formations of the left hemisphere.

 To clarify the nature of the volumetric process of GM, the patient was sent to TsNIRRI for a PET study.

A brain PET scan from 04/09/98 was carried out in a static mode 5 minutes after intravenous administration of 250 MBq of ¹¹ C sodium butyrate and lasted 15 minutes. On a series of tomoscintigrams of the brain in the projection of the bridge of the cerebellum on the left, a two-sided heterogeneous focus of pathological increased accumulation of radiopharmaceuticals with clear contours, oval in shape, 41x30x29 mm in size was determined. The accumulation of radiopharmaceuticals in the outbreak was 2.4 times (140%) higher than its accumulation in the white matter of GM. Conclusion: malignant neoplasm of the cerebellopontine angle on the left. 04/22/98, in the neurosurgical department of hospital No. 2, the patient underwent an operation to completely remove a tumor of the base of the occipital bone on the left and the back side of the temporal pyramid on the left. The histological conclusion N 122121 from 05.17.98, malignant schwannoma. Based on the results of PET, the patient was prescribed a course of radiation therapy.

 Example 2. Patient I., born in 1945, medical history N 1180, was admitted to the Central Research Institute of Radiotherapy, 12.05.98, with a diagnosis of glioblastoma of the right frontoparietal lobe for further examination and treatment.

 From the anamnesis. In 1996, epileptic seizures, periodic headaches, accompanied by a gradual decrease in vision, memory, weakness in the left arm and leg, first appeared. When examined in September 1996, CT revealed a massive formation of GM.

 September 21, 1996 was operated on at the Research Institute of Neurosurgery, where subtotal removal of glioblastoma of the right frontal and parietal lobes was performed.

 04/14/98 was re-operated at the Research Institute of Neurosurgery. Subtotal glioblastoma removal of the right frontal and parietal lobes was performed. The diagnosis was verified histologically twice in the study of intraoperative biopsy.

 From March 12, 1998 to April 20, 1998, at the Central Research Institute of Radiotherapy, the patient received a course of gamma therapy according to the method of single-beam sector swing using the ROKUS-M apparatus in a total dose of 50 Gy and a course of polychemotherapy.

Repeatedly entered TsNIRRI 05/12/98, due to deterioration: upon admission, the state of moderate severity, complaints of frequent epileptic seizures, severe headaches. In order to exclude continued tumor growth, the patient underwent a comprehensive examination:
MRI from 05/15/98: evidence of continued tumor growth is inconclusive, volumetric formation of the posterior parts of the right frontal lobe of a rounded shape 40 mm in diameter, well delimited from the surrounding brain substance, surrounded by a zone of pronounced perifocal changes with the presence of a perifocal cyst.

05/20/98, in order to exclude the continued growth of a malignant tumor and correct treatment, the patient underwent positron emission tomography. PET was performed in static mode 5 minutes after intravenous administration of 300 MBq of ¹¹ C sodium butyrate and lasted 15 minutes. On a series of tomoscintigrams of the brain in the postoperative zone in the area of the right frontoparietal lobe, a focus of pathological increased accumulation, radiopharmaceuticals of irregular oval shape with clear contours, size 35x30x38 mm, was revealed. The accumulation of radiopharmaceuticals in the focus was 3 times (200%) higher than in the white matter of GM. Anterior to the tumor is a focus of pathological reduced accumulation of the drug, 40x35x38 mm in size. Accumulation in the outbreak is 4 times (300%) lower than in the white matter of GM. PET conclusion: continued growth of a malignant tumor of the frontoparietal lobe on the right, postoperative cyst in the deep sections of the parietal and frontal lobes of the brain on the right.

In parallel with 05/28/98, the patient underwent a PET study of GM with an RFP of ¹⁸ F-FDG. PET was performed in static mode 40 minutes after intravenous administration of 290 MBq of ¹⁸ F-FDG and lasted 20 minutes. PET conclusion: on a series of tomoscintigrams of the brain in the region of the right frontoparietal lobe in the projection of the postoperative zone, a focus of pathological increased accumulation of irregular radiopharmaceuticals with irregular shapes with clear contours, size 35x30x37 mm, was revealed. The accumulation of radiopharmaceuticals in the outbreak is 2.6 times (160%) higher than in the white matter of GM. No other focal changes in the GM were found. Conclusion: continued growth of a malignant tumor in the right parietal lobe of the brain.

 According to the results of the examination, the patient underwent correction of radiation treatment and chemotherapy.

 Example 3. Patient F., born in 1957, medical history N 1243, was admitted to the Central Research Institute of Radiography on 05/20/98 with a diagnosis of volumetric formation of the posterior parts of the right frontal lobe of the GM of unclear etiology.

 From the anamnesis. Sick since December 1995, when, against the background of gradually increasing headaches, epileptic seizures with loss of consciousness first appeared. Subsequently, seizures began to recur.

Ophthalmologist examination - without pathology,
EEG: diffuse irritation phenomena prevailing in the right frontotemporal region, iris of the temporal lobe on the right.

 Examination by a neurologist: epileptic syndrome, nystagmus, left-sided pyramidal insufficiency, represented by flattening of the nasolabial folds, deviation of the tongue to the left, bilateral stem irritation symptoms.

 MRI: volumetric formation of the posterior parts of the right frontal lobe of an unclear etiology of round shape, 45 mm in diameter, well delimited from the surrounding brain substance, surrounded by a zone of pronounced perifocal changes with the presence of a perifocal cyst.

In order to determine the nature of volumetric education 05/26/98, a PET study was conducted. 400 MBq with ¹¹ C sodium butyrate were introduced, the study was started 6 minutes after its introduction, the scan duration was 15 minutes. On a series of brain tomoscintigrams in the area of the right parietal lobe in the projection of the postoperative zone, a pathologically increased accumulation of radiopharmaceuticals of irregular shape with clear contours, 25x35x20 mm in size, was revealed. The ratio of RFP accumulation in the focus to the white matter of the brain is 1.14 (14% higher). Conclusion PET: benign volume formation in the right parietal lobe.

 06/05/98, the patient was operated on: partial removal of a tumor of the right frontoparietal lobe of GM. According to a histological examination of a biopsy obtained intraoperatively: a benign tumor - oligoastrocytoma.

 At the time of the outpatient examination on September 30, 1998, the patient's condition was satisfactory, there were no additional complaints.

 To date, the proposed method for examining 24 patients with volumetric masses of GM. Of these, 15 patients revealed malignant brain tumors of different localizations, and in 9 patients - volume formations of a benign nature.

The proposed diagnostic method in comparison with the known has several significant advantages:
1. A method of providing differential diagnosis of volumetric masses of GM with a significant reduction in radiation exposure to the patient in comparison with the prototype method.

2. The use of the method is associated with lower economic costs, since the synthesis of ¹¹ C-sodium butyrate, unlike ¹⁸ F-FDG, does not require the use of expensive reagents, and the equipment for its production, created in Russia, is simple and affordable.

 The method was developed in the PET department of TsNIRRI and passed clinical testing in 24 patients with a positive result.

Sources of information
1. Mineura K., Sasajima T., Kowada M., et al. Innovative Approach in the Diagnosis of Gliomatosis Cerebri Using Carbon-11-L-Methionine Positron Emission Tomography. J. Nucl. Med., 1991; 32 (4): 726-728.

 2. Delbeke D., Meyerowitz C., Lapidus R. L., et al. Optimal cutoff levels of F-18 fluorodeoxyglucose uptake in the differentiation of low-grade from high-grade brain tumors with PET. Radiology 1995; 195 (1): 47-52.

 3. The decision to grant a patent dated March 20, 1998 according to Application N 97118335/14 with priority dated November 13, 1997.

Claims (1)

A method for the diagnosis of volumetric brain formations by means of positron emission tomography using a radiopharmaceutical, characterized in that ¹¹ C sodium butyrate is used as a radiopharmaceutical, which is administered to the patient intravenously in an amount of 250-400 MBq for 5-6 minutes before conducting a positron emission tomographic study, and in the presence of a pathological increase of focal accumulation of ¹¹ C-sodium butyrate, not less than 50% compared with its content in the white matter, diagnose cancerous th tumor, and with increasing accumulation of no more than 20% reduction in his or - benign.