Method of predicting survival potential of patients with malignant gliomas

FIELD: medicine.

SUBSTANCE: in patient's urine content of 6-sulfatoximelatonin is determined. If determined content of 6-sulfatoximelatonin after operation before complex treatment equals 292.7 nmol/ml survival to 2.3±0.5 months is predicted, if 22.4 nmol/ml is determined, survival for more than 12 months is predicted. If after chemical therapy determined content of 6-sulfatoximelatonin equals 268.2 nmll/ml, predicted survival time equals to 2.1±0.6 months, if content is 32.8 nmol/ml - more than 12 months. If after a month after treatment determined content of 6-sulfatoximelatonin equals 479.3 nmol/ml predicted is survival for 1.2±0.5 months, in case of 37.4 nmol/ml - survival for more than 12 months.

EFFECT: increased accuracy of predicting survival of patients with low-differentiated glial brain tumours.

7 dwg, 1 tbl, 3 ex

The invention relates to medicine, namely to the neuro-Oncology, and can be used to predict survival of patients with poorly-differentiated glial brain tumors.

Gliomas are a group of malignant brain tumors neuroectodermal origin. The life expectancy of patients with glial brain tumors after surgical treatment of the following: patients with anaplastic astrocytomas is about 24 months, and in patients with glioblastomas rarely exceeds 12 months (Annin E.A., goldfinches VI, Osinsky S. p., "ON the feasibility of surgical treatment of malignant gliomas, and prospects for intra-arterial chemotherapy". // Ukrainian journal of minimally invasive and endoscopic surgery. - 1998. No. 2; 4. - P.50).

There is a method of forecasting for tumors of the adrenal glands (Vysotskaya O.V. Marchenko I.A. Study of metalloproteinases expression in tumors of the adrenal glands. Abstracts of the V conference of young scientists of Russia with international participation "Fundamental science and clinical progress of medicine" 19-22 may 2008, p.97-98.) The author investigated the expression of three metalloproteinases: MMP-1, MMP-7 and MMP-9 in benign tumors: adenoma cortical substance of the adrenal gland, pheochromocytoma and malignant tumors of the brain substance NADP is chechnikov - pheochromocytoma. Showed a tendency to increase the level of expression of the studied metalloproteinases in the case of malignant degeneration of the tissues of the adrenal glands. It is observed that the expression of MMP was quite low in most normal cells, but significantly increased in malignant tumors and correlated with poor clinical prognosis.

However, this method is to predict the effectiveness of treatment for tumors of the adrenal glands and can not be used when predicting the survival of patients with malignant gliomas of the brain.

There is a method of predicting the effectiveness of treatment of patients with glial tumors (Absalyamova O.V., kites A.G., Hinnies, VA, Kobyakov GL, Golan A., Urakov SV, Amanov RD "the Influence of molecular-genetic factors on the prognosis of patients with oligodendroglial and mixed tumours. Abstracts of the V conference of young scientists of Russia with international participation "Fundamental science and clinical progress of medicine" 19-22 may 2008, p.6-7), selected as a prototype. The authors assessed the impact of 1p19q deletions and 9R for prognosis and efficacy of treatment in this group of patients by fluorescence in situ hybridization. In patients with 1p19q deletion median time to progression was longer in group HT+LT - 45 months, in case the application is accompanied by LT - 30 months. Thus, the presence of tumor codelli 1p19q is associated with improvement in terms of survival, in the presence of deletions 9R survival worsens. The 9P deletion was detected in the absence of codelli 1p19q.

However, this method is quite extensive, costly and time-consuming in execution, which does not allow to use it as a production method for determining the prognosis of survival of patients with gliomas.

The aim of the present invention is the simplification and acceleration of the method for predicting survival of patients with poorly-differentiated glial brain tumors.

This objective is achieved in that in the blood of patients after surgery to complex treatment determine the hormone of the pineal gland - melatonin and urinary 6-COM 6-sulfatoxymelatonin. at the level of 6-COM 6-sulfatoxymelatonin 292,7 nmol/ml predict survival of patients to 2.3±0.5 months, when the level of 6-SOMS of 22.4 nmol/ml, the survival rate of more than 12 months after chemotherapy with 6-CATFISH 268,2 nmol/ml, the survival rate to 2.1±0.6 months, and at 6-SOM is 32.8 nmol/ml - more than 12 months, after a month of treatment at the level of 6-CATFISH 479,3 nmol/ml predict the survival rate of 1.2±0.5 months, and at 6-COM 6-sulfatoxymelatonin or 37.4 nmol/ml, the survival rate of more than 12 months.

The invention of "a Method for predicting vigeveno and patients with malignant gliomas is a new, as it is unknown the level of achievements of medicine in the field of predicting the survival of patients with poorly-differentiated glial brain tumors on the basis of biochemical studies.

Analysis of the known methods for predicting gives grounds to speak about the novelty of the proposed method, which presents the research objective indicator in the urine of patients.

Unlike the prototype of the proposed "a Method for predicting survival in malignant gliomas" is carried out within 1 business day and enables correction of therapeutic effects in accordance with the test objective reaction to this effect.

The developed method involves an inventive step, as it is not obvious to a person skilled from the known level of development of medicine and evaluating the effectiveness of anticancer therapy. In the known sources of Russia, CIS and abroad such a way is not found.

The invention is industrially applicable as it can be repeatedly reproduced in hospitals with cancer with biochemical laboratories.

Biochemical determination of 6-SOMS (6-sulfatoxymelatonin) in urine is as follows:

Urine ill is x going in the morning on an empty stomach. Determination of the level of melatonin conducted according to the method of Levin IM, kvetnoy I.M., Thunder, NV (Increased sensitivity and specificity fluorometric determination of melatonin in urine // lab. case, 1988. No. 5. - P.54-57). To 40 ml of urine add 2 ml of 2% R-RA 1-cysteine in bidistilled water and then with 40% sodium hydroxide pH adjusted to 12.0. the solution is filtered to 10 ml of the filtrate add 50 ml of chloroform and intensively stirred on a magnetic stirrer for 20 minutes the Aqueous phase is discarded and the chloroform extract is washed twice with 50 ml of bidistilled water and then 5 ml of 0.1 M hydrochloric acid. The chloroform is evaporated at a temperature of 60°C under vacuum until a dry residue, which is poured 0.6 ml 5 N. hydrochloric acid. 0.2 ml of the acid phase is transferred into two tubes, one of which is of 0.02 ml of hydrogen peroxide. In both test tubes poured in 0.6 ml of 0.015% solution articleimage aldehyde in 0.1 N. hydrochloric acid and incubated in a water bath at a temperature of 100°C for 10 minutes In each tube add 1 ml of water and fluorimetric.

For evidence cited extracts from the histories, confirming the clinical effect of the proposed forecasting Method to predict survival in patients with malignant gliomas.

An example of clinical application No. 1.

Observation # 1. Patient P., born in 1985, Hist. bolezn the No. 18046/R.

Diagnosis: Anaplastic astrocytoma of the left frontal lobe of the brain.

From the anamnesis: 28.09.2004, made osteoplastic craniotomy with radical removal of the tumor.

Histogenesis No. 764640: anaplastic astrocytoma. In neurological status: the state of moderate severity, hepatico-abulcasis syndrome, right-Central-side hemiparesis (4 points) with right-hand hemihypesthesia, generalized epileptic seizures, motor aphasia. CT brain performed after the operation revealed postoperative edema elective 3 lobe left frontal, left parietal, right frontal (figure 1) CT brain of the patient P. after surgery before the start of the comprehensive treatment. Level 6-SOMS (6-sulfatoxymelatonin) 292,7 nmol/ml

Patients received a course of complex treatment of the consideration received 60 Gy to the removed tumor bed and put 500 mg of carmustine, 200 mg of etoposide on the background of anti-edema therapy.

In the process of treatment was a gradual positive trend in the form of recovery of speech, sensitivity and strength in the right extremities, reducing the frequency and severity of epileptic seizures. When the control CT brain performed after the end of treatment, a significant reduction of postoperative swelling, which occupies only the left frontal portion, and the absence of dislocations with the coherent structures (figure 2) CT brain of the patient P. after a course of complex treatment (complete remission). Level 6-SOMS (6-sulfatoxymelatonin) is 32.8 nmol/ml currently disease-free period in this patient is 5 years, quality of life is satisfactory. After a comprehensive treatment with a positive clinical effect level 6-SOMS (6-sulfatoxymelatonin) was 32.8±3.1 nmol/ml, which confirms its importance as a prognostic criterion for determining the length of life of the patients.

Observation # 2. Patient M., born in 1965, East. disease No. 2875/O.

Diagnosis: Glioblastoma left frontal lobe of the brain.

From the anamnesis: 03.05.2005, in RNII made osteoplastic craniotomy with radical removal of the tumor.

Histogenesis No. 788232-238: glioblastoma.

In neurological status: the state of moderate severity, hepatico-abulcasis syndrome, generalized epileptic seizures, motor aphasia. CT brain performed after the operation revealed postoperative swelling occupying the entire left frontal portion with a shift of median structures to the right by 4 mm (figure 3) CT brain of the patient M to the beginning of the comprehensive treatment. Level 6-SOMS (6-sulfatoxymelatonin) 268,2 nmol/ml patients received a course of complex treatment of the consideration received 60 Gy to the removed tumor bed and put 500 mg of carmustine, 200 mg of etoposide on the background of antitumor therapy. the process of treatment was a gradual positive trend in the form of recovery of speech, reducing the frequency and severity of epileptic seizures. When the control CT brain performed after the end of treatment showed complete regression of post-operative edema and absence of dislocation median structures (figure 4) CT brain of the patient M after a course of complex treatment. Level 6-SOMS (6-sulfatoxymelatonin) or 37.4 nmol/ml

Currently disease-free period in this patient is 4.5 years, quality of life is satisfactory.

One month after treatment the positive clinical effect is confirmed by the determination of the level SOM (6-sulfatoxymelatonin) 37,4±3.3 nmol/ml

Observation # 3. Patient L., born in 1951, East. disease No. 21353/X.

Diagnosis: Glioblastoma right temporo-parietal brain areas. From the anamnesis: 19.04.07, in RNII made osteoplastic craniotomy with radical removal of the tumor, histogenesis No. 936310: glioblastoma. In the postoperative period complained of headaches, weakness, numbness in the left extremities. In neurological status: the state of moderate severity, cerebral syndrome, left-Central-side hemiparesis (3 points), left hemihypesthesia. The Karnofsky index (40%), General health status - 3 points. On the fifteenth day of the postoperative period, the control CT of the brain, in the operational area in which Estella; hypodensity lesion in the right temporal lobe size 92×72×90 mm, compression of the right lateral ventricle with a shift of the mid brain structures 5 mm to the left (figure 5) CT brain patient L. after the operation.

Patients received a course of complex treatment according to the described method, the total received 60 Gy to the removed tumor bed and put 500 mg of carmustine, 200 mg of etoposide. After a course of complex treatment is marked as an absence of positive dynamics in the absence of regression of focal neurological symptoms. The index on the Karnofsky scale was 80%, General health status in ECOG-who - 2 points. CT brain performed one month after treatment negative clinical effect after the end of treatment, which is expressed in the absence of reduction of postoperative swelling and dislocation median structures (6) CT brain patient L. after a course of complex treatment. Level 6-SOMS (6-sulfatoxymelatonin) was 479,3±43,1 nmol/ml

Dynamic observation over the next 1.5 months (CT one month after XT+DHT) demonstrates, despite ongoing after XT+DHT basic therapy, progressive deterioration of the quality of life of the patient and a negative treatment outcome (7) CT brain patient L. 1 month after the combined treatment.

Thus, given the clinical observations correlate with the level of melatonin in the urine, which can serve as a prognostic criterion for determining the length of life of the patients.

The proposed method was the study of 107 patients with glial brain tumors in the course of cancer therapy. Research data presented in the table.

As can be seen from the presented data, the level of melatonin in the urine of patients with effective treatment was superior to performance in the urine of healthy donors 2-3,5 times, whereas in the absence of clinical effect he was promoted more than 20 times, which is confirmed by the survival of patients.

Technical and economic efficiency "Method for predicting survival in malignant gliomas" is that

- able to objectify the outcome of specific therapy;

- can be individualized for each patient's specific treatment and make necessary corrections;

- reduced chemotherapy as you don't have to waste time holding ineffective treatment;

- reduced toxic side effects ineffective antitumor therapy.

A method for predicting survival in patients with malignant gliomas of different who himself, however, what in the urine of the patient determine the content of 6-sulfatoxymelatonin, when identifying the content of 6-sulfatoxymelatonin after surgery before comprehensive treatment equal 292,7 nmol/ml predict survival to 2.3±0.5 months, the detection of 22.4 nmol/ml, the survival rate of more than 12 months; in the identification of content 6-sulfatoxymelatonin after chemotherapy equal 268,2 nmol/ml predict survival to 2.1±0.6 months, when is 32.8 nmol/ml - more than 12 months; in the identification of content 6-sulfatoxymelatonin one month after treatment equal 479,3 nmol/ml predict the survival rate of 1.2±0.5 months, when or 37.4 nmol/ml, the survival rate of more than 12 months.