Method for treating cerebral metastases of generalized skin melanoma

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with generalized skin melanoma at single and multiple cerebral metastases and extracerebral lesions. The method includes systemic immunochemotherapy. For this purpose, on removing a single cerebral metastasis and melanomatous focus or at multiple cerebral lesions when operation is contraindicated it is necessary to carry out a 2-wk-long course of autohemoimmunochemotherapy, that is: 400 ml patient's autoblood should be sampled into a vial with hemoconservant and after sedimentation it should be divided into 2 equal fractions - plasma and autologous cell suspension (ACS). In separate vials it is necessary to prepare 3 media - 200 ml autoplasma (medium N1) and per 100 ml ACS (medium N2 and N3). One should incubate for 1 h in thermostat at 37° C medium N1 with 100 mg carmustine (mixture N1), medium N2 - with 25 mg metothrexate and 1 mg vincristine (mixture N2), medium N3 - with Reaferon at the dosage of 5×106 IU Reaferon (mixture N3). On the 1st d of the course one should inject mixtures intravenously by drops successively every mixture per 60 min, mixture N2 should be injected repeatedly on the 8th d of the course, mixture N3 should be injected by drops along paracetamol intake thrice weekly during the whole 2-wk-long course of therapy. Additionally, one should fulfill intravenous infusions of 150 mg carboplatin and 15 mg bleomycin upon 200 ml autoblood by drops on the 2nd and 4th d of the course, correspondingly. Totally, one should carry out 3-6 courses. The innovation provides stable regression of neurological symptoms due to decreasing the volume of cerebral metastasis and reactive perifocal cerebral edema and increasing relapse-free and metastasis-free periods and, also, life period in patients.

EFFECT: higher efficiency of therapy.

2 ex

 

The invention relates to medicine, in particular to integrated care in cancer, and can be used as a self-and postoperative treatment of patients with generalized skin melanoma, stage IV disease and IV clinical group, with solitary and multiple metastases in the brain, as well as with extracerebral lesions, the clinical course of which, as is known, is a rapidly progressive character.

There is a method of treatment of generalized melanoma, stage IV disease and IV clinical group by systemic intravenous drugs derived nitrosodiethylamine (carmustin, Nigran, dacarbazine, lomustin) in the form of various modes of their combination with mono - and chemotherapy (see the "Chemotherapy of neoplastic diseases". Guide for clinicians, edited by Nieremontowany. Moscow, 2000. - P.93-96). This method of treatment is justified in the application when the occurrence of cerebral metastases of melanoma, as these these drugs take a leading place in terms of penetration through the blood-brain barrier.

However, this method of treatment has disadvantages due to the low frequency of positive responses to the treatment and stabilization of the primary tumor process in generalized chalk is ome. In addition, even though a high capacity products derived nitrosodiethylamine to penetrate the blood-brain barrier, their application does not renders prophylactic action progression of the metastatic process in the brain, in particular the relapse-dissemination.

There is a method of systemic drug therapy generalized melanoma, stage IV disease and IV clinical groups, including those with metastases in the brain, chemoimmunotherapy (biochemotherapy), lies in the combined use of known cytotoxic agents and immunomodulators group of interferon (intron a, IFN, Roferon) and interleukins (Roncoleukin) (see "Biological methods of treatment of oncological diseases". Guide for clinicians, edited by Vttest, Shellman, Charoenpura. Moscow, 2002. - S-429). It is shown that using chemoimmunotherapy, compared to standard systemic chemotherapy, it is possible to achieve a higher frequency of positive responses to treatment, to increase the life expectancy of patients with generalized skin melanoma.

However, despite the advantages of this method, it has some significant drawbacks, namely high frequency of organ-specific toxicity, in particular mielodepressii, the development of brain edema, the need is ü long-term (more than 6 months.) use cytokinetics drugs due to their rapid elimination and short of the expected effect.

Known "Method of treatment of non-Hodgkin lymphoma (see RF patent №2180594, bull. No. 8 dated March 20, 2003), we selected as a prototype, namely, that of the total number of 250 ml of peripheral venous autologous blood of the patient 150 ml of autologous blood incubated with anti-tumor chemotherapy, the remaining 100 ml incubated with drug pharmaceutical firm Schering-plough" Intron a dose of 15×106ME, then both mixtures in separate vials placed in a thermostat at a temperature of 37°With exposure time 1 hour, then intravenous drip pour in patient mix blood with anticancer chemotherapy for 25-30 minutes, and the mixture of blood with Intron a for 2-3 hours with prior sedation, the procedure is repeated on the 8th day, a total of 6 cycles of autohomeomorphism (AGAT).

Despite the clinical efficacy, reduced toxicity, the possibility of achieving positive immunomodulation known method of treatment has some limitations, first, the probability of development of brain edema in specific secondary Central nervous system, and secondly, the lack of completeness antimetastatic activity in generalized solid cancers, which are not sensitive to any cytotoxic effects.

The aim of the invention is an improvement is the direct and immediate results of treatment of patients with generalized skin melanoma stage IV disease and IV clinical group, with metastatic brain lesion and the presence of extracerebral metastases and decrease the likelihood of cerebral oedema.

This goal is achieved by the fact that patients generalized skin melanoma stage IV disease and IV clinical group, with metastatic lesions of the brain, or deleting a single cerebral metastasis, or when multiple lesions of the brain where surgery is contraindicated, conduct a differentiated course of drug therapy (autobiography), consisting in the following. Peripheral venous autochrome patient in 400 ml take in a bottle with geoconservation "Gleyzer". Using sedimentation within 4 hours autochrome divided into two equal volume fractions - autoplaza and autologous cell suspension. In separate vials prepared three environments for dissolving drugs - 200 ml autoplasma (Wed # 1) and 100 ml of cell suspension (Wednesday # 2 and # 3). Later in thermostat at a temperature of 37°With exposure time 1 hour Wednesday No. 1 incubated with derivative nitrosodiethylamine, carmustine at a dose of 100 mg (mixture No. 1), environment No. 2 with methotrexate (25 mg) and vincristine (1 mg) (blend # 2), environment No. 3 - with highly purified recombinant interferon domestic production by IFN at a dose of 5×106ME (blend # 3). 1-day course at Azania mixture injected intravenously, drip sequentially one after the other, a 60-minute infusion every. Blend # 2 pour in again on the 8th day. Blend # 3 receives under the guise of paracetamol 3 times a week for 2 weeks (total of 6 infusions). The generally accepted standard of treatment, additionally spend drip infusion carboplatin (150 mg) and bleomycin (15 mg) intravenously in 200 ml of autologous blood in the 2nd and 4th days of the cycle, respectively. Total patients receive from 3 to 6 courses of autobiography.

The invention is a Method of treatment of cerebral metastases generalized melanoma of the skin" is new, because it is unknown the level of medicine in the field of Oncology, in the complex treatment of cancer patients generalized skin melanoma with metastatic brain lesion, stage IV disease and IV clinical group.

The novelty of the invention lies in the fact that patients generalized skin melanoma stage IV disease and IV clinical group, with metastatic lesions of the brain, or deleting a single cerebral metastasis, or when multiple lesions of the brain where surgery is contraindicated, conduct a differentiated course of drug therapy (autobiography), consisting in the following. Peripheral venous autochrome patient in 400 ml take in a bottle with geoconservation "Glogic is p". Using sedimentation within 4 hours autochrome divided into two equal volume fractions - autoplaza and autologous cell suspension. In separate vials prepared three environments for dissolving drugs - 200 ml autoplasma (Wed # 1) and 100 ml of cell suspension (Wednesday # 2 and # 3). Later in thermostat at a temperature of 37°With exposure time 1 hour Wednesday No. 1 incubated with derivative nitrosodiethylamine, carmustine at a dose of 100 mg (mixture No. 1), environment No. 2 with methotrexate (25 mg) and vincristine (1 mg) (blend # 2), environment No. 3 - with highly purified recombinant interferon domestic production by IFN at a dose of 5×106ME (blend # 3). In the 1st day of the course, the compounds injected intravenously, drip sequentially one after the other, a 60-minute infusion every. Blend # 2 pour in again on the 8th day. Blend # 3 receives under the guise of paracetamol 3 times a week for 2 weeks (total of 6 infusions). The generally accepted standard of treatment, additionally spend drip infusion carboplatin (150 mg) and bleomycin (15 mg) intravenously in 200 ml of autologous blood in the 2nd and 4th days of the cycle, respectively. Total patients receive from 3 to 6 courses of autobiography.

The invention is a Method of treatment of cerebral metastases generalized melanoma of the skin" involves an inventive step, as for a specialist oncologist it explicit education is not a consequence of level of development of medicine in this area in the complex treatment of cancer patients generalized skin melanoma with metastatic brain lesion, Stage IV disease and IV clinical group.

The invention is a Method of treatment of cerebral metastases generalized melanoma of the skin" is industrially applicable, as may be used in health care, hospitals with cancer, oncologic dispensaries, cancer research institutes.

EXAMPLES of SPECIFIC performance

Clinical example 1

Patient Z.-N., born in 1953, the case history No. 15697/N.

Diagnosis: Disseminated melanoma skin of the chest wall, pT2N0M1, with metastatic lesions of the soft tissues of the chest wall, the parenchyma of both lungs, mediastinal lymph nodes, metastatic lesion of the left parietal and right parietal-occipital lobes of the brain, stage IV.

From the anamnesis: 30.10.2002 at the place of residence of the patient was performed excision of the primary tumor melanoma skin of the chest wall (HA - nevus-melanoma), and then were executed endolymphatic chemotherapy with 50 mg of methotrexate and the rate of remote gamma-therapy on the area of the scar and axillary box to the left in SOD 40 Gr. 13.02.03 performed excision education axillary region to the left (HA No. 312-325: metastasis of melanoma and soft tissue). Upon further examination (radiography) from 25.03.03 revealed metastatic lesion in the right lung, and therefore the year received chemotherapy with Mustafina and 4 of chemotherapy with dacarbazine. Control examination (CT) from 03.11.03 showed the presence of multiple metastases in both lungs from 0.7 to 3 cm in diameter. With 18.11.03 received a second course chemoradiation treatment, the patient's condition remained relatively satisfactory. Deterioration occurred in early 2004, when the patient noted the emergence of speech disorders, periodic convulsive twitching in the right limbs, constant headaches, dizziness, nausea and vomiting. Was sent to a neurologist on CT brain, in which 07.03.2004 identified two metastatic tumor in the left parietal and right parietal-occipital lobes of the brain sizes up to 23×16×20 mm and 17×10×15 mm, respectively, with marked perifocal edema. After detection of brain metastases was directed to spetslechenie in RNII.

Upon admission to the Department of neurosurgery 02.04.04: the patient's condition is relatively satisfactory, clear consciousness; in the neurological status - signs of moderate motor aphasia, focal seizures in the right limbs, cerebral syndrome (headache, dizziness, nausea, vomiting), mild paresis of the right arm and discoordinated; somatic - active patient, the skin is pale pink, body temperature increased up to subfebrile figures, l is gcih heard hard breathing.

Repeated CT-examination of the chest, carried out in the hospital, confirmed the presence of multiple metastases in both lungs from 0.7 to 3 cm in diameter, with no signs of exudative pleurisy. Lesions of other organs were found.

Given the presence of the patient more than one cerebral metastasis, surgery was not indicated, so the treatment began with a graded course of autobiography on the method developed by us. 1 day 200 ml of autoplasma was introduced 100 mg of carmustine intravenous drip; methotrexate (25 mg) and vincristine (1 mg) were injected intravenously in 100 ml of autologous blood cell suspension in the 1st and 8th days; immunomodulator IFN was also introduced under the guise of paracetamol intravenously in 100 ml of autologous blood cell suspension at a dose of 5×106ME 3 times a week for 2 weeks. The drugs carboplatin at a dose of 150 mg and bleomycin 15 mg were administered intravenously in 200 ml of autologous blood in the 2nd and 4th days of the course. Said treatment the patient satisfactorily, without side effects. On the background of treatment with interferon failed to avoid the typical flu-like syndrome (aching body, hyperthermia), which, however, did not cause any problems and was short-lived.

By the end of the first course of treatment, before discharge of sudeley, noted positive clinical dynamics, expressed in a regression of neurological manifestations of the disease, namely of aphasia, focal seizures in the extremities, headache, nausea, vomiting and discoordination. CT-control brain after the first induction course of therapy from 21.04.04 showed a significant regression of perifocal edema of the brain substance, the stabilization of the growth of metastatic brain tumors. The patient was discharged in satisfactory condition.

Subsequently, in a Department of neurosurgery, RNII patient was a 3 course autobaterie developed above. In General, the treatment of the patient satisfactorily.

After the main courses of autobiography during dynamic survey noted persistent stabilization as the primary tumor process, so cerebral metastatic disease. According to the control CT brain from 10.11.2004 - metastatic nodes in the left parietal and right parietal-occipital lobes of the brain to its previous size without hampering growth and expressed perifocal edema, cancer dissemination in the brain substance no; CT of the chest from 11.11.2004 - in light of multiple metastatic changes without negative growth.

Now lie the patient is alive without progression, her quality of life is satisfactory.

Clinical example 2

The patient is co, VA, born in 1956, case history No. 11206/so

Diagnosis: Melanoma of the skin on the right lumbar region, pT2N0M1, with metastatic lesions of the right frontal-temporal lobe of the brain, stage IV.

From the anamnesis: pigment formation on the back for several years, special attention has been paid to doctors did not address. Considers himself ill for 1 month, when I first noted the emergence of persistent headache, weakness in left hand; the relatives of the patient were noted he single episode of loss of consciousness with the development of generalized convulsive seizure. Was sent to a district neurologist on CT brain, which 30.06.2004 revealed a large bulk single lesion in the right fronto-temporal lobe brain size 53×66×60 mm with a marked perifocal oedema with compression of the anterior horn of the right lateral ventricle and the shift of median structures to the opposite side of 7 mm was directed to spetslechenie in RNII.

Upon admission to the Department of neurosurgery 01.07.04: the patient's condition is satisfactory, clear consciousness; in the neurological status - cerebral syndrome (headache), mild left-sided spastic hemiparesis; somatic - pain is active, the skin is pale pink, body temperature normal, are heard in the lungs vesicular breath; in the right lumbar region pigment education 3,0×to 2.5×3,0 see

Upon further examination in the hospital data for the defeat of the internal organs (lungs, liver) not found.

Given the solitary nature of metastatic brain tumors, 08.07.04 the first stage treatment was performed osteoplastic craniotomy in the right fronto-temporal region with total destruction of cerebral metastasis of melanoma within the visible healthy tissue (HA No. 753329-332: metastasis of melanoma). The postoperative period was uneventful, with no complications; wound healed by first intention, the sutures were removed on the 10th day after the operation.

After stabilization of the patient, the second stage of treatment 27.07.04 was performed excision of the primary tumor melanoma skin right lumbar region with simultaneous plastic sliding sickle cutaneous flap (HA No. 756112-113: melanoma of spindle-shaped cells). The postoperative period was uneventful, with no complications; wound healed by first intention, the sutures were removed on the 12th day after the operation.

After surgical treatment have started carrying adjuvant differentiated course of autobiography on the developed methodology. 1 day 200 ml of autoplasma was centuries who were 100 mg of carmustine intravenous drip; methotrexate (25 mg) and vincristine (1 mg) were injected intravenously in 100 ml of autologous blood cell suspension in the 1st and 8th days; immunomodulator IFN was also introduced under the guise of paracetamol intravenously in 100 ml of autologous blood cell suspension at a dose of 5×106IU 3 times a week for 2 weeks. The drugs carboplatin at a dose of 150 mg and bleomycin 15 mg were administered intravenously in 200 ml of autologous blood in the 2nd and 4th days of the course. Treatment the patient satisfactorily, without side effects.

Before discharge from hospital the patient has fully recovered, in the neurological status of the pathological signs were not noted, was discharged in satisfactory condition.

Subsequently, in a Department of neurosurgery, RNII the patient was a 4 year autobaterie developed above. Treatment at all stages took place without complications and adverse reactions expressed.

After the main courses of autobiography during dynamic survey noted persistent stabilization as the primary tumor process, so cerebral metastatic disease. According to the control CT brain 14.02.2005 - at the disposal of cerebral metastases spinal fluid cavity, data for recurrence no. In General surveys the years of data for metastatic lung damage, liver and other internal organs were not found.

Currently, the patient is alive without evidence of progression of cancer, quality of life is satisfactory.

TECHNICAL and ECONOMIC EFFICIENCY

"Treatment of cerebral metastases generalized melanoma of the skin" is that the method contributes to effective regression of neurological symptoms due to cerebral metastasis and reactive perifocal edema of the brain substance, a significant decrease in the intensity perifocal brain edema, improve patients ' quality of life, manifested in the increase in their activity, the increase in relapse-free and resetstatistics periods, and duration of life for cancer patients, based on the development of the phenomenon of counter stabilization of generalized neoplastic process.

The method of treatment of cerebral metastases generalized melanoma of the skin, including system immunochemotherapy, characterized in that after removal of a single cerebral metastasis and hearth melanoma or multiple lesions of the brain where surgery is contraindicated, the patient conduct a two-week course of autohomeomorphism, namely: peripheral venous blood of the patient (autochrome) in 400 ml pick in the LAF is he geoconservation "Gleyzer", autochrome after settling in for 4 hours divided into 2 equal to the volume fraction of the plasma and autologous cell suspension, in separate vials cook 3 medium for dissolving drugs - 200 ml autoplasma environment (No. 1) and 100 ml of autologous cell suspension (Wednesday # 2 and # 3), incubated in a thermostat at a temperature of 37°With exposure time 1 hour on Wednesday, No. 1 carmustine at a dose of 100 mg (mixture No. 1), environment No. 2 with methotrexate at a dose of 25 mg and vincristine at a dose of 1 mg (blend # 2), environment No. 3 with IFN at a dose of 5·106ME (blend # 3), while in the 1st day of the course, the compounds injected intravenously drip, sequentially one by one, 60-minute infusion every, blend # 2 pour in again on the 8th day of the course, blend # 3 introduce drip under the guise of paracetamol 3 times per week throughout the two-week course, conducted additionally intravenous drip infusion carboplatin at a dose of 150 mg and bleomycin at a dose of 15 mg per 200 ml of autologous blood in the 2nd and 4th days of the course, respectively; all from 3 to 6 courses autohomeomorphism.



 

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1 ex

FIELD: medicine, surgical hepatology.

SUBSTANCE: one should sample autoblood into standard tanks with a hemostabilizing agent, introduce a wave guide of He-Ne laser through air guide needle or separate needle into a tank with conserved autoblood before autohemotransfusion followed by blood irradiation at output power being 10 mW, wave length of 0.63 mcm, exposure of about 15-20 min in uninterrupted mode. The innovation suggested stimulated hemopoiesis and clotting system being of desensitizing, membranotropic, immunocorrecting action upon patient's body that leads to stable improvement of cell composition and enables to prepare patients for surgical therapy in shorter terms and more reliably.

EFFECT: higher efficiency of reconstruction.

1 ex

FIELD: medicine.

SUBSTANCE: method involves intraperitoneal treatment with Furacilini solution. Intravenous injection of 0.4% sodium hypochlorite solution is administered after the operation at a dose of 1/10 of circulating blood volume. 10-12 h later, it is administered for the second time at the same dose. Ultraviolet blood irradiation is applied at the next day after the operation in treating 1.5-2.0 ml of blood per 1 kg of patient body weight with irradiation power of 150 W/m. The treatment is applied every other day not less than 3-4 times.

EFFECT: increased blood thyroxin concentration.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves taking 400 ml of patient blood before beginning treatment. Plasma is separated. 15 ml of auto plasma is taken and incubated with 9x106 MU of recombinant interferon α2b for 1 h at t 37°C and endolymphatically introduced to the patient at the first treatment day. The rest of the autoplasma is divided into two equal portions and saved in refrigerator. Next day, one autoplasma portion is taken and incubated with chemopreparations for 30 min at t 37°C in standard doses. Doxorubicin, Bleomycin, Vinbastin, Dacarbason are intravenously introduced as drop infusion. Said procedure of intravenous infusions of chemopreparations incubated with autoplasma is repeated at the ninth treatment day. 40 mg of prednisolone per day is introduced from the first to the tenth day. The treatment course is repeated when needed.

EFFECT: enhanced effectiveness of treatment.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves making lumbar puncture in postoperative period. Subarachnoid space is catheterized and 5 ml of liquor is taken and incubated with 5 mg of Nimustin for 30 min at 38°C and introduced through the catheter into the subarachnoid space.

EFFECT: enhanced effectiveness of treatment; reduced toxic effect.

Curative agent // 2283133

FIELD: medicine, medicinal agents, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as ointment, gel, vaginal or rectal suppository and designated for treatment of candidomycosis and comprising ketoconazole or fluconazole (variants) in the dose 0.01-0.4 g/1 g of agent, and recombinant alpha-interferon in the dose 150000-3000000 IU/g (for rectal and vaginal suppository) and 5-50000 IU/g (for ointment and gel). Invention provides the development of agent with prolonged effect as ointment, gel, vaginal or rectal suppository showing good penetrating capacity and possessing an antimycotic effect.

EFFECT: valuable medicinal and pharmaceutical properties of agent.

14 cl, 4 tbl, 6 ex

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