Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory?

Mesenchymal stem cells (MSC) are characterized by tolerogenic potential and therefore, are used in the treatment of autoimmune diseases such as graft-versus-host disease (GVHD) reactions after allogeneic hematopoietic cell transplantation to improve the transplant functions, as well as for the therapy and prevention of cytokine storm in COVID-19 patients and some other conditions. However, MSC can exhibit proinflammatory activity, which causes risks for their clinical use. We studied the cytokine profile of bone marrow MSC culture and demonstrate intensive production of IL-6, IL-8, and chemokine MCP-1, which participate in the pathogenesis of cytokine storm and GVHD. At the same time, no anti-inflammatory IL-4 and IL-10 were detected. To reduce the risks of MSC application in the GVHD therapeutic protocols, further studies of the conditions promoting generation of MSC with tolerogenic potential and approved clinical standards of MSC use are required.

[The analysis of the association of the polymorphic variants of the TPMT, COMT, and ABCC3 genes with the development of hearing disorders induced by the cisplatin treatment]. / Analiz assotsiatsii polimorfnykh variantov genov TPMT, COMT i ABCC3 c razvitiem narusheniia slukha, indutsirovannogo priemom tsisplatina.

Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) are conferring increased risk of developing cisplatin-induced hearing loss. However, in other studies the results were not replicated. In the present study, we replicated the previous studies based on an independent cohort of Russian patients. SNP genotypes for rs 12201199, rs4646316 and rs 1051640 were determined in DNA samples obtained from 16 patients who developed hearing loss and a group of 34 patients whose hearing was retained. The association between TPMT (rs 12201199), COMT (rs4646316), and ABCC3 (rs 1051640) variants and the hearing loss was not observed in our cohort.

[Neurosurgical aspects of the treatment of neuroblastoma patients]. / Neirokhirurgicheskie aspekty lecheniya bol'nykh s neiroblastomoi.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. The neoplasm grows from progenitor cells of the sympathetic nervous system and can be detected anywhere along the sympathetic neurological circuit: retroperitoneally, mediastinally, cervically, and pelvically. Examination of children with suspected neuroblastoma is comprehensive and performed in strict compliance with a therapeutic protocol. A decision on the treatment regimen is made based on the tumor staging and the risk group of the patient. The diagnosis and treatment of NB patients are comprehensive and can be fully carried out only at the pediatric oncology department. In 10-15% of cases, an hourglass tumor spreads to the intervertebral foramina or spinal canal at one or more levels. A tumor node is always located extradurally with respect to the spinal cord. Symptoms of spinal cord compression of various severity are observed in 5-7% of patients. We present several cases of patients with neuroblastoma with intraspinal extension. Despite apparent benefits of primary surgical decompression of the spinal cord, modern experience of treatment of children with intraspinal tumor extension does not reveal advantages of surgery over chemotherapy. Neurological disorders of various nature and severity persist in the majority of patients in the long-term period, regardless of primary treatment. A higher level of spinal deformities after surgical tumor resection is observed. The issue of spinal cord decompression should be discussed by the neurosurgeon and pediatric oncologist, and the most common method of choice may be chemotherapy. The article discusses the indications and contraindications for neurosurgical interventions in NB patients and addresses the issues of NB metastasis to the brain and cranial bones as well as the opsoclonus-myoclonus syndrome.

[Turcot syndrome. Rare observation and literature review].

The Turcot syndrome is a rare disease which is characterized by a combination of a brain tumor with a y at which the neoplasm of the colon. About 150 of such observations are described in world literature. Our own observation and a literature review are presented in this article.

Incidence and survival of pediatric soft tissue sarcomas in moscow region, Russian Federation, 2000-2009.

The aim of the study was to assess the incidence and survival rates of soft tissue sarcomas (STSs) in children 0-14 years of age in Moscow Region, Russian Federation. The database of childhood population-based cancer registry of Moscow Region was used as a data source. Tumors were stratified according to International Classification of Childhood Cancer, 3d ed. Sixty-eight cases of STS were registered from 2000 to 2009. Crude incidence rate was 0,78, and age-standardized incidence rate using World Standard Population was 0,81 per 100.000 children/year. The highest age-specific incidence was observed in infants: 1,76 per 100.000 children/year. Rhabdomyosarcoma (RMS) was the most common histological type comprising 54,4% of all STS. 5-year observed survival (OS) of all patients with STS was 64,1 (95% CI 55,0-73,2). There was no statistically significant difference in OS between RMS-59,2 (95% CI 47,0-71,4) and nonrhabdomyosarcoma STS-69,3 (95% CI 55,8-82,8) (P = 0.63). Incidence and survival rates of STS observed in the study were comparable to the other Eastern European countries.

[Efficiency of the ALL-MB-2002 protocol in children with acute lymphoblastic leukemia].

AIM: To evaluate the efficiency of the original ALL-MB-2002 protocol within the multicenter study of treatment of acute lymphoblastic leukemia (ALL) in children. SUBJECTS AND METHODS: A total of 1873 primary patients with ALL aged 1 to 18 years, of whom 1544 patients were enrolled in this study, were notified at 36 clinics of Russia and Belarus from April 15, 2002, to January 1, 2008. RESULTS: With the median observation of 4.12 years, 7-year event-free survival (EFS) was 73 +/- 13%; overall survival (OS) 78 +/- 2%; relapse-free survival 82 +/- 1%. The rates of EFS and OS were equal and amounted to 76 +/- 2 and 80 +/- 2% in the standard-risk group (SRG) and intermediate-risk group (ImRG), respectively. In the high-risk group (HRG) patients, EFS and OS were as high as 30 +/- 6 and 37 +/- 6%, respectively. The frequency of relapses with central nervous system lesion was as much as 4.7% in all the patients, 6-year cumulative risk for isolated neurorecurrences being 2.5% in the SRG patients. Adolescents, patients with the baseline leukocytosis (more than 100 x 10(9)/l), and those with a splenic size of over 4 cm or more from the costal arch margin had substantially worse survival rates. A poor early response to therapy (on induction days 8 and 15) was also associated with its lower efficiency. CONCLUSION: Despite a considerable rise in the number of centers and a slight increase in the intensity of therapy, the results of the new ALL-MB-2002 protocol are as minimum equivalents obtained in the use of the previous ALL-MB-91 protocol. A significant improvement in the overall results of therapy and a reduction in the cumulative risk for isolated neurorecurrences were noted in the ImRG patients.

Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia.

Until 1990, the survival of children with acute lymphoblastic leukaemia (ALL) in Russia was below 10%. To establish a protocol feasible under conditions there, ALL-MB 91 was designed to avoid prolonged bone marrow aplasia, thereby reducing needs for extensive supportive care, blood transfusions, long-lasting hospitalization and costs. High-dose therapies were avoided, anthracycline use was limited and CNS radiation therapy only foreseen in high-risk patients (about 30%). This was randomized against a modified BFM protocol. From 1995 to 2002, 834 patients of age up to 18 years were registered in 10 centres and 713 received after central randomization the allocated risk-stratified treatment. After a median follow-up of 7 years, the event-free survival (EFS) was 67+/-3% on ALL-MB 91 (N=358) vs 68+/-3% on ALL-BFM 90m (N=355). The overall survival (OS) was 71+/-3% vs 74+/-2%, respectively. Anaemia, thrombocytopenia, agranulocytosis >10 days and hospitalization (median 35 vs 68 days) were lower on ALL-MB 91 (P<0.01, N=197). While EFS and OS were similar with both protocols, ALL-MB 91 significantly incurred fewer toxicity and resource requirements and, therefore, has been increasingly used across Russia.

[The results of a multicenter trial of acute lymphoblastic leukemia treatment on ALL-MB 91/ALL-BFM 90m in children: analysis of efficacy and toxicity].

AIM: A comparative analysis of efficacy and toxicity of two chemotherapy regimens: standard German protocol ALL-BFM 90m and less intensive original test protocol ALL-MB 91 in a multicenter trial of acute lymphoblastic leukemia (ALL) in children. MATERIAL AND METHODS: In 1995-2002 a total of 834 patients with newly diagnosed ALL aged 0-18 years were admitted to 10 clinics of Russia. Of them, 713 were randomized in two groups: treatment program ALL-BFM 90m (n = 355) and ALL-MB 91 program (n = 358). RESULTS: In 7-year follow-up median, 10-year event-free survival (EFS) and overall survival (OS) did not differ significantly between the groups and was 67 +/- 3 and 68 +/- 3% (ALL-MB 91) and 74 +/- 2, 71 +/- 3% (ALL-BFM 90m), respectively. Though the rate of isolated recurrences in CNS in patients on the protocol ALL-MB 91 was 2.8%, they developed only in 0.8% patients of the standard risk group. Anemia, thrombocytopenia and agranulocytosis developed less frequently, hospital stay was significantly shorter on the test protocol vs the control one (p < 0.01). CONCLUSION: EFS and OS on the test (ALL-MB 91) and control (ALL-BFM 90m) protocols were equivalent in lower toxicity and cost of therapy.

[Results of the treatment of childhood acute lymphoblastic leukemia according to the Berlin-Moscow-91 protocol in 1991-2000]. / Rezul'taty lecheniia ostrogo limfoblastnogo leikoza u detei po protokolu Moskva-Berlin-91 v 1991-2000 gg.

The report deals with the results of application of an original protocol--the Berlin-Moscow-91 (BM-91)--for the treatment of acute lymphoblastic leukemia (ALL) in children. The researchers' major concern was to improve survival and cut down side-effects incidence as well as to prevent and successfully manage occult neuroleukemia as a potential source of relapse. Patients aged 5 months-15 years received the BM-91 and ALL BFM-90m treatment first at one clinic and later at several centers. Out of 852 children with primary diagnosis of ALL admitted to Russian hematological hospitals (March 2, 1991-November 3, 2000), 687 were included into the study; 329 received the MB-91 protocol. Nine-year recurrence-free survival was 73% while overall survival--80%. Toxic side-effects after L-asparaginase were reported in 27 (7.9%). It is concluded that good results in childhood ALL treatment can be achieved without resorting to high-dosage chemotherapy and radiation in most cases.

[Treatment of acute lymphoblastic leukemia in children according to the ALL-BFM-90m protocol in the Russian Federation and the Republic of Belarus]. / Lechenie ostrogo limfoblastnogo leikoza u detei po protokolu OLL-BFM-90m v Rossiiskoi Federatsii i Respublike Belarus'.

Prognosis for children treated according to the BFM-90m protocol (Berlin-Frankfurt-Munster Group) for acute lymphoblastic leukemia (ALL) improved significantly as compared with previous modalities. Methotrexate was used in the dose of 1,000 mg/m2, 36 h. The paper presents the 10-year results for this modification. Patients aged 0-15 years were treated at hematological hospitals of Moscow, other Russian towns and in Minsk, Belarus, (July 5, 1990-November 11, 2000). BFM-90m treatment was given to 682 children out of 1,326 with primary diagnosis of ALL; a comparative trial of the MB-91 protocol hed been carried out at the same clinics since 1991. During 10 years, recurrence-free survival was 72% while overall survival--77%. Toxicity of side-effects was tolerable. The BFM-90m treatment showed significantly better results in both countries.

[Effect of the structure of the prosthetic group on the catalytic properties of prostaglandin H synthetase]. / Izuchenie vliianiia struktury prosteticheskoi gruppy na kataliticheskie svoistva prostaglandin-H-sintetazy.

The effect of vinyl groups of protohemin IX on its cofactor properties with respect to prostaglandin H synthetase has been studied. It was shown that substitution of ethyl groups or a hydrogen for vinyl groups affects neither binding of the prosthetic group to the apoenzyme nor catalytic properties of holo-prostaglandin H synthetase. Replacement of vinyl groups with bulkier substituents (hydroxyethyl or acetyl groups) decreases holoenzyme stability and catalytic activity. By comparison of the cofactor properties of protoporphyrin and hematoporphyrin macrocycles with different central ions (Fe3+, Mn2+, 2H+ in the case of protoporphyrin, and Fe3+, Mg2+, Cd2+ and Cu2+ in the case of hematoporphyrin), the presence of Fe3+ ions was shown to be mandatory for prostaglandin H synthetase activity. It was demonstrated that the cofactor structure modifications do not affect the holo-prostaglandin H synthetase inactivation rate constant in a reaction.